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Study Description

The participants of this study will be children, adolescents, and young adults with residual osteosarcoma, which cannot be removed completely through surgery.

Participants will have achieved a partial response or stable disease at the end of conventional chemotherapy. Osteosarcoma is cancer of the bone. The cancer cells make immature bone cells, known as osteoid.

Osteosarcoma is very rare, but it is the most common type of bone cancer in children and teens. It is most common in teens and young adults.

In this study, participants will receive either cabozantinib and best supportive care or the best supportive care alone. Best supportive care will be provided at the investigator's discretion and according to institutional guidelines.

It includes antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including radiotherapy), etc. but does not include tumor specific therapy.

Cabozantinib will be taken by mouth (orally), as a tablet, once a day. Cabozantinib will be provided to participants who tolerate it for as long as their disease does not progress. Participants in the study receiving best supportive care alone may switch to treatment with cabozantinib and best supportive care if their disease progresses and if other eligibility criteria are met.

Participants may withdraw consent to participate at any time.

The estimated duration of the study for participants is 24 months, however a participant could remain in the study longer if demonstrating treatment benefit.

Inclusion Criteria

• Participants must be ≥5 and ≤30 years of age at the time of study entry.
• Histologically or cytologically confirmed diagnosis of high-grade osteosarcoma as defined by a local pathologist
• Participants with unresectable residual disease after standard chemotherapy treatment at diagnosis or first relapse (treated with systemic chemotherapy). A minimum of 4 cycles of systemic chemotherapy (or minimum of 2 cycles if chemotherapy was stopped early due to toxicity) must have been received.
• Measurable residual or evaluable disease by RECIST version 1.1. Participants will be considered with evaluable disease if they have only non-measurable disease as per RECIST version 1.1 criteria.
• Absence of Progressive Disease (PD) (defined by the investigator according to RECIST version 1.1) at study entry. Note, the two most recent radiological evaluations (e.g. computerised tomography (CT) or magnetic resonance imaging (MRI) scan) including the one following completion of chemotherapy should be available later to facilitate BIRC review.
• Chemotherapy must be the last anticancer treatment received by participants before study entry and must have been completed at least 4 weeks but no longer than 2 months before randomization.
• Participants must have recovered to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) from the acute toxic effects of all prior anticancer therapy at study entry, unless AEs are clinically non significant and/or stable on supportive therapy, per investigator clinical judgment.
• Life expectancy >6 months.
• Performance level: participants must have a Lansky or Karnofsky performance status score of ≥70 corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0-1.
• Adequate organ and marrow function.
• Adequately controlled blood pressure (BP) with or without antihypertensive medications.
• Male and/or female (according to their reproductive organs and functions assigned by chromosomal complement) (FDA 2016)
• Contraception and barriers as well as pregnancy testing is required as appropriate for the age and sexual activity of pediatric participants and as required by local regulations.
• All participants (typically ≥18 years) and/or their parents or legal guardians must sign a written informed consent and assent must be obtained from minor participants according to local guidelines.

Exclusion Criteria

• Low grade osteosarcoma and periosteal osteosarcoma
• Previous treatment with cabozantinib or another Mesenchymal-epithelial transition (MET)/hepatocyte growth factor (HGF) inhibitor (e.g., tivantinib, crizotinib).
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before first dose of study intervention.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study intervention (or washout of at least 5 half-lives, whichever is shorter).
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery or major surgery e.g., removal or biopsy of brain metastasis) and stable for at least 4 weeks prior to randomization. Eligible participants must be neurologically asymptomatic and without systemic corticosteroid treatment at the time of randomization. Note: Participants with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures on a stable dose of anti-convulsant may be enrolled.
• Participants who have an uncontrolled/active infection requiring systemic therapy.
• Participants who are unable to swallow intact tablets.
• Participants with uncontrolled, significant intercurrent or recent illness.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Any other active malignancy at time of first dose of study intervention or diagnosis of another malignancy within 3 years prior to first dose of study intervention that requires active treatment.
• Pregnancy or breast-feeding.
• Participants who in the opinion of the investigator may not be able to comply with the requirements of the study are not eligible
• Major surgery (eg, orthopaedic surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major surgery must have occurred 4 weeks before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Participants with clinically relevant ongoing complications from prior surgery are not eligible.

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Study Description

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.

The study will be conducted in two sequential phases:

Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later.

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Phase A (Feasibility Phase) - Open at SickKids

A feasibility phase will be conducted to establish the maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using the Rolling 6 design.

Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination with vinblastine (4mg/m2) will be used as the starting dose and will be de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Phase B (Expansion/Efficacy Phase) - Not Yet Open

Once the MTD/RP2D of the combination, vinblastine + tovorafenib has been established, the expansion/efficacy phase will be initiated at the dose determined in Phase A.

Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Inclusion Criteria

• Patients must be less than or equal to 25 years of age at the time of enrollment
• Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.
• Diagnosis:
  • All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
  • Patient must have progressive or recurrent LGG.
  • Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.
  • Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.
• Prior Therapy:
  • Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.
  • Patients must have fully recovered from the acute toxic effects (≤ Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.
    • i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.
    • iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.
    • iv. Patients must have recovered from acute effects of any prior surgery. 
    • v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2, except ongoing retinopathy which must be ≤ Grade 1.
• Performance Level: a) Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Tumor Tissue Sample Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline. Submission of tumor tissue and a blood sample are mandatory and must be submitted within 14 days from enrollment onto the study and prior to initiation of treatment. Biopsy may be either at initial diagnosis or recurrence.
• Organ function: 
  • Adequate bone marrow function defined as:
    • i. Absolute neutrophil count ≥ 1000/mm3
    • ii. Platelet count (unsupported) ≥ 100 x 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to enrollment)
    • iii. Hemoglobin (unsupported)≥ 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion > 4 weeks prior to enrollment)
    • iv. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor.
  • Adequate hepatic and renal function defined as:
    • i. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (patients with documented Gilbert's disease may be enrolled with sponsor approval and total bilirubin ≤ 2 x ULN)
    • ii. Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • iii. Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) ≤ 2.5 x ULN
    • iv. Serum creatinine within normal limits or estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 based on local institutional practice for determination.
  • Thyroid functions tests within institutional normal range. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting therapy are eligible.
  • Adequate cardiac function defined as:
    • i. Left ventricular ejection fraction (LVEF) of ≥ 50% as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) ≥ 25% (Tissot et al., 2018) as measured by ECHO, within 14 days before enrollment (while not receiving medications for cardiac function). If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result.
    • ii. QTc (by Fridericia's formula) < 470ms as measured by electrocardiogram (ECG) within 14 days before enrollment (while not receiving medications for cardiac function).
  • Adequate central nervous system (CNS) function defined as:
    • i. Patients with seizures should be stable and not have experienced a significant increase in seizure frequency within 14 days prior to enrollment.
    • ii. Patients with neurologic deficits should have deficits that are stable for a minimum of 14 days prior to enrollment.
    • iii. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to enrollment.
• Study specific:
  • Baseline ophthalmology assessment within 28 days of study enrollment.
  • MRI assessment within 28 days of study enrollment. MRI done for clinical indication but within the window for study would be permitted as baseline.
  • Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
  • Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Effective birth control methods are described in Appendix H.
  • Ability to swallow tablets or liquid, or gastric access via a nasal or gastric tube.
  • Patient is able to start treatment within 14 working days of screening.
  • Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study ICF and applicable pediatric assent form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.

Exclusion Criteria

• Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
• Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
• History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
• Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study.
• Major surgery within 14 days (2 weeks) prior to enrollment (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval > 470 ms based on triplicate ECG average.
• Concomitant medications that are strong inhibitors or inducers of CYP2C8 or CYP3A4 within 14 days before initiation of therapy. Concomitant medications that are substrates of BCRP with a narrow therapeutic index within 14 days before initiation of therapy
• Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed.
• Active systemic bacterial, viral, or fungal infection.
• Nausea and vomiting ≥ National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2 (for those not controlled by supportive care), malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
• Patient has CTCAE v5.0 Grade 3, creatine phosphokinase (CPK) elevation (> 5 × ULN - 10 × ULN).
• Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures).
• Pregnancy or lactation.
• History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS). Patients with hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product.
• Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a multicenter pilot study of SurVaxM (SVN53-67/M57-KLH) for children and young adults with progressive or relapsed medulloblastoma, high grade glioma, ependymoma and newly diagnosed diffuse intrinsic pontine glioma.

Survivin (BIRC5) is an inhibitor of apoptosis (IAP) protein that is highly expressed in many cancers. Survivin's high level of expression in certain pediatric malignancies makes it an attractive molecular target for new therapies, including active specific vaccination-based immunotherapy.

The design of the SurVaxM vaccine employs several strategies to create an effective antitumor immunogen, including: 1) incorporation of multiple MHC class I epitopes, 2) peptide modification to enhance binding to certain MHC class I molecules, 3) cytokine helper support, and 4) antibody-mediated tumor cell killing. All of these effects would not be expected with the unmodified class-I restricted short survivin peptides employed in previously studied glioma vaccines.

There are no prior clinical trials of SurVaxM in pediatric patients; however, SurVaxM has been studied in several adult trials, including a phase I study conducted at Roswell Park Comprehensive Cancer Center. Following the single-institution phase I trial, a multicenter phase IIa trial (NCT024455557) was conducted in 63 patients with newly diagnosed glioblastoma. All patients in this study underwent surgical resection of their tumors. Patients then underwent chemoradiation with temozolomide according to the Stupp protocol. This was followed by a one-month hiatus from chemotherapy, during which priming doses of SurVaxM were initiated. The priming phase of vaccination was then followed by initiation of standard adjuvant chemotherapy with temozolomide and maintenance doses of SurVaxM as an add-on to standard chemotherapy. There have been no regimen-limiting toxicities (RLT) or grade ≥ 3 SAE attributable to SurVaxM, with most toxicities being related to temozolomide. The most common AE was grade 1-2 injection site reaction with 2 patients experiencing Montanide-related granulomatous panniculitis with local skin ulceration at vaccine injection sites, both of which resolved. Humoral and survivin-specific CD8+ T cell responses were observed in almost all patients. Twelve-month overall survival (OS12) was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Although not a randomized trial, these results are superior to overall survival reported in various studies in which patients received standard of care treatment for this disease. A randomized phase IIb clinical trial of standard therapy plus SurVaxM is currently being developed with intent for drug registration, if successful.

The primary objective of this trial is to assess the toxicity profile of SurVaxM in emulsion with Montanide plus sargramostim in children with relapsed or progressive medulloblastoma and high-grade glioma, ependymoma and non-recurrent diffuse intrinsic pontine glioma post-radiation therapy. Patients will be enrolled into three separate strata based on age and diagnosis. Enrollment will be staged to allow for safety evaluations between strata.

Each patient will receive 500 micrograms SurVaxM as a 1:1 mixture with Montanide ISA 51 in a water-in-oil emulsion. The SurVaxM-Montanide emulsion injection will be followed immediately by sargramostim (or biosimilar) given via a second separate subcutaneous injection in close proximity to the vaccine injection site. Patients will receive four injections administered over a 6-week period, followed by 14 days of follow-up, called the Priming Phase (8 weeks total). Beginning 8 weeks after the fourth priming dose, a maintenance dose of SurVaxM with Montanide ISA 51 may be given every 8 weeks (± 2 weeks) for two years or until an off-treatment criterion is met.

