Canadian clinical trial registry

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Study Description

Brief Summary:

This is a pilot study that will evaluate disease status in children that have been newly diagnosed high-grade glioma with TRK fusion. The evaluation will occur after 2 cycles of the medication (Larotrectinib) have been given. The study will also evaluate the safety of larotrectinib when given with chemotherapy in your child; as well as the safety larotrectinib when given post-focal radiation therapy.

Detailed Description:

In this pilot study, we will assess the disease control rate (Continued Complete Response-CCR, Complete Response-CR, Partial Response-PR and Stable Disease-SD) as well as survical rate (overall survival- OS and progression free survival- PFS) in children with newly diagnosed HGG with TRK fusion who receive 2 cycles of larotrectinib monotherapy administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule. After 2 monotherapy cycles of larotrectinib, patients with CCR or CR will continue to receive larotrectinib maintenance therapy as monotherapy for a total of 12 cycles. Patients ≤ 48 months with PR or SD after 2 cycles of larotrectinib will go on to receive combination therapy with standard backbone chemotherapy (BABYPOG or HIT-SKK). Patients > 48 months of age (or patients ≥ 36 months of age, or patients with DIPG >18 months of age, at the discretion of the local investigator) will receive focal radiation therapy. A surgical cohort study will be explored whereby patients who have had a tumor biopsy/partial resection at their local institution and are planned to subsequently undergo definitive resection will receive 3-5 days (6-10 doses) of larotrectinib pre-surgery.

The study design of this trial requires 15 patients evaluable for disease control and for safety/ toxicity of larotrectinib as monotherapy. The surgical cohort will enroll up to 4 patients and will count towards the total 15 evaluable patients. A minimum of 6 patients will be evaluable for safety toxicity of larotrectinib in combination with standard-of-care chemotherapy or radiotherapy.

Inclusion Criteria

• Age: Patients ≤ 21 years of age (birth to 21 years of age) at the time of study enrollment will be eligible.
• Diagnosis: Patients with newly-diagnosed high-grade (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors are documented in a CLIA/CAP certified lab (or clinically equivalent method considered standard in non-US sites) to harbor an NTRK fusion alteration by FISH, PCR, or next generation sequencing are eligible. Patients must have had histologically verified high-grade glioma such as anaplastic astrocytoma, glioblastoma, or H3 K27-mutant diffuse midline glioma verified at a CONNECT site.

For sites that do not have CLIA-certified equivalent (certified laboratory) to assess NTRK fusion, testing will be conducted centrally at NCH. NTRK testing will be performed by NGS using targeted RNA-sequencing (Archer Solid Tumor analysis) Please submit 10 unstained sections on charged slides at 10uM thickness, or 10 scrolls cut at 10uM thickness, along with submission of an H&E slide. Formalin-fixed paraffin embedded (FFPE) tissue block and FFPE tissue scroll specimens must contain minimum of 25% tumor Snap-frozen tissue specimens are also acceptable and they must contain a minimum of 10% tumor. Please note that turn-around time for this test is up to 21 days.

• Disease Status: Patients with disseminated DIPG or HGG are eligible only if the patient is to receive chemotherapy only, i.e. no craniospinal RT is intended to be given. MRI of spine must be performed if disseminated disease is suspected clinically by the treating physicians. Patients with primary spinal tumors are eligible only if the patient is to receive either chemotherapy or focal radiation therapy, i.e. no craniospinal RT is intended to be given. Patients with leptomeningeal disease only, with no definitive identifiable primary tumor, and documented NTRK fusion, must be discussed with the Study Chair on a case-by-case basis.
• Surgical Cohort ONLY: Patients with newly-diagnosed HGG with NTRK fusions who have undergone prior biopsy and for whom further resection is indicated for a more definitive surgery at an enrolling site will be eligible to enroll onto the surgical study. DIPG patients are not eligible for the surgical cohort.
• Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). 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.
• Prior Therapy: Patients must not have received any prior anti-cancer chemotherapy. Prior use of corticosteroids are allowed (see below Exclusion Criteria)
• Organ Function Requirements: Adequate Bone Marrow Function Defined as:

Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) Hemoglobin >8 g/dL (may receive transfusions) - Adequate Renal Function Defined as: Serum creatinine within normal institutional limits, or Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2

- Adequate Liver Function Defined as: Total bilirubin ≤ 2.5 × institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal

- Adequate Cardiac Function Defined as: Shortening fraction of ≥27% by echocardiogram, or Ejection fraction of ≥ 50% by gated radionuclide study.

