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Study Description

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

Both Australia (Zero Childhood Cancer) and Canada (PROFYLE) have developed precision oncology programs for the pediatric population through which samples from childhood/adolescent cancers undergo in depth genetic profiling. OPTIMISE is a companion platform trial, which will link patients to novel targeted agents based on their tumor profile. The trial will have multiple basket arms based on the most common genetically altered pathways the investigators have identified in these childhood cancers. Each arm of the trial will be histopathology agnostic and test a rational, novel combination therapy, to maximise potential clinical benefit.

The information below is for Treatment Arm A which will be combining, for the first time, paxalisib with conventional chemotherapy in paediatric patients with high-risk malignancies.

Inclusion Criteria

• Patients must be diagnosed with a solid tumor, CNS tumor or lymphoma that has progressed despite standard therapy, or for which no effective standard therapy exists.
• Age <21 years at inclusion; patients 21 years and older may be included after approval by the Study Chair if they have a pediatric type recurrent/refractory malignancy.
• Patients must be enrolled on a precision medicine study (i.e. PROFYLE, ZERO or equivalent as agreed with Study Chair.
  • Tumour profiling should be performed as close to the time of study enrolment as possible; at a minimum profiling should have been performed on a sample obtained within 12 months prior to enrolment, or had confirmation that the targeted molecular aberration is still present from a tumour sample collected within the 12 months prior to enrolment. Patients for whom tumour profiling has been performed outside this window may only be enrolled after approval by the Study Chairs.
• Patients are eligible to enrol using existing sequencing results or other criteria such as immunohistochemistry (provided a report from a CLIA‐approved or equivalent laboratory is provided), but concurrent enrolment on a precision medicine study is still required.  
• Patients enrolled in a Phase I cohort must have either evaluable or measurable disease.
• Patients enrolled in a Phase II cohort must have measurable disease. Evaluable and measurable disease are defined by standard imaging criteria (RECIST V1.1, RAPNO or RANO) for the patient's tumor type.
• Disease evaluations, laboratory tests, and other clinical assessments that are considered standard of care may be undertaken at the patient's local oncology treatment centre with results transferred to study site for evaluation.
• Performance status: Karnofsky performance status (for patients > 16 years of age) or Lansky play score (for patients ≤ 16 years of age) ≥ 50%.
• Life expectancy ≥ 6 weeks.
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer-directed therapy prior to enrolment.
• Adequate organ function.
  • Haematologic criteria:
    • Peripheral absolute neutrophil count (ANC) ≥1.0 x 109/L (unsupported) (i.e. at least 7 days post filgrastim; at least 14 days post PEG‐filgrastim (if administered)).
    • Platelet count ≥75 x 109/L (unsupported; defined as no platelet transfusions within prior 7 days).
    • Haemoglobin ≥80 g/L (transfusion is allowed).
  • Renal and hepatic function:
    • Serum creatinine ≤1.5 x upper limit of normal (ULN) for age
    • Total bilirubin ≤1.5 x ULN
    • Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN except in patients with documented tumour involvement of the liver who must have AST and ALT ≤10 x ULN
• Able to comply with scheduled follow-up and with management of toxicity.
• Females of childbearing potential must have a negative serum or urine pregnancy test.
• Fertile males must agree to use adequate contraception during the study and following completion of treatment.
• Provide a signed and dated informed consent form.

Additional Inclusion Criteria for Arm A

• For Cohort A1: Patients must have evaluable or measurable disease.
• For Cohort A2, Molecularly selected: Tumour must have a demonstrated pathogenic/likely pathogenic mutation in the PI3K/AKT/mTOR pathway from tumour DNA analysis, including:
  • Loss of function (LoF) in tumour suppressor genes or genes that normally act to downregulate the PI3K/AKT/mTOR pathway (PTEN, PIK3R1, TSC1, TSC2, DEPTOR)
    [Rationale: LoF variants involving these genes can lead to increased signalling of the PI3K/AKT/mTOR pathway. This includes single nucleotide variants (SNV), copy number 
    loss and structural variants (SV) leading to disruption of normal gene function.]
  • Gain of function (GoF) variants in oncogenes or genes that normally lead to upregulation of the PI3K/AKT/mTOR pathway.