Inclusion Criteria

• DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNS tumor that is progressive or recurrent defined as progression in any known residual tumor, or the appearance of one or more new lesions, or new cerebrospinal fluid (CSF) positivity for malignant cells, after having failed standard therapy. At the time of diagnosis or recurrence, all tumors must have histologic verification of one of the following:
  • Medulloblastoma
  • Glioblastoma multiforme (GBM)
  • Anaplastic astrocytoma
  • High-grade astrocytoma, NOS
  • Anaplastic oligodendroglioma
  • Anaplastic ependymoma (WHO Grade III)
  • Ependymoma (WHO Grade II)
  • Diffuse Intrinsic Pontine Gliomas (DIPG) Patients:
    • Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 14 to 56 days post-completion of radiation therapy if they do not have any evidence of progression. Patients with diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and are proven to be a glioblastoma multiforme (GBM), or astrocytoma (Grade II or Grade III). DIPG patients with disseminated disease are not eligible, and MRI of spine must be performed if disseminated disease is suspected by the treating physician.
• DEMONSTRATION OF SURVIVIN EXPRESSION: For patients with relapsed or progressive medulloblastoma, HGG, or ependymoma, demonstration of survivin expression as assessed after screening consent/assent of at least 1% on tumor tissue by immunohistochemistry (ICH) is required and must have been performed in the central laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility. For patients with DIPG, diagnostic biopsy for histologic confirmation is not required, and tumor expression of survivin is therefore not required for eligibility for these patients.
• DISEASE STATUS: Patients must have either measurable or evaluable disease. Patients with recurrent or progressive GBM, anaplastic astrocytoma, high grade astrocytoma (NOS), anaplastic oligodendroglioma, anaplastic ependymoma (WHO Grade III) or ependymoma (WHO Grade II) with metastatic disease or leptomeningeal disease are eligible so long as there is clear MRI evidence of evaluable disease.
• AGE: 
  • Stratum 1 (progressive or recurrent) patients must be ≥10 years of age and ≤ 21 years of age at the time of study screening.
  • Stratum 2 (progressive or recurrent) patients must be ≥1 year of age and < 10 years of age at the time of study screening.
  • Stratum 3 (newly diagnosed DIPG) patients must be ≥1 year of age and ≤ 21 years of age at the time of study enrollment
• PRIOR THERAPY: 
  • Patients with recurrent or progressive disease must have received prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality.
  • Patients must have recovered from the acute treatment related toxicities (defined as ≤ Grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
  • Patients with newly diagnosed DIPG must have completed radiation therapy
• CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment.
• INVESTIGATIONAL/ BIOLOGIC AGENT:
  • Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.
  • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
• RADIATION:
  • Recurrent or Progressive CNS tumor patients must have had their last fraction of:
  • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
  • Focal irradiation ≥ 14 days prior to enrollment.
  • DIPG Patients: Patients with DIPG are eligible after completion of initial radiotherapy (with or without concurrent treatment) and in the absence of progressive disease.
  • Patients must have completed radiation therapy at least 14 days prior to enrollment but no longer than 56 days and cannot have received any other tumor-directed treatment except the following: Patient may have received temozolomide or other non-investigational agents during irradiation at the treating physician's discretion. If the patient has received such agents concurrently with radiation, then patient must have recovered from the acute treatment related toxicities (defined as < Grade 1) prior to enrollment.
• CELLULAR THERAPY: Patient must be:
  • ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease.
  • ≥ 3 months since autologous stem cell transplant prior to enrollment.
  • > 42 days since completion of any other type of adoptive cellular therapy prior to enrollment.
• CRANIAL SURGERY: Patients who have had recent cranial surgery (VP shunt, ETV, tumor resection) are eligible for inclusion, but the vaccine may not be administered prior to post-operative Day 14.
• NEUROLOGIC STATUS: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study.
• PERFORMANCE STATUS: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks prior to enrollment must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below:
  • Absolute neutrophil count ≥ 0.75 x 109 cells/L
  • Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
  • Hemoglobin ≥ 8 g/dl (may receive transfusions)
  • PT/INR, PTT ≤ 1.5 x ULN
  • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)
  • ALT(SGPT) ≤ 3 x institutional upper limit of normal
  • Albumin ≥ 2 g/dl
  • Blood creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for age/gender:
  • Age 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)
  • Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
  • Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
  • Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
  • Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
  • Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• INFECTIOUS DISEASES
  • Human Immunodeficiency Virus (HIV) Infected Individuals: Patients who are known to be Human immunodeficiency virus (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral load for 6 months prior to study enrollment.
  • Hepatitis B Chronically Infected Individuals: For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Hepatitis C (HCV) Infected Individuals: Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with known HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• CORTICOSTEROIDS: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. A maximum dose of 0.1 mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) is permitted at study entry. Effort should be made to reduce to lowest tolerated steroid dose. Patients must be willing to use brief courses (at least 72 hours) of steroids as directed for potential inflammatory side effects of the therapy if recommended by their treating physician.
• GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at least 14 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). Two (2) weeks must have elapsed if the patient received a long-acting formulation.
• PREGNANCY - Pregnant women or nursing mothers are excluded from this study because SurVaxM is an agent with the potential for teratogenic effects. Female patients of childbearing potential must have a negative serum or urine pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
• INFORMED CONSENT - The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• BREAST FEEDING WOMEN - Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SurVaxM breastfeeding should be discontinued if the mother is treated with SurVaxM. Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed.
• CONCURRENT ILLNESS:
  • Active, uncontrolled infection requiring treatment (including HIV infection)
  • Patients with spinal cord primary tumors
  • Patients with relapsed or progressive DIPG or midline glioma
  • Patients with Grade I myxopapillary ependymoma
  • Patients with WHO Grade I or II gliomas are not eligible unless tumor is located within the pons or brainstem
  • Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, with the exception of:
  • Patients with vitiligo or resolved asthma/atopy
  • Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
  • History of or ongoing pneumonitis or significant interstitial lung disease
  • Patients with any clinically significant unrelated systemic illness (significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
  • Any medical condition that, in the opinion of the Principal Investigator, would compromise the patient's ability to participate in the study.
• CONCOMITANT MEDICATIONS:
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Patients who are receiving any cannabidiol (CBD) or medical marijuana treatment are ineligible.
  • Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
  • Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14 days of the start of protocol therapy are ineligible.
  • Patients may not be on immunosuppressive therapy, including corticosteroids (except as defined in the corticosteroids inclusion criteria) at time of enrollment. However, patients who require intermittent use of bronchodilators, local steroid injections, or topical steroids will not be excluded from the study.
  • Patients may not be receiving concomitant chemotherapy, immunotherapy, radiotherapy, radiosurgery, interferon, allergy desensitization injections, growth factors, interleukins, or any investigational therapeutic medication at the time of enrollment.
• INABILITY TO PARTICIPATE: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity of therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
• ALLERGY: Known allergy or hypersensitivity to Keyhole Limpet Hemocyanin (KLH), granulocyte colony-macrophage stimulating factor (sargramostim) or MRI contrast agent.
• BLEEDING DISORDER: Patients with a known coagulopathy or bleeding diathesis or requires the use of systemic, anticoagulant medication are not eligible.
• BULKY DISEASE: Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as any of the following:
  • Tumor with evidence of clinically significant uncal herniation causing midbrain compression or midline shift greater than 5 mm
  • Tumor with a diameter >4cm in one dimension on T2/FLAIR
  • Tumor that in the opinion of the site investigator, shows significantly rapid progression of mass effect in either the brain or spinal cord such that the priming phase of vaccination (i.e., 6 weeks) cannot be completed before clinical deterioration is likely to occur.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a Phase I study to evaluate the safety profile of a type of immune therapy called HER2 CAR T cells (short for HER2 chimeric antigen receptor T cells). In addition to looking for side effects, we will study how well this treatment works against a brain tumor called ependymoma that has come back after treatment (recurrent) or has not responded well to treatment (progressive) in children. The HER2 CAR T cells used in this trial are made from the patient's own blood. A new gene, called the HER2 CAR, will be inserted into patient's T cells to allow them recognize a protein on the tumor called HER2. These HER2-specific CAR T cells may be able to target and kill ependymoma tumors that express HER2. This research is also studying how doable it is to provide this type of CAR T cell treatment to children being treated at different hospitals.