- Adequate Pulmonary Function Defined as: Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest).

- Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. See Section 5.5.2 and Appendix III for EIAED guidelines.

- Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. 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 an effective contraceptive method.
• Concomitant Medications Investigational Drugs: Patients who have previously received or are currently receiving another investigational drug are not eligible.

Anti-cancer Agents: Patients who have previously received or are currently receiving other anti-cancer agents, including chemotherapy, immunotherapy, monoclonal antibodies, biologic or targeted therapy, are not eligible

• Infection: Patients must not have any active, uncontrolled systemic bacterial, viral or fungal infection.
• Patients who have received prior solid organ transplantation are not eligible.
• Patients must not have malabsorption syndrome or other condition affecting oral absorption.
• Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer. (See Appendix III.) Strong inducers or inhibitors of CYP3A4 should be avoided from 7 days prior to enrollment to the end of the study.
• 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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Centres

Study Description

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

This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

Stratum A, B, D and E Inclusion Criteria :

• Patient must have one of the following diagnoses to be eligible: 
  • Stratum A, currently closed to enrollment: Patients must have a recurrent, progressive or refractory DIPG following radiation therapy with or without chemotherapy
    • Histologic diagnosis is not required for patients with typical imaging findings of DIPG (defined as patients with a diffuse expansile mass centered in and involving at least 2/3 of the pons); patients with brainstem tumors who have undergone biopsy with a diagnosis of high-grade glioma or diffuse infiltrating glioma are also eligible
  • Stratum B: Patients must have a histologically confirmed diagnosis of a non-brainstem high-grade glioma (NB-HGG) that is recurrent, progressive or refractory following therapy which included radiotherapy; spinal primary disease is eligible
  • Stratum D: Patients must have a histologically confirmed diagnosis of ependymoma that is recurrent, progressive or refractory following therapy which included radiotherapy
  • Stratum E: Patients must have a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive or refractory following therapy which included radiotherapy
• Patients must have adequate pre-trial formalin-fixed paraffin-embedded (FFPE) tumor material available for use in the biology studies mutational analysis and genome wide sequencing for each stratum
  • Patients with DIPG who have tissue available are requested to submit similar tissue as patients in other strata; however, this is not required for eligibility
• All subjects must have measurable disease in 2-dimensions on MRI scan of the brain; disease should be consistently measured with the two largest perpendicular dimensions
• Patient must be >= 1 but =< 18 years of age at the time of enrollment during the safety portion. Patients < 22 may be enrolled during the efficacy portion of the study.
• Patients must have received prior radiation therapy and/or chemotherapy and recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study; there is no upper limit to the number of prior therapies that is allowed
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea
• Biologic or investigational agent (anti-neoplastic): Patient must have 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; the duration must be discussed with and approved by the study chair
• Monoclonal antibody treatment and/or agents with 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
• Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
• Patients must have had their last fraction of:
  • Craniospinal irradiation >= 3 months prior to enrollment
  • Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
  • Local palliative radiation therapy (XRT) (small port) >= 2 weeks
• Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
• Patients must be fully recovered from all acute effects of prior surgical intervention
• Both males and females of all races and ethnic groups are eligible for this study
• Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 70; 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
• Absolute neutrophil count >= 1000 cells/uL
• Platelets >= 75,000 cells /uL (unsupported, defined as no platelet transfusion within 7 days)
• Hemoglobin >= 8 g/dl (may receive transfusions)
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
• Albumin >= 2 g/dl
• Serum creatinine based on age/gender as noted below; patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible
  • Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
  • Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
  • Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
  • Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
  • Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
  • Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
• Human immunodeficiency virus (HIV)- infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must be off all colony-forming growth factor(s) for at least 1 week prior to registration (e.g. filgrastim, sargramostim, erythropoietin); 2 weeks must have elapsed for long-acting formulations
  • 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
• Female subjects of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; pregnant women are excluded from this study because pembrolizumab (MK-3475) is an agent with the potential for teratogenic effects; because there is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab (MK-3475), breastfeeding should be discontinued if the mother is to be treated with pembrolizumab (MK-3475)
• Patients of childbearing or child fathering potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity while being treated on this study and for 6 months after the last dose of study medication
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document, inclusive of assent where appropriate, according to institutional guidelines