• Cohort A3, Expanded drug-selection: Patients will be eligible if they have a demonstrated PI3K/AKT/mTOR pathway aberration in tumour from RNA expression analysis or proteomic analysis which would be predicted to benefit from PI3K/AKT/mTOR inhibition after discussion with the Arm A Study Chair, or demonstrated individual tumour sensitivity to a drug acting on this pathway through pre-clinical studies (in vitro and/or in vivo studies, which may include high-throughput drug screen and/or patient derived xenografts (PDX) and/or neurospheres). Patients with pathogenic/likely pathogenic mutation in relevant genes not meeting criteria for Cohort A2 will also be eligible.
• For Cohorts A2 and A3: Measurable disease as per RECIST, RAPNO or RECIL criteria. Patients with neuroblastoma will also be eligible if they have disease that is only evaluable by MIBG.
• For all Cohorts: Adequate cardiac function defined as
  • Shortening fraction of ≥27% by echocardiogram, or ejection fraction of ≥50% by gated 
    radionuclide study (MUGA); and
  • QTC <480 msec by the Fridericia formula.

Other inclusion or exclusion criteria may apply. 

Exclusion Criteria

• Patients with symptomatic CNS primary or metastatic tumors who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs.
• Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), unstable ischemia, congestive heart failure within 12 months of screening.
• Known active viral hepatitis or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Presence of any ≥Grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity, lymphopenia or clinically stable peripheral neuropathy
• Major surgery within 21 days of the first dose of investigational drug.
• Known hypersensitivity to any study drug or component of the formulation.
• Pregnant or nursing (lactating) females.
• Any other concomitant serious medical condition or organ dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the investigational drugs.

Additional Exclusion Criteria for Arm A:

Exclusion criteria for all Cohorts:

• Patients with significant uncontrolled hyperglycaemia that in the opinion of the investigator would compromise patient safety.
• Diabetic participants who require insulin therapy.
• Patients with active pneumonitis that is clinically symptomatic. 
• Patients with a history of myocardial infarction or coronary artery disease

Other inclusion or exclusion criteria may apply. 

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Study Description

In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 2500 mg/m2 BID on each day of study.

Subjects will be evaluated in 3 Cohorts:

Cohort 1: Molecular High Risk Medulloblastoma

Cohort 2: Molecular Very High Risk Medulloblastoma

Cohort 3: Relapsed/Refractory Medulloblastoma

A total of 118 subjects across all cohorts will be enrolled to ensure that there will be 107 evaluable subjects (32-39 per cohort)

Inclusion Criteria

• Age: 0-21 years of age at diagnosis
• Pathology All patients must either have a pathologically confirmed diagnosis of medulloblastoma with molecular grouping identified by either Nanostring or methylation profiling.
  • Cohort 1- Molecular High Risk:
    • Metastatic non-MYC amplified Group 3
    • Metastatic Group 4
    • Metastatic non-WNT/non-SHH (Must be non-MYC amplified)
  • Cohort 2- Molecular Very High Risk
    • Metastatic OR MYCN amplified OR TP53 mutant non-infant (>3 yrs) SHH
    • MYC amplified Group 3
    • Non-WNT, non-SHH infant (< 3 yrs)
  • Cohort 3: Relapsed/Refractory Medulloblastoma
• Pre-enrollment tumor survey:
  • Prior to enrollment on this study, a determination of mandatory disease staging must be performed:
    • Tumor imaging studies including: Brain and spine MRI
    • Lumbar Puncture only if previously positive
    • Bone Marrow aspiration/biopsy only if previously positive
    • This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to first dose of study drug, but must be done within a maximum of 4 weeks before first dose of study drug.
• Disease Status: Subjects must have no evidence of disease, or stable* residual nonbulky** disease.
  • *Stable residual disease defined as non-progression over 2 separate imaging studies at least 6 weeks apart
  • **Non-bulky disease defined as maximal cross-sectional area < 3cm^2 at enrollment. Patients with leptomeningeal disease are allowed to participate on study.
• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days after last dose of conventional chemotherapy. Patients who have undergone high dose chemotherapy (HDCT) with autologous stem cell transplantation (SCT) are eligible if more than 45 days have elapsed since date of last SCT.
• Patients must have a Lansky or Karnofsky Performance Scale score of ≥ 50% (see Appendix II) and patients must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.
• Patients must have adequate organ functions at the time of registration:
  • Hematological: Hematological recovery as defined by ANC ≥750/μL, platelets ≥30 (non-transfused x 7 days)
  • Liver: Adequate liver function as defined by AST and ALT <10x upper limit of normal
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

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

Exclusion Criteria

• BSA of <0.25 m2
• Metastatic disease outside of CNS
• Relapsed/refractory patients who are radiation-naïve and age 5 years or older at time of enrollment
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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

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Study Description

Brief Summary:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Detailed Description:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

• Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
• Arm 3: Subjects who are relapsed or refractory with active disease.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
• All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
• Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.

• Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. 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.
  4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
  5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
  6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

  7. Stem Cell Transplant:

     1. Allogeneic: No evidence of active graft vs. host disease
     2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
  8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
• Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
• Life expectancy > 2 months
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.

• Subjects must have adequate organ functions at the time of registration:

  • Hematological: Total absolute neutrophil count ANC ≥750/μL
  • Liver: Subjects must have adequate liver function as defined by AST and ALT <5x upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA of <0.25 m2.
• Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
• Subjects that received a dose of DFMO in combination with etoposide are not eligible.
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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Study Description

This is a prospective, multicenter clinical trial in subjects with newly diagnosed high-risk neuroblastoma to evaluate the efficacy and safety of administering naxitamab with standard induction therapy.

All subjects will be followed for disease response, event free survival, overall survival and toxicity. Extent of disease will be measured and assessed for changes throughout the course of the study. All efficacy analyses will be performed on the evaluable population which will consist of all enrolled subjects (subjects who initiate treatment with naxitamab in combination with GM-CSF plus standard induction therapy) and who have measurable disease at baseline.

The initial chemotherapy Induction regimen will utilize sequential administration of 5 cycles of multi-agent chemotherapy. Naxitamab will be added to all 5 Induction cycles.

Subjects with an activating ALK mutation or ALK amplification will have ceritinib added to their treatment regimen as soon as results are available.

Stem cell mobilization and collection will occur after the 2nd cycle of induction.

Surgical resection of the primary tumor will ideally occur after the 4th cycle of Induction but may be delayed until after the 5th cycle of Induction if medically necessary.

Disease status evaluations will occur at the following time points: (1) pre-treatment, (2) post Cycle 2 Induction (3) Prior to surgical resection (if performed), (4) End of Induction (which includes surgery and 5 cycles of chemotherapy), and (5) End of Additional/Salvage Therapy as needed.

The current standard of care for high-risk neuroblastoma involves 5-7 cycles of induction chemotherapy with surgical removal of the tumor after 4-5 cycles of chemotherapy, followed by high-dose chemotherapy plus autologous stem cell transplant, then radiation to the primary tumor bed, followed by anti-GD2 immunotherapy and cis retinoic acid. This results in a less than 60% disease free survival for high-risk NB, a survival rate that still greatly needs improvement. Two areas in which improvements can be made include: 1) to improve response rate to induction chemotherapy and 2) to improve EFS by improving maintenance therapy to prevent relapse.

We hypothesize that the addition of anti-GD2 therapy to induction chemotherapy will result in improved end of induction responses and improved survival.

Inclusion Criteria

• Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Subjects with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

a) Subjects with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) Stage 4 are eligible with the following: i. Age > 18 months (> 547 days) regardless of biologic features or ii. Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or iii. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: i. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or ii. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.

c) Subjects with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

• Subjects must be age ≤ 21 years at initial diagnosis
• Subjects must be >12 months of age at enrollment
• Ability to tolerate Peripheral blood stem cell (PBSC) collection: No known contraindication to PBSC collection. Examples of contraindications would include a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.
• Adequate Cardiac Function Defined As:
  • Shortening fraction of ≥ 27% by echocardiogram, or
  • Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.
• Adequate liver function must be demonstrated, defined as:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND
  • ALT (SGPT) < 5 x upper limit of normal (ULN) for age
• Subjects must have adequate renal function defined as a serum creatinine based on age/gender as follows:

  • Age Maximum Serum Creatinine (mg/dL), Male/Female

    • 1 to < 2 years 0.6 0.6

    • 2 to < 6 years 0.8 0.8

    • 6 to < 10 years 1 1

    • 10 to < 13 years 1.2 1.2

    • 13 to < 16 years 1.5 1.4

    • ≥ 16 years 1.7 1.4

• A negative serum pregnancy test is required for female participants of childbearing potential (≥13 years of age or after onset of menses)
• Both male and female post-pubertal study subjects must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) from the time of informed consent until 6 months after study treatment discontinuation. Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence.
• Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• Subjects who are less than 1 year of age
• Subjects who are 12-18 months of age with INSS Stage 4 and all stage 3 subjects with favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible.
• Subjects who have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.
• Treatment with immunosuppressive treatment (local steroids excluded) within 4 weeks prior to enrollment
• Inadequate pulmonary function defined as evidence of dyspnea at rest, exercise intolerance, and/or chronic oxygen requirement. In addition, room air pulse oximetry < 94% and/or abnormal pulmonary function tests if these assessments are clinically indicated.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study.)
• Subjects receiving any investigational drug concurrently.
• Subjects with any other medical condition, including but not limited to malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study.
• Subjects with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of investigational medicinal products (IMPs) or to significantly increase the severity of the toxicities experienced from trial treatment.

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Study Description

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

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

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

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

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

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

Participants may withdraw consent to participate at any time.

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

Inclusion Criteria

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

Exclusion Criteria

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

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Study Description

Brief Summary:

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.

Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.

Detailed Description:

The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.

The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.

A. Dose Escalation/De-escalation Phase:

Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.

B. Dose-Expansion Phase:

Participants will receive the RP2D of quizartinib for their respective age group.

During both dose escalation and dose expansion phases, participants will receive:

Re-Induction Therapy

• Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles
• In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as a single agent

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:

After re-induction therapy, participants will be evaluated for eligibility to undergo allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants may receive a single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without quizartinib) if an allogeneic HSCT is not available immediately. The options for consolidation therapy are as follows:

• High intensity chemotherapy with quizartinib, or
• Low intensity chemotherapy alone, or
• Low intensity therapy with quizartinib as a single agent

Continuation Therapy:

Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of quizartinib continuation therapy at the same dose received during re-induction in the dose expansion phase.

Long-term Follow-up:

The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation Therapy or permanent discontinuation of quizartinib at any time. After completion of the 30-day safety follow-up visit, subsequent visits will occur at the following frequencies to assess survival and anti-leukemic treatments:

• every 3 months for the first 2 years, and then
• once a year thereafter until the last participant enrolled has been followed for three years from the date of enrollment

Inclusion Criteria

• Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with >5% blasts in bone marrow, with or without extramedullary disease
• Is in first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1 to 2 cycles of induction chemotherapy) at remission induction - prior HSCT is permitted
• Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol
• Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed
• Has protocol-defined adequate performance status score
• Has fully recovered from the acute clinically significant toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy, per protocol guidelines
• Has protocol-defined adequate renal, hepatic and cardiac functions
• If of reproductive potential, is permanently sterile or agrees to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of study drug or cytarabine, whichever is later
• If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
• Participant/legal representative is capable of understanding the investigational nature of the study, potential risks, and benefits, and the patient (and/or legal representative) signs a written assent/informed consent
• Meets protocol-specified guidelines before inclusion in the continuation therapy phase

Exclusion Criteria

• Has been diagnosed with isolated central nervous system relapse, certain kinds of leukemia, or with myeloid proliferations related to Down syndrome
• Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol
• Has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient must be off vasopressors and have negative blood cultures for at least 48 hours prior to the start of systematic protocol therapy.
• Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
• Has known history of human immunodeficiency virus (HIV)
• Has history of hypersensitivity to any of the study medications or their excipients
• Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol
• Has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance, interfere with consent/assent, study participation, follow up, or interpretation of study results
• Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)
• Is otherwise considered inappropriate for the study by the Investigator

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Study Description

Patients with relapsed or refractory leukemia or lymphoma are often refractory to further chemotherapy. In this study, the investigators will attempt to use T cells obtained directly from the patient, which can be genetically engineered to express a chimeric antigen receptor (CAR). The CAR used in this study can recognize CD22, a protein expressed on the surface of leukemia and lymphoma cells. The phase 1 part of this study will determine the safety and appropriate dose level of these CAR T cells, and the phase 2 part of the study will determine how effective this CAR T cell therapy is. Both patients who have never had prior CAR T cell therapy and those who have had prior CAR T cell therapy may be eligible to participate in this study.