The primary objectives of the Phase I study are to determine the safety of intravenous injection of HER2-specific CAR T cells after lymphodepleting chemotherapy, and to evaluate the multicenter feasibility of administering up to three infusions of HER2-CAR T cells after lymphodepletion.

Patients will receive one infusion of HER2psecific CAR T cells after lymphodepleting chemotherapy. Following recovery from their first treatment (no earlier than 8 weeks and no later than 12 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions after lymphodepleting chemotherapy if they meet laboratory parameters. The length of time on study for patients enrolled on the Phase I study is anticipated to be 9 months on treatment. Patients will then be followed for 15 years after treatment.

Surgical Study

The objective of the Surgical study is to evaluate the post-treatment tumor tissue for presence of HER2-specific CAR T cells administered intravenously in children undergoing surgical resection. The surgical study will be initiated following completion of the safety evaluation period of 6 patients treated in the Phase I study.

Once the surgical study is open for enrollment, all patients who have clinical indication for surgery, except those needing urgent surgery, will be eligible for enrollment to the surgical study. Patients will receive one infusion of HER2-specific CAR T cells after lymphodepleting chemotherapy 4-6 weeks before surgical resection of their tumor, at which time samples will be taken for analysis. Following recovery from surgery (no earlier than 8 weeks and no later than 15 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions if they meet laboratory parameters.

The first patient in the surgical study will complete a 6-week safety evaluation period prior to enrollment of the subsequent patient. The length of time on study for patients enrolled on the Surgical study is anticipated to be 10 months on treatment. Patients will then be followed for 15 years after treatment.

Dosing

All patients on Phase I and Surgical study will receive HER2 CAR T cells at a patient-specific dose level 1 (8x10^7 CAR-positive T cells/m^2) for infusion. The cell dose will be based on the patient weight and height obtained by the treating institution at the time of procurement. For patients whose BMI is greater than 95th percentile for given age and sex, the Body surface area (BSA) will be calculated using the ideal body weight.

In the event that dose level 1 is found to have excessive toxicity, three additional doses of CAR T cells at dose level -1 (5x10^7 CAR-positive T cells/m^2) will be made to be used in the event that dose de-escalation occurs before a patient is enrolled for treatment.