Stratum C Inclusion Criteria :

• Diagnosis of hypermutated brain tumors. Patients with brain tumors and increased tumor mutation burden as determined by
  • Confirmed diagnosis of CMMRD syndrome by Clinical Laboratory Improvement Act (CLIA)-certified germline gene sequencing OR
  • Confirmation of high mutation burden by whole genome/exome sequencing performed in a CLIA-certified laboratory and/or the use of Foundation One next generation sequence panel or another CLIA approved targeted sequencing lab with publicly available correlations between number of mutations found in the panel and mutations per megabase and/or genome; for protocol purposes a high mutation burden will be defined as at least 180 non-synonymous coding-region mutations by whole exome/genome sequencing (well above two standard deviations of the number of median similar mutations described in pediatric CNS cancers) AND/OR a high tumor mutation burden (TMB) or intermediate TMB based on the reporting parameters of the panel; TMB parameters provided for the Foundation One reports are high tumor mutation burden is >= 20 mutations per megabase or intermediate TMB is between 6 to 19 mutations per megabase OR
  • Confirmed diagnosis of Lynch syndrome by CLIA-certified germline gene sequencing; patients with Lynch syndrome will not be accounted for in primary objective unless their tumors are determined to have the minimum number of mutations described above but they will still be eligible for this study
    • Low-grade tumors in patients with CMMRD or Lynch syndrome do not have to reach the threshold of 100 mutations for study inclusion
• Patients must have a histologically confirmed primary brain tumor that is recurrent, progressive or refractory; inclusion criteria encompasses all types of brain tumors (e.g. gliomas, embryonal tumors or any other type of brain tumor as long as other eligibility criteria are met;
  • Patients with high-grade gliomas are eligible for this clinical trial at least 2 weeks after completion of radiotherapy independent of tumor progression/recurrence as long as they are not enrolled on any other therapeutic clinical trial and there is macroscopic residual disease
  • Patients with other concomitant tumors associated with CMMRD syndrome including gastrointestinal polyps/adenomas and carcinomas, lymphomas and leukemias will be eligible as long as they are not requiring anticancer therapy directed against these other cancers and meet all other eligibility criteria
• Patients must have adequate pre-trial FFPE tumor material available and be willing to provide a blood sample for use in the genome wide sequencing studies; while tissue is required for genome-wide sequencing of tumor and germline samples, patients will be deemed eligible for the study with a minimum of approximately 10 unstained slides for the planned analysis
• Subjects must have measurable disease in 2-dimensions on MRI scan of the brain and/or spine with the exception allowed for non-progressed HGGs; disease should be consistently measured with the two largest perpendicular dimensions
• Patients must have received prior radiotherapy and/or chemotherapy with the following exceptions:
  • Patients with secondary CNS cancers after a previous medical problem/malignancy who cannot receive full dose of radiotherapy (> 50 Gy) as long as they meet all other eligibility criteria
  • Patients with progressive low-grade gliomas and CMMRD or Lynch syndrome Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study; there is no upper limit to the number of prior therapies that is allowed
• Patient should be < 30 years at the time of enrollment
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea
• Patient must have 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; the duration must be discussed with and approved by the study chair
• Monoclonal antibody treatment and/or agents with 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
• Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollme
• Patients must have had their last fraction of:
  • Craniospinal irradiation >= 3 months prior to enrollment
  • Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
  • Local palliative radiation therapy (XRT) (small port) >= 2 weeks
• Patient must be:
  • >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
  • >= 5 years since allogeneic bone marrow transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
• Patients must be fully recovered from all acute effects of prior surgical intervention
• All races and ethnic groups are eligible for this study
• Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks 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
• Absolute neutrophil count >= 1000 cells/uL
• Platelets >= 75,000 cells/uL (unsupported, defined as no platelet transfusion within 7 days)
• Hemoglobin >= 8 g/dl (may receive transfusions)
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• ALT (SGPT) =< 3 x institutional upper limit of normal
• Albumin >= 2 g/dl
• Serum 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 m^2 are eligible
  • Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
  • Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
  • Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
  • Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
  • Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
  • Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
• HIV- infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must be off all colony-forming growth factor(s) for at least 1 week prior to registration (i.e. filgrastim; sargramostim; erythropoietin); 2 weeks must have elapsed for long-ac

Additional inclusion and exclusion criteria may apply. 