Inclusion Criteria

• Male and female subjects aged ≤ 30 years. First 2 enrolled subjects: age ≥ 18 and ≤ 30 years
• Evidence of refractory or recurrent CD22+ leukemia or lymphoma
• Able to tolerate apheresis, or subject with sufficient existing apheresis product or T cells for manufacturing investigational product.
• Life expectancy ≥ 8 weeks
• Lansky or Karnofsky, as applicable, score ≥ 50
• Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy, if the subject does not have a previously obtained apheresis product that is acceptable and available for manufacturing of CAR T cells
• ≥ 7 days post last chemotherapy and biologic therapy, with the exception of intrathecal chemotherapy and maintenance chemotherapy
• ≥ 7 days post last corticosteroid therapy
• ≥ 3 days post Tyrosine Kinase Inhibitor (TKI) use
• ≥ 1 day post hydroxyurea
• 30 days post most recent CAR T cell infusion
• Adequate organ function
• Adequate laboratory values, including absolute lymphocyte count ≥ 100 cells/uL
• Subjects of childbearing or child-fathering potential must agree to use highly effective contraception from consent through 12 months following infusion of investigational product on trial
• Subject and/or legally authorized representative has signed the informed consent form for this study

Exclusion Criteria

• Presence of active malignancy other than disease under study
• History of symptomatic CNS pathology or ongoing symptomatic CNS pathology
• CNS involvement of leukemia or lymphoma that is symptomatic and in the opinion of the investigator, cannot be controlled during the interval between enrollment and CAR T cell infusion
• Subjects with uniform expression of CD19 on their malignant cells who are eligible but have not attempted CD19 directed CAR T cell therapy
• For subjects having had a previous stem cell transplant: presence of active GVHD, or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment
• Presence of active severe infection,
• Presence of primary immunodeficiency syndrome
• Subject has received prior virotherapy
• Pregnant or breastfeeding
• Subject and/or legally authorized representative unwilling to provide consent/assent for participation in the 15-year follow-up period, required if CAR T cell therapy is administered
• Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol

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Study Description

This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.

Inclusion Criteria

• Patients must be ≤ 21 years of age at the time of study enrollment
• Newly diagnosed American Joint Committee on Cancer (AJCC) stage II-IV nasopharyngeal carcinoma (NPC)
  • Patients must have had histologic verification of the malignancy at original diagnosis
  • Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
• Patients must have had histologic verification of the malignancy at original diagnosis
• Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
• Patients must have a Lansky (for patients ≤ 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of ≥ 60%
• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to start of protocol therapy)
• Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to start of protocol therapy)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 or (within 7 days prior to start of protocol therapy)
• A serum creatinine based on age/gender (within 7 days prior to start of protocol therapy) Age: Maximum serum creatinine (mg/dL)
  • 1 month to < 6 months: 0.4 mg/dL (male); 0.4 mg/dL (female) 6 months to < 1 year: 0.5 mg/dL (male); 0.5 mg/dL (female)
  • 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)
  • 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
  • 6 to < 10 years 1 mg/dL (male); 1 mg/dL (female)
  • 10 to <13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
  • 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
  • ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and (within 7 days prior to start of protocol therapy)
• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L* (within 7 days prior to start of protocol therapy)
  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Shortening fraction of ≥ 27% by echocardiogram, or
• Ejection fraction of ≥ 50% by radionuclide angiogram
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and T-cell count above the lower limit of normal 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

Exclusion Criteria

• Patients who received prior radiotherapy to the head or neck
• Patients who received prior chemotherapy or radiation for the treatment of any cancer in the last 3 years. These patients must also be in remission
• Patients with a diagnosis of immunodeficiency
• Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive agents). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Note: Patients with well-controlled asthma and no need for systemic steroids for the treatment of asthma in the last 12 months will not be excluded
• Patients with a condition requiring systemic treatment with either corticosteroids (> 0.25 mg/kg (10 mg) daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 0.25 mg/kg (10 mg) daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Patients with detectable viral load of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or active tuberculosis
• Patients who have undergone solid organ or allogeneic hematopoietic transplant at any time
• Due to risks of fetal and teratogenic adverse events as seen in animal studies, a negative pregnancy test must be obtained in females of childbearing potential, defined as females who are post-menarchal. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Females of childbearing potential that are sexually active must agree to either practice 2 medically accepted highly-effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 5 months after the last dose of nivolumab, 6 months after the last dose of gemcitabine, and 14 months after the last dose of cisplatin, whichever is longer
• Males of childbearing potential that are sexually active must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 3 months after the last dose of gemcitabine, and 11 months after the last dose of cisplatin, whichever is longer
• Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy through 5 months after the last dose of nivolumab
• 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