Inclusion Criteria

Inclusion Criteria - Treatment

1. Diagnosis: Patients with a histologically confirmed diagnosis of HER2 positive ependymoma that is recurrent or progressive. Histologic verification may be from time of diagnosis or time of recurrence. In cases where there is question of recurrence, histologic verification, or verification of progression on follow up imaging is required prior to enrolling for protocol treatment.
2. Disease Status: 
   • Phase I (Stratum 1) - Patients must have evaluable disease to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows:
     • Measurable disease (enhancing or non-enhancing tumor):
       • at least 1 cm, or
       • at least two times (in both perpendicular diameters) the MRI slice thickness, plus the interslice gap.
     • Non-measurable disease (tumor that is too small to be accurately measured):
       • less than 1 cm in at least one perpendicular dimension, or
       • less than two times the MRI slice thickness, plus the interslice gap.
     • Note: Leptomeningeal disease is considered non-measurable but evaluable.
     • Surgical Study (Stratum 2) - Patients with measurable disease (Section 3.3.1.2.1) in whom tumor resection is clinically indicated and feasible after the CAR T cell infusion.
3. Age: Patient must be ≥ 1 but ≤ 22 years of age at the time of enrollment for treatment.
4. HER2 CAR T cell product: The patient must have, at a minimum, one prescribed dose of the cryopreserved, autologous HER2 CAR T cell product available for infusion.
5. Prior Anti-neoplastic Therapy:
   • Cytotoxic chemotherapy: Patients must not have received cytotoxic chemotherapy for at least 28 days prior to study enrollment for treatment and must have recovered from the acute treatment related toxicities (defined as < grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
   • Biological, targeted, or investigational agents (anti-neoplastic): Patients must have a period of at least 28 days from the last receipt of said drug and must have recovered from all acute toxic effects.
     • For agents that have known acute adverse events occurring beyond 28 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
   • Monoclonal antibodies, checkpoint inhibitors, and other agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
   • Adoptive cellular therapies: Patient must have recovered from any acute toxicity potentially related to the cellular product and received their last dose of the cellular product at least 90 days prior to study enrollment. (Note: Patients who have previously received an adoptive cellular therapy may continue long-term follow up evaluations per the prior study's evaluation schedule as needed for assessment of long-term toxicities including genotoxicity.)
   • Radiation: Patients must have had their last fraction of:
     • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >50% of pelvis or spine ≥ 3 months prior to enrollment (90 days) prior to enrollment.
     • Focal palliative irradiation to the tumor ≥ 42 days prior to enrollment. c. Patients who receive tumor-directed radiation (non-palliative) should have confirmed disease progression on the imaging study done at least 6 weeks after the completion of the last fraction of radiation.
   • Surgery: Patients must have not had surgery within 14 days of enrollment for treatment and must have adequate wound healing and recovered from other acute effects from surgery. One exception is the placement of central venous catheter which will be allowed at any time point until treatment initiation on the study.
6. Growth Factors: Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). 14 days must have elapsed if the patient received a long-acting formulation.
7. Corticosteroids: Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least 14 days prior to enrollment for treatment, and corticosteroid dose must be less than or equal to dexamethasone 0.5 mg/m2/day (or equivalent) during the 14 days preceding enrollment. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
8. Neurologic Status: In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment for treatment on the study. Patients with seizure disorders may be enrolled if seizures are well controlled.
9. Performance Status: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week of enrollment must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
10. Organ Function: Patients must have adequate organ and bone marrow function as defined in Section 3.2.1.4.
11. Pregnancy Prevention: Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
12. Informed Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
    • Patients who meet eligibility criteria per Section 3.3.1.2.1 must be enrolled using Phase I treatment consent (Stratum 1).
    • Patients who meet eligibility criteria per Section 3.3.1.2.2 must be enrolled using Surgical Study treatment consent (Stratum 2).

Please note there is additional criteria for screening, outlined below: 

1. Tumor: Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.

2. Prior Therapy: Patient must have received standard of care therapy including maximal safe surgical resection followed by local adjuvant radiation therapy prior to enrollment.

3. Adequate Pre-trial Tumor Tissue: Patient must have adequate pre-trial tumor material available to determine HER2 status. Tumor tissue from the most recent resection or biopsy of recurrent disease in preferred. If unavailable, tumor tissue from prior recurrences or from the time of initial diagnosis is acceptable.

   a. One exception will be patients who have previously received HER2-directed therapy (including but not limited to trastuzumab); these patients will need evaluation of tumor HER2 status after stopping treatment due to the possibility of HER2 downregulation or loss. Tumor biopsy will not be performed for the purpose of HER2 screening. Patients will not be eligible for screening on PBTC-059 if tumor tissue is not available or inadequate for HER2 testing. Tumor screening by Immunohistochemistry (IHC) will be done centrally using the testing method validated at Texas Children's Hospital. Sample for screening must be shipped within 7 days of enrollment for screening.

4. Known HIV Positivity: Patients that are known to be HIV-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.

5. Age: Patient must be ≥ 1 but ≤ 21 years of age at the time of screening consent.

6. Screening Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.

7. Potential Eligibility for Study Treatment Enrollment: Patients are screened for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 if their tumor is HER2-positive.

Please note there is additional criteria for procurement, outlined below: 

Criteria for Procurement: All subjects must meet following inclusion and exclusion eligibility criteria at the time of peripheral blood procurement for manufacturing the HER2 CAR T-cell product. No exceptions will be given. All clinical and laboratory evaluations to establish eligibility for procurement must be done within 14 days prior to enrollment. See Section 6.1 for details of laboratory requirements and planning of procurement blood collection date.