Exclusion Criteria

• Active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents except participants with vitiligo or resolved asthma/atopy or participants with hypothyroidism stable on hormone replacement or Sjogren’s syndrome
• History of or ongoing pneumonitis or significant interstitial lung disease
• Other malignancies
• Known active Hepatitis B (HbsAg active) or Hepatitis C (HCV RNA-qualitative is detected)
• History of severe hypersensitivity reaction to a monoclonal antibody
• Bulky tumor on imaging (not greater than 4cm in one dimension)
• Receiving any other anti-cancer or investigational drug therapy

(via: PBTC45: Brain Tumor Clinical Trial - St. Jude Children’s Research Hospital (stjude.org))

Additional inclusion and exclusion may apply.

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Centres

Study Description

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

This phase I trial studies the side effects and best dose of volitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib (savolitinib) administered orally daily in children with refractory, progressive or recurrent primary CNS tumors.

II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study.

II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival [PFS]) and the presence of specific genomic alterations (e.g. MET amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific subgroups of disease.

OUTLINE: This is a dose-escalation study.

Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.

Inclusion Criteria

• Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
  • Note: Refractory disease is defined as the presence of persistent abnormality on conventional magnetic resonance imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
• Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. MET pathway activation status must be confirmed using Food and Drug Administration (FDA) approved testing prior to enrollment. MET pathway activation is defined as:
  • MET kinase domain mutations, allelic frequency >= 5% OR
  • MET or HGF amplification, >= 6 copies OR
  • Chromosome 7 gain OR
  • MET fusion
    • If a MET aberration is identified using local testing at a Pediatric Brain Tumor Consortium (PBTC) institution, final confirmation for eligibility to the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study chair review
• Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
  • Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
• Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
• Patients must be > 5 years and =< 21 years of age at the time of study enrollment
• Body surface area (BSA)
  • Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
  • Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
  • Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67 m^2
  • Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2 and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the dose finding phase only)
• Patients must have failed prior standard therapy for their tumor. Patients with medulloblastoma must have received radiation therapy in addition to platinum and alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have at least received radiation therapy. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
• 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 it included nitrosourea
• Biologic or investigational agent (anti-neoplastic):
  • Patients 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:
    • Patients 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
• Patients must have had their last fraction of:
  • Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment
  • Focal irradiation > 4 weeks prior to enrollment
• Patients must be:
  • >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
  • >= 3 months since autologous stem cell transplant prior to enrollment
• Both males and females of all races and ethnic groups are eligible for this study
• Neurologic Status
  • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
  • Patients with seizure disorders may be enrolled if seizures are well controlled
  • Patients must be able to swallow whole tablets to be eligible for study enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
  • 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
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell transfusions are not allowed within 14 days prior to enrollment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5 x ULN with ALT and AST =< 1 x ULN
• Albumin >= 2 g/dL
• Serum creatinine based on age/gender. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
  • Age: Maximum serum creatinine (mg/dL)
  • 2 to < 6 years: 0.8 (male and female)
  • 6 to < 10 years: 1 (male and female)
  • 10 to < 13 years: 1.2 (male and female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
• International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
• Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for >= 2 weeks
• Cardiac function:
  • Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3 electrocardiograms (EKGs)
• Oxygen saturation as measured by pulse oximetry is > 93% on room air
• Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment
• Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
• 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
  • Women of child-bearing potential should use effective contraception from the time of enrollment until 4 weeks after discontinuing study treatment
  • Male study participants should use a condom with female partners of child-bearing potential during the study and for 4 weeks after discontinuing study treatment
  • If the female partner of a male study participant is not using effective contraception, men must use a condom during the study and for 6 months after discontinuing study treatment
  • Male study participants should avoid fathering a child and refrain from sperm donation from study start to 6 months after discontinuing study treatment
• 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

Other inclusion criteria may apply and will be discussed with you by the study team.

Exclusion Criteria

• 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 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
• Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis
• Patients with any clinically significant unrelated systemic illness 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 uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile for age, height, and gender, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
  • The normal blood pressure by height, age and gender tables can be assessed in the Generic Forms section of the PBTC member's webpage
• Patients with any of the following cardiac diseases
  • Congestive heart failure (New York Heart Association >= grade 2)
  • Clinically significant cardiac arrhythmia
  • Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
  • Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
  • Family history of unexplained sudden death under 40 years of age in first-degree relatives or
  • Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
• 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
• Concurrent Therapy
  • Patients who are receiving any other anticancer or investigational drug therapy
  • Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates should not be used during the trial or used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. Patient drug information handout and wallet card should be provided to patients
  • Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib, cabozantinib, or onartuzumab)
• Patient is currently receiving any of the following herbal preparations or medications and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's wort). These herbal medications include, but are not limited to: cannabis products, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• Patient has undergone major surgical procedure =< 28 days prior to beginning study drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting is required following port-a-cath placement
• 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
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study

Other exclusion criteria may apply and will be discussed with you by the study team.

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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. 

Brief Summary:

This phase I trial is to find out the best dose, possible benefits and/or side effects of magrolimab in combination with dinutuximab in treating patients with neuroblastoma that has come back (relapsed) or does not respond to treatment (refractory) or relapsed osteosarcoma. Magrolimab and dinutuximab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. The combination of magrolimab and dinutuximab may shrink or stabilize relapsed or refractory neuroblastoma or relapsed osteosarcoma. In addition, this trial may help researchers find out if it is safe to give magrolimab and dinutuximab after surgery to remove tumors from the lungs.

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of Hu5F9-G4 (magrolimab) in combination with dinutuximab in children and young adults with relapsed/refractory (R/R) neuroblastoma (NBL) or relapsed osteosarcoma.

II. Determine the recommended phase 2 dose (RP2D) of Hu5F9-G4 (magrolimab) given in combination with dinutuximab in children and young adults.

III. Determine the safety and feasibility of administering Hu5F9-G4 (magrolimab) in combination with dinutuximab to patients that undergo pulmonary resection of metastatic osteosarcoma within three weeks of surgery.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics (PK) of Hu5F9-G4 (magrolimab) in children and young adults.

II. Evaluate the event free survival (EFS) in two cohorts of patients who are treated at the recommended phase 2 dose (RP2D) (measurable relapsed osteosarcoma and patients with pulmonary relapse undergoing resection) and compare to historical controls.

III. Observe and record anti-tumor activity. IV. Evaluate the overall response rate (ORR) of patients in the NBL cohorts (measurable R/R NBL and evaluable R/R NBL) and osteosarcoma patients (measurable relapsed osteosarcoma) in the expansion cohorts treated at the RP2D.

EXPLORATORY OBJECTIVES:

I. To explore biomarkers of response and resistance including genomic (CD47 expression, Fc receptor [FcR] polymorphisms, SIRPa polymorphisms, and KiR phenotype) and immunologic (dinutuximab HACA, magrolimab ADA, peripheral and bone marrow immune subsets, and circulating cytokines).

II. To explore biomarkers of response in the tumor microenvironment through multiplexed ion beam imaging (MIBI) on resected tissue or archival tissues including comparison of pre- and post- treatment tumor tissues from patients undergoing staged resection of pulmonary osteosarcoma.

OUTLINE: This is a dose de-escalation study of magrolimab with fixed-dose dinutuximab followed by a dose-expansion study. Patients are assigned to 1 of 2 arms.

ARM A: Patients receive magrolimab intravenously (IV) over 2 hours on days 1, 8, and 15 of cycles 1-2 and days 1 and 15 of subsequent cycles, and dinutuximab IV over 10 hours on days 2-5. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive magrolimab IV over 2 hours on days 1, 8, and 15 of cycles 1-2 and days 1 and 15 of subsequent cycles, and dinutuximab IV over 10 hours on days 2-5. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with pulmonary osteosarcoma may undergo surgical resection of tumor after cycle 1. After surgery, these patients continue receiving magrolimab and dinutuximab every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, at 2, 4, 6, 9, and 12 months, and then yearly for 4 years.