1. Tumor: Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
2. Performance Score: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week of procurement must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score provided the neurological deficit is stable as described in Section 3.3.1.7.
3. Prior Therapy: Patients must have received last dose of cytotoxic chemotherapy greater than 21 days preceding the date of enrollment for procurement.
4. Organ Function: Patient must have adequate organ and bone marrow function as defined below:
   • Peripheral absolute neutrophil count (ANC) > 1.0 x 109 cells/L
   • Platelet count ≥ 75 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 4 days)
   • Hemoglobin ≥ 8 g/dL (may receive red blood cell transfusions)
   • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
   • Alanine transaminase (ALT /SGPT) and Aspartate aminotransferase (AST/SGOT) ≤ 3 x institutional upper limit of normal (ULN) for age
   • Serum creatinine < 1.5 x institutional upper limit of normal for age and gender. Patients that do not meet the criteria but have a 24-hour Creatinine Clearance or Glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
   • Pulmonary Function
     • Oxygen saturation as measured by pulse oximetry is ≥ 93% on room air
5. Concomitant Medication: Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least two weeks prior to procurement, and corticosteroid dose must be less than or equal to dexamethasone 0.75 mg/m2/day (or equivalent). Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
6. Procurement Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
7. Potential Eligibility for Study Enrollment: Patients whose blood samples have been successfully procured for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 and to begin treatment within 180 days from the date of procurement. The treatment slot will not be held beyond the specified 180 days, and such patients may not be able to receive treatment on this study depending on slot availability.

Exclusion Criteria

Exclusion Criteria: Treatment

1. Patients with Bulky Tumors on Imaging Studies
   • Bulky tumors will be defined as those:
     • > 6 cm in single maximum dimension, or
     • tumor causing uncal herniation or mass effect leading to midline shift with or without symptoms or signs of impending herniation or
     • obstruction to Cerebrospinal fluid (CSF) flow.
2. Infratentorial tumors with symptoms or signs arising from brain stem involvement by the tumor. Patients with stable cranial nerve deficit(s) secondary to prior surgery will not be excluded.
3. Surgical Study (Stratum 2): Patients who have urgent need for surgical resection of tumor.
4. Pregnancy or Breast-feeding
   • Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of start of enrollment for treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant or breast-feeding women are excluded from this study because there is an unknown but potential risk of adverse events to the fetus or the nursing infant with the use of T cells genetically modified to express HER2 CAR. Pre-clinical studies in mice demonstrate the target antigen HER2 is necessary for normal fetal development of cardiac trabeculae, cranial sensory ganglia, and motor neuron development.75 Additionally, the lymphodepleting chemotherapy drugs fludarabine and cyclophosphamide are both Pregnancy Class D drugs.
5. Concurrent Illness: 
   • Patients with active autoimmune disease, documented history of autoimmune disease/syndrome, or any other condition that requires ongoing systemic steroids or systemic immunosuppressive agents, except a. Patients with vitiligo or resolved asthma/atopy b. Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome c. Patients requiring physiologic doses of corticosteroids (up to 0.5 mg/m2/day dexamethasone equivalent)
   • History of or ongoing pneumonitis or significant interstitial lung disease
   • Ongoing or active uncontrolled infection
   • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator, would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
   • Patients with any of the following cardiac diseases
     • New York Heart Association (NYHA) functional class III or IV
     • Clinically significant cardiac arrhythmia including, but not limited to, Torsade de pointes or requiring a pacemaker
     • Left ventricular ejection fraction below 50% as determined by echocardiography (ECHO)
   • Known HIV positivity
     • HIV-positive patients are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
6. Concomitant Medications:
   • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
   • Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible.
     • Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
   • Herbal preparations/medications (except for vitamins) including, but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment.
7. Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
8. Allergy: Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition (murine protein-containing products, Dimethylsulfoxide (DMSO), or dextran 40).

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Study Description

OUTLINE: Patients are assigned to Part A or Part B.

Please note: Part A is now completed. 

PART A: Patients receive tiragolumab intravenously (IV) over 30-90 minutes on day 1 of each cycle and atezolizumab IV over 30-60 minutes on day 1 of each cycle starting in cycle 2. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients undergo standard imaging scans including x-rays, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)-CT throughout the trial. Patients also undergo blood sample collection on study.

PART B: Patients receive atezolizumab IV over 30-60 minutes on day 1 and tiragolumab IV over 30-90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients also undergo standard imaging scans including x-rays, CT, MRI, and/or FDG PET-CT, throughout the trial. Patients also undergo blood sample collection on study.

After completion of study treatment, patients are followed up at months 3, 6, 9, 12, 18, 24, 36, 48, and 60, up to 5 years.

PRIMARY OBJECTIVES:

I. To evaluate the safety of tiragolumab as monotherapy in pediatric patients (<18 years) with SMARCB1 or SMARCA4 deficient tumors. (Part A) II. To evaluate antitumor activity of the combination of tiragolumab and atezolizumab as assessed by objective response rate in patients with SMARCB1 or SMARCA4 deficient tumors per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 (for non-central nervous system [CNS] tumors) or CNS response criteria (for CNS tumors). (Part B) III. To evaluate the safety and adverse event profile of this combination therapy in subjects with SMARCB1 or SMARCA4 deficient tumors, with a particular focus in pediatric patients < 12 years of age.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of tiragolumab alone in part A and tiragolumab and atezolizumab (part A and B) when given in combination in pediatric, AYA (adolescents and young adults), and adult patients.

II. To estimate the PFS (progression free survival), OS (overall survival), and duration of response of combination tiragolumab and atezolizumab in patients with SMARCB1 or SMARCA4 deficient tumors.

EXPLORATORY OBJECTIVES:

I. To assess the association of response rate to somatic genetic mutations of SMARCB1 or SMARCA4 and PD-L1 expression.

II. To assess the association of response rate to the molecular subtypes of rhabdoid/atypical teratoid rhabdoid tumor (ATRT).

III. To assess changes in circulating and tumoral immune markers in patients treated with this combination therapy and correlate to response when feasible.