Inclusion Criteria

• Patients must have a history of histologically or cytologically confirmed NBL or osteosarcoma

• Patients must have:

  • Relapsed/refractory high-risk neuroblastoma (NBL) (defined as disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction therapy) or
  • Relapsed osteosarcoma (relapsed after frontline therapy and/or there must not be any potentially curative treatment options available at the time of enrollment)
• Cohort B1: Measurable NBL (defined as those lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm by chest x-ray, as >= 10 mm with CT scan, or >= 10 mm with calipers by clinical exam)
• Cohort B2: Evaluable NBL (iobenguane [MIBG] and/or bone marrow disease only)
• Cohort B3: Measurable osteosarcoma (defined as those lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam)
• Cohort B4: Patients with relapsed resectable pulmonary osteosarcoma who are scheduled for a surgical resection
• Note: Subjects will not have measurable disease due to recently resected pulmonary metastases. Investigational therapy must begin within three weeks of resection. Staged resections are permissible; investigational therapy will be administered in between resections. Patients should receive one cycle of investigational therapy in between resections but can receive additional cycles to accommodate the most appropriate surgical schedule as determined by the treating physicians. Every effort will be made to have at least half of this cohort (five of ten patients) be those requiring a staged resection

• There is no limit to the number of prior treatment regimens. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. Acute toxicity of any previous therapy must have resolved to grade 1 or less or stabilized, unless specified elsewhere

  • Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea)
  • Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
  • At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic non-myelosuppressive regimen
  • At least 4 weeks must have elapsed since prior therapy with 131I-MIBG
  • Monoclonal antibodies: At least 3 weeks must have elapsed since prior therapy that included a monoclonal antibody
  • Patients who have received prior therapy with GD2 antibodies, regardless of response to therapy, will be eligible
  • At least 7 days must have elapsed since the last pharmacologic dose of systemic steroids
• Arm A: Age >= 1 or < 18 years of age
• Arm B: Age >= 1 or =< 35 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2; Subjects > 16 years of age: Karnofsky >= 50%; Subjects =< 16 years of age: Lansky scale >= 50%
• Absolute neutrophil count >= 1,000/mcL
• Hemoglobin >= 9.5 g/dL, transfusion support acceptable
• Platelets >= 100,000/mcL, independent of transfusions
• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) for age (sum of conjugated and unconjugated)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN
• Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• Female patients of childbearing potential must not be nursing or planning to be pregnant and must have a negative urine or serum pregnancy test within 30 days before enrollment and within 72 hours before the first administration of study treatment

  • Note: Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential

• The effects of Hu5F9-G4 (magrolimab) monoclonal antibody on the developing human fetus are unknown and dinutuximab is known to be teratogenic. For this reason, female patients of childbearing potential must be willing to use one highly effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study and continue for 4 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

  • Male patients who are sexually active with a woman of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception (condom plus spermicidal gel) and refrain from sperm donation during the study and for 4 months after the last dose of study treatment. If the partner is pregnant, male patients must use barrier method contraception (condom) during the study and for 4 months after the last dose of study treatment to prevent fetal exposure to study treatment
• All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will be obtained according to local institutional policy

Exclusion Criteria

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-GD2 monoclonal antibody (dinutuximab) or Hu5F9-G4 (magrolimab) monoclonal antibody or other agents used in this study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who are receiving any other investigational agents
• Pregnant women are excluded from this study because Hu5F9-G4 (magrolimab) is a monoclonal antibody on the developing human fetus are unknown and dinutuximab may cause fetal harm. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Hu5F9-G4 (magrolimab) or dinutuximab, breastfeeding should be discontinued if the mother is treated with Hu5F9-G4 (magrolimab) or dinutuximab
• Patients who have received prior treatment with CD47 or SIRPalpha-targeting agents
• Patients with red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of RBCs transfused during the 4-week period prior to screening. RBC transfusions are permitted during the screening period and prior to enrollment
• Patients with known inherited or acquired bleeding disorders are not eligible
• Patients with prior hemolytic anemia or Evans syndrome in the last 3 months
• Patients with significant medical diseases that would worsen the risk-benefit ratio of participating in this study. This includes but is not limited to acute myocardial infarction within the last 6 months, unstable angina, significant acute or chronic infections, or severely immunocompromised state