Inclusion Criteria

• Patients must be >= 12 months of age at the time of study enrollment. For part A, patients must be <18 years old at enrollment. For part B, there is no upper age limit
  • The Part B (phase 2) cohorts will initially open concurrently with the part A but will only enroll patients at least 18 years of age. Patients <18 years of age will be included in the part B cohorts only after the tiragolumab monotherapy dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory Improvement Act (CLIA) certified lab with the following disease histologies:
  • Renal medullary carcinoma
  • Malignant rhabdoid tumor (extra-CNS)
  • Atypical teratoid rhabdoid tumor (CNS)
  • Poorly differentiated chordoma
  • Epithelioid sarcoma
  • Other SMARCB1 or SMARCA4 deficient tumors
• Part A: Patients must have either measurable or evaluable disease Part B: Patients must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group (COG) Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
    • >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer Agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf
  • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
  • Stem cell infusions (with or without total-body irradiation [TBI]):
    • Autologous stem cell infusion including boost infusion: >= 30 days
  • Cellular therapy: >= 30 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • External radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131 metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have had prior TIGIT targeting therapy
  • Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (i.e. OX-40, CD137)
  • Patients must not have received live/attenuated vaccine within 30 days of first dose of treatment
  • Patients must not be receiving concomitant systemic steroid medications and > 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
    • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
    • The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
    • The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are acceptable
  • Treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to study enrollment
• For patients with solid tumors without known bone marrow involvement
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
  • Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment):
  • Age; Maximum Serum Creatinine (mg/dL)
    • 1 to < 2 years; Male: 0.6; Female: 0.6
    • 2 to < 6 years; Male: 0.8; Female: 0.8
    • 6 to < 10 years; Male: 1; Female: 1
    • 10 to < 13 years; Male: 1.2; Female: 1.2
    • 13 to < 16 years; Male: 1.5; Female: 1.4
    • >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment) OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (must be performed within 7 days prior to enrollment)
  • Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
  • Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (must be performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
  • Note: can have history of hypercalcemia as long as controlled and asymptomatic

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of therapy and at least 90 days after final dose of tiragolumab and 150 days after final dose of atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
  • It is not known if atezolizumab or tiragolumab are present in breast milk; however, IgG immunoglobulins are found in milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during therapy and for at least 150 days after the last dose of atezolizumab and 90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
  • Corticosteroids:
    • Patients must not be receiving concomitant systemic steroid medications and >= 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
      • The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
      • The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
      • The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g. 48 hours of corticosteroids for a contrast allergy) are acceptable
  • Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible
  • Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment because these agents could potentially alter the efficacy and safety of study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not eligible
• Patients with known, untreated CNS metastases will be excluded with the following exceptions:
  • Patients with a history of CNS metastases that have been previously treated may enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are not excluded. Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
  • Patients < 18 years old at enrollment, who have known hepatitis B or C
  • Patients >= 18 years old at enrollment with:
    • Positive hepatitis B surface antigen (HBsAg), OR
    • Positive total hepatitis B core antibody (HBcAb) who have a quantitative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
    • Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid (RNA) test
    • Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is required to determine eligibility. The HBV DNA test is required only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is required to determine eligibility. The HCV RNA test is required only for patients who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not eligible except patients who are stable on anti-retroviral therapy, have a CD4 count >= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart Association class III or IV congestive heart failure, myocardial infarction, or cerebrovascular accident) within 3 months prior to study enrollment, unstable arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks prior to study enrollment, or the anticipation of the need for a major surgical procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) are not eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

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Study Description

This phase I/II trial tests the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy in treating children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic change called H3 K27M mutation.

It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. Glioma is a type of cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when it is growing and spreading quickly. The term, risk, refers to the chance of the cancer coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the brainstem that controls functions like breathing, swallowing, speaking, and eye movements). This trial has two parts. The only difference in treatment between the two parts is that some subjects treated in Part 1 may receive a different dose of selinexor than the subjects treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to determine the dose of selinexor that can be given without causing side effects that are too severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against HGG or DIPG.

Selinexor blocks a protein called CRM1, which may help keep cancer cells from growing and may kill them. It is a type of small molecule inhibitor called selective inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.

CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor orally (PO) on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a magnetic resonance imaging (MRI) and may undergo a biopsy during screening.

MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.

FOLLOW UP: After completion of study treatment, patients are followed every 3 months for year 1 (i.e., 3, 6, 9, 12 months), then every 6 months for years 2-3 (i.e., 18, 24, 30, 36 months), and finally once yearly for years 4-5 of this study.

Inclusion Criteria

PRE-ENROLLMENT

• Patients must be =< 25 years of age at the time of enrollment on APEC14B1 part A central nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening
  • Please note:
    • This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.
    • Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are >= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
  • Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)
• For patients with non-pontine tumors:
  • Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A. 
  • The specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery
• For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821

MAIN ENROLLMENT

• Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• Patients must have newly-diagnosed DIPG or HGG (including DMG).
• Stratum DIPG: 
  • Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.
  • Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS], and/or H3 K27M-mutant) by institutional diagnosis.
• Stratum DMG (with H3 K27M mutation)
  • Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
  • Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.
• Stratum HGG (without H3 K27M mutation)
  • Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
  • Please note: 
    • Patients who fall in this category and who are >= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available
    • Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =<16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Meet clinical criteria as follows:
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)
  • Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
  • Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) OR
    • A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):
      • Age / Maximum Serum Creatinine (mg/dL):
        • 1 to < 2 years / male: 0.6; female: 0.6
        • 2 to < 6 years / male: 0.8; female: 0.8
        • 6 to < 10 years / male: 1; female: 1
        • 10 to < 13 years / male: 1.2; female: 1.2
        • 13 to < 16 years / male: 1.5; female: 1.4
        • >= 16 years / male: 1.7; female: 1.4
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
  • Serum amylase =< 1.5 x ULN
  • Serum lipase =< 1.5 x ULN
  • No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0).
  • For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.
• All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria

• Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
• Patients who are currently receiving another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents are not eligible.
• Patients >=18 years of age who have H3 K27M-wild type HGG.
• Patients who have an uncontrolled infection.
• Patients who have received a prior solid organ transplantation.
• Patients with grade > 1 extrapyramidal movement disorder.
• Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.
• Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
• Patients who are not able to receive protocol specified radiation therapy.
• Female patients:
  • Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants. It is not known whether selinexor is excreted in human milk.
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.