• Patients on the following medications at the time of enrollment:

  • Immunotherapy or immunosuppressive drugs (e.g. chemotherapy or systemic corticosteroids) EXCEPT for the following:

    • The only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions. The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency
  • Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor) EXCEPT for erythropoietin and darbepoetin alpha
  • Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to potentially interfere with major organ function (e.g. hypericin)
• Patients administered a live vaccine within 28 days prior to enrollment

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Study Description

Brief Summary:

This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking the TRK enzymes needed for cell growth.

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.

SECONDARY OBJECTIVES:

I. To determine event-free survival (EFS), overall survival (OS), and duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.

II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.

III. To describe the toxicity of larotrectinib in children with solid tumors and acute leukemia.

IV. To determine the percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) at baseline and after 1 week, 4 weeks, 24 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at progression.

EXPLORATORY OBJECTIVES:

I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib.

II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.

III. To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib.

IV. To evaluate the surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib.

V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers.

VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors.

VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib.

VIII. To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment.

IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.

X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia.

XI. To evaluate the change in neurocognitive/behavioral functioning over time between baseline and 2 years post-diagnosis of patients treated on this protocol using parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function Scales-Preschool Version [BRIEF-P] or BRIEF Global Executive Composite Score), psychosocial functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory [PedsQL] Total score).

OUTLINE:

Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study.

After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years from the date of study entry.

Inclusion Criteria

• COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement Act/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be identified by fluorescence in situ hybridization (FISH) or molecular techniques (reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, an ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the upstream TRK fusion partner is not required.
• COHORT B: Patients must have a histologic diagnosis of any solid tumor other than infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility) unless the patient has a diagnosis of congenital mesoblastic nephroma in which case an ETV6 rearrangement is sufficient for eligibility. Identification of the upstream TRK fusion partner is not required.
• COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility). Identification of the upstream TRK fusion partner is not required.
• SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must have disease that cannot be completely resected without a predicted functional, neurologic, or significant cosmetic deficit in the opinion of the investigator.
• LEUKEMIA (COHORT C): Patients must have >= 5% blasts in the bone marrow. Extramedullary disease is permitted.
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. 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.

• COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than surgical resection is permitted.

  • Patients who experience recurrence after surgery alone and no other anti-cancer therapy will be eligible.
  • If not eligible due to prior anticancer therapy, patients may be eligible for the larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with commercial larotrectinib off study.

• COHORT C: Patients with relapsed leukemia (Cohort C) 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. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.

    • A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, thioguanine [6MP], and/or methotrexate).
    • A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment

    • >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.

      • Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy.
  • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.
  • Anti-cancer agents that are 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. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction.
  • 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. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator.
  • 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]):

    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD).
    • Autologous stem cell infusion including boost infusion: >= 42 days.
  • Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • 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 BM radiation.
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody): >= 42 days after systemically administered radiopharmaceutical therapy.
  • Patients must not have received prior exposure to TRK inhibitors (including larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).
• For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement: Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions).
• Patients with solid tumors 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.
• For patients with leukemia: Platelet count >= 20,000/mm^3 (within 7 days prior to enrollment) (may receive platelet transfusions; must not be known to be refractory to red cell or platelet transfusion)
• For patients with leukemia: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive RBC transfusions; must not be known to be refractory to red cell or platelet transfusion)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

  • 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)
  • 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)
  • 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
  • 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
  • 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
  • 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
  • 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

  • >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)

    • For patients < 1 month of age, serum creatinine levels must be < 1.5 x the treating institution's creatinine upper limit of normal (ULN) for patients < 1 month of age or the creatinine clearance or radioisotope GFR must be >= 70 mL/min/1.73 m^2.
• Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment). After approval of the study chair or designee, infants with a higher total bilirubin due to physiologic or breast milk jaundice are eligible if the conjugated (direct) bilirubin is =< 2 mg/dL
• Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with solid tumors: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
• Patients with leukemias: Conjugated (direct) bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).
• Patients with leukemias: SGPT (ALT) =< 225 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with leukemias: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
• Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen for >= 14 days and well controlled.
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) except tendon reflex decreased resulting from prior therapy must be =< grade 2.