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Study Description

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis. Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell lymphoma (BCL)-2 that restores programmed cell death in cancer cells.

This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st relapsed AML unable to receive additional anthracycline.

This is randomized trial of venetoclax in combination with intensive chemotherapy (fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles that would inform and evaluate if this agent is an effective option for this population to improve its poor prognosis. Participants can receive up to two cycles of induction chemotherapy before hematopoietic stem cell transplantation (HSCT). Participants benefiting from treatment and who are not able to proceed to HSCT have the possibility to continue to receive azacitidine in monotherapy (Arm A, control arm) or in combination with venetoclax (Arm B, experimental arm).

Inclusion Criteria

• Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in USA/Canada/Australia/New Zealand sites/LLS territory).
• Participants must be ≥ 29 days of age and ≤ 21 years of age at enrollment.
• Participants must have one of the following:
  • Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in:
    • Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy
    • First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
• Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
• Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to start of protocol treatment:
  • Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea that can be given up to 24 hours prior to start of protocol treatment.
  • Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
  • Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate before start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.
  • Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment.
  • Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or ≥7 days for short-acting growth factor before start of protocol treatment.
  • Radiation therapy (RT) (before start of protocol treatment):
    • ≥ 14 days have elapsed for local palliative RT (small port);
    • ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis;
    • ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation.
  • Stem Cell Infusions (before start of protocol treatment):
    • ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI])
    • No evidence of active graft versus host disease (GVHD).
  • Participants who are receiving cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. Participants must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment
  • Cellular Therapy: ≥ 42 days after the completion of donor lymphocyte infusion (DLI) or any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) before start of protocol treatment.
  • Participants with prior exposure to venetoclax are eligible in this trial
• Adequate organ function:
  • Adequate Renal Function defined as:
    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m^2, or
    • Normal serum creatinine based on age/sex
  • Adequate Liver Function defined as:
    • Direct bilirubin < 1.5 x upper limit of normal (ULN), and
    • Alkaline phosphatase ≤ 2.5 x ULN, and
    • Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) ≤ 2.5 x ULN. If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
  • Cardiac performance: Minimum cardiac function defined as:
    • No history of congestive heart failure in need of medical treatment
    • No pre-treatment diminished left ventricular function on echocardiography (shortening fraction [SF] < 25% or ejection fraction [EF] < 40%)
    • No signs of congestive heart failure at presentation of relapse.
• Participant, parent or guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation.

Exclusion Criteria

• Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
• Participants with Down syndrome.
• Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
• Participants with isolated CNS3 disease or symptomatic CNS3 disease.
• Participants with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
• Participants who are currently receiving another investigational drug (GO is not considered investigational in this study).
• Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
• Participants with known prior allergy to any of the medications used in protocol therapy.
• Participants with documented active, uncontrolled infection at the time of study entry.
• No known human immunodeficiency virus (HIV) infection.
• Post menarchal female participants with positive pregnancy test.
• Concomitant Medications
  • Participants who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of study treatment.
  • Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment.
  • Participants who have hypersensitivity to the active substance or to any of the excipients listed in summary of product characteristics (SPC).
• Pregnancy or Breast-Feeding:
  • Participants who are pregnant or breast-feeding.
  • Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy.
  • Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy.

Additional criteria to receive a gemtuzumab ozogamicin infusion:

Gemtuzumab ozogamicin should not be given:

• to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 4
• to participants with history of VOD/SOS grade 3
• to participants with CD33 negative leukemic blasts (determined at local lab)

Note that these participants are eligible for the study but will not be treated with gemtuzumab ozogamicin.

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Study Description

Brief Summary:

Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D).

Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Detailed Description:

Enrollment of subjects into Phase 1 will proceed concurrently by age as follows:

• Subjects <12 years old will initially be enrolled in the Phase 1 part to determine the pediatric RP2D for this age group; once the pediatric RP2D is determined, subjects age <12 years old may be enrolled into the Phase 2 part of the study.
• Subjects 12 to 25 years old will be directly enrolled into the Phase 2 part concurrent with Phase 1 enrollment.

Phase 1:

Approximately 12 pediatric subjects with locally advanced or metastatic solid tumors, including a primary central nervous system (CNS) tumor, or anaplastic large cell lymphoma (ALCL), with disease progression or who are non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists.

Phase 2:

Subjects will be enrolled in one of 3 cohorts as follows:

Cohort 1: approximately 10-20 subjects with solid tumors characterized by NTRK fusion, TRK tyrosine kinase inhibitor (TKI)-naïve, and centrally confirmed measurable disease at baseline.

Cohort 2: approximately 23 subjects with solid tumors characterized by NTRK fusion, TRK TKI-pretreated, and centrally confirmed measurable disease at baseline.

Cohort 3: approximately 20 subjects with solid tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease not otherwise eligible for Cohort 1 or 2.

Inclusion Criteria

Key Inclusion Criteria:

1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required.
2. Age <12 years.
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50.
9. Life expectancy greater than or equal to 12 weeks.
10. Adequate hematologic, renal and hepatic function.

Phase 2 Inclusion Criteria:

1. Age 12 to <25 years

2. Cohort Specific Inclusion Criteria:

   • Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;
   • Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;
   • Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 2.
3. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.

Exclusion Criteria

1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
3. Known active infections (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.

5. Any of the following cardiac criteria:

   • Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.