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. Female patients of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method for the duration of study therapy and for at least one month after the final dose of larotrectinib. Males of reproductive potential with a non-pregnant female partner of child-bearing potential must use a highly effective contraception for the duration of the study and for at least one month after the final dose of larotrectinib. Because of the unknown risk of larotrectinib in nursing infants, nursing women should discontinue breastfeeding during treatment with larotrectinib and for 3 days following the final dose.
• Patients with solid tumors, including CNS tumors, requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients with leukemia may receive systemic corticosteroids for cytoreduction up to 24 hours prior to the start of protocol therapy. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid.
• Patients who are currently receiving another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents are not eligible [except leukemia patients receiving corticosteroids or hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Patients with leukemia should receive a single dose of intrathecal cytarabine, hydrocortisone, and/or methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the baseline lumbar puncture.
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial.
• Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
• Patients with malabsorption syndrome or other conditions that significantly limit enteral absorption are not eligible.
• Patients who are unable to swallow capsules or liquid and do not have gastric access via a nasogastric or gastrostomy tube are not eligible.
• Patients who have an uncontrolled infection are not eligible.
• Patients who have received 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.
• Patients with high grade gliomas (HGG) are not eligible.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

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Study Description

This study aims to use clinical and biological characteristics of acute leukemias to screen for patient eligibility for available pediatric leukemia sub-trials. Testing bone marrow and blood from patients with leukemia that has come back after treatment or is difficult to treat may provide information about the patient's leukemia that is important when deciding how to best treat it and may help doctors find better ways to diagnose and treat leukemia in children, adolescents, and young adults.

PRIMARY OBJECTIVES:

I. To utilize clinical and biological characteristics of acute leukemias to screen for patient eligibility for available phase I/II Pediatric Acute Leukemia (PedAL) sub-trials.

II. To maintain a longitudinal and comprehensive registry from relapse in children and young adults with recurrent and refractory leukemia.

OUTLINE:

Patients undergo collection of blood and/or bone marrow samples at baseline, end of treatment cycle(s), and at relapse/refractory disease status (if applicable).

After completion of study, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.

Inclusion Criteria

• Patients must be less than 22 years of age at the time of study enrollment
• Patient must have one of the following:
  • Patient has known or suspected relapsed/refractory (including primary refractory) AML
    • This includes isolated myeloid sarcoma
  • Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome
  • Patient has known or suspected relapsed ALL that meets one of the following criteria:
    • Second or greater B-ALL medullary relapse, excluding KMT2Ar.
    • Any first or greater B-ALL medullary relapse involving KMT2Ar.
    • Any first or greater T-ALL medullary relapse with or without KMT2Ar.
  • Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL)
  • Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML) or treatment-related myelodysplastic syndrome (t-MDS)
  • Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS)
  • Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Not outlined on clinicaltrials.gov

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Study Description

The primary purpose of this study is to assess the safety and tolerability of RP-6306 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Phase 1, multi-center, open-label, dose-escalation study to:

• Evaluate the safety profile and MTD of RP-6306 when administered orally to establish the recommended Phase 2 dose and schedule
• Characterize the PK and pharmacodynamics of RP-6306 monotherapy
• Assess preliminary anti-tumor activity associated with RP-6306 monotherapy

Inclusion Criteria

• Male or female and ≥12 years-of-age at the time of informed consent.
• Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, or 2 for patients >16 years of age.
• Locally advanced or metastatic resistant or refractory solid tumors.
• Patients <18 years of age must weigh at least 40 kg.
• Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
• Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
  • CCNE1 amplification (non-equivocal) as determined by tumor NGS or FISH
  • FBXW7 deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
  • PPP2R1A deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
• Measurable disease as per RECIST v1.1.
• Ability to swallow and retain oral medications.
• Acceptable hematologic and organ function at screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Resolution of all toxicities of prior therapy or surgical procedures.
• Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

Exclusion Criteria

• Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
• History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
• Patients who are pregnant or breastfeeding.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
• Major surgery within 4 weeks prior to first dose of RP-6306.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled hypertension.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.