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Study Description

The purpose of this study is to assess the safety and tolerability of epcoritamab in pediatric participants with relapsed/refractory aggressive mature B-cell neoplasms and young adult participants with Burkitt's or Burkitt-like lymphoma/leukemia. Adverse events and change in disease activity will be assessed.

Epcoritamab is an investigational drug being developed for the treatment of relapsed/refractory aggressive mature B-cell neoplasms. Participants will receive subcutaneous (SC) of epcoritamab. Approximately 15 pediatric participants with a diagnosis of relapsed/refractory aggressive mature B-cell neoplasms and and young adult participants, ages of 18-25, with a diagnosis of Burkitt's or Burkitt-like lymphoma/leukemia will be enrolled at 50 sites globally.

Participants will receive subcutaneous epcoritamab in 28-day cycles. Participants will be followed for a minimum of 3 years after enrollment.

Inclusion Criteria

• Participants >= 1 and < 18 years old at time of primary diagnosis with Burkitt's or Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma (DLBCL), or other aggressive mature (CD20+) B-cell lymphomas. Participants up to 25 years of age with Burkitt's or Burkitt-like lymphoma/leukemia are also eligible.
• Disease pathologically confirmed (tumor tissue) by local testing.

• Relapsed or primary refractory disease meeting any of the following criteria:

  • Progressive disease at any time during second-line chemoimmunotherapy (CIT).
  • Best response of stable disease (SD) after a minimum of 2 cycles of second-line CIT.
  • Best response of partial response (PR) after a minimum of 3 cycles of second-line CIT.
  • Complete Response (CR) after a minimum of 3 cycles of second-line CIT therapy but unfit or ineligible for consolidation with cell therapy.
  • Not in CR and unable to initiate or tolerate (i.e., must discontinue) second-line CIT.
  • Have received cell therapy (allogeneic or autologous transplant or chimeric antigen receptor T-cell (CAR-T) therapy) as consolidation but have not obtained or maintained a CR.
• Recovery from toxic effects of prior chemoimmunotherapy.
• Performance status by Lansky (< 16 years old at evaluation) or Karnofsky (>= 16 years old at evaluation) score >= 50 or Eastern Cooperative Oncology Group (ECOG) score <= 2 .
• Adequate bone marrow, hepatic, and renal function.

Other inclusion criteria may apply

Exclusion Criteria

• Known central nervous system (CNS) involvement by lymphoma at screening as confirmed by screening magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET) brain scans (participants with evidence of CNS disease only in the cerebrospinal fluid (CSF) will be eligible).
• Other malignancy requiring therapy.
• Currently receiving anti-cancer therapy, including chemotherapy (excluding intrathecal therapy), radiotherapy, small molecules, monoclonal antibodies, cell therapy, or other investigational agents.

Other exclusion criteria may apply

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Study Description

Brief Summary:

The study evaluates CLR 131 in children, adolescents, and young adults with relapsed or refractory malignant solid tumors and lymphoma and recurrent or refractory malignant brain tumors for which there are no standard treatment options with curative potential.

Part A of this study is now closed and is exclusively enrolling on Part B for brain tumours. 

Detailed Description:

Even with standard, highly toxic multimodality therapies and salvage regimen, most pediatric patients with primary metastatic or relapsed solid tumors are confronted with a poor prognosis. For these patients there is currently no accepted successful treatment regimen. There is a need for new drugs, including targeted radiopharmaceuticals, preferably with cancer-specific uptake and broad applicability for these rare pediatric malignancies.

CLR 131 is a radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Cellectar Biosciences' novel cancer-targeted small-molecule compound (CLR1404) is radiolabeled with the isotope iodine-131 (I-131). CLR 131 has demonstrated tumor selective uptake across numerous adult and pediatric cancer cell types. Therapeutic efficacy has been demonstrated in various pediatric and adult-type cancer xenograft models, confirming the ability of CLR 131 to target tumors.

Based on the critical unmet medical need for effective agents with novel mechanisms of action in relapsed pediatric cancers and initial preclinical and clinical experience with radioiodinated CLR1404, Cellectar Biosciences has chosen to assess CLR 131 in a phase 1 pediatric trial.

Inclusion Criteria

All Patients

• Previously confirmed (histologically or cytologically) pediatric solid tumor (e.g., neuroblastoma, sarcoma), lymphoma (including Hodgkin's lymphoma), or malignant brain tumors that are clinically or radiographically suspected to be relapsed, refractory, or recurrent for which there are no standard treatment options with curative potential. Note: patients with diffuse intrinsic pontine glioma (DIPG) may enroll without histological or cytological confirmation. Patients with a diagnosis of ependymoma may enroll with prior Sponsor approval.
  • Refractory is defined as:
    • Lack of response (stable disease) or disease progression while on therapy
    • Disease progression within 3 months of cessation of therapy
• ≥ 10 years of age and ≤ 25 years of age at time of consent/assent
• If ≥ age 16 years, Karnofsky performance status of ≥ 60. If < age 16 years, Lansky performance status ≥ 60
• Platelets ≥ 75,000/µL (last transfusion, if any, must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
• Absolute neutrophil count ≥ 750/µL
• Hemoglobin ≥ 8 g/dL (last transfusion must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
• Using the bedside Schwartz formula, estimated GFR (creatinine clearance) > 60 ml/min/1.73m2
• Alanine aminotransferase < 3 × ULN
• Bilirubin < 2 × ULN
• Patients who have undergone autologous or allogeneic bone marrow transplant must be at least 3 months from transplant.
• Patients enrolling at total dose levels > 30 millicurie (mCi)/m2 must have availability or ability to collect an autologous hematopoietic stem cell back-up product prior to CLR 131 administration. At minimum, 2 x 10^6/kg cryopreserved CD34+ cells must be available.
• Patient or his or her legal representative is judged by the Investigator to have the initiative and means to be compliant with the protocol.

Patients with Recurrent or Refractory Brain Tumors

• At least 1 measurable lesion with longest diameter of at least 10 mm on any imaging sequence.
• Patients with previously known neurological deficits must be clinically stable for one week prior to enrollment and be able to complete all study related procedures. Patients with documented or newly diagnosed neurological deficits will be enrolled at the investigator's discretion.
• If patient receives steroids for neurological symptom control, the dose must be stable (unchanged for one week prior to registration) or on a steroid tapering regimen. Initiation of steroids per routine care immediately prior to CLR 131 dosing is acceptable.

Exclusion Criteria

• Patients receiving active treatment for central nervous system metastases or those that are likely to require active treatment during anticipated participation in this trial. Patients with stable brain metastases treated with steroids may enroll at the investigator's discretion
• For solid tumor and lymphoma patients only, central nervous system involvement unless previously treated with surgery, systemic therapy, or radiotherapy with the patient neurologically stable. Patients with metastatic brain tumors that have been previously treated are allowed, provided the patient is neurologically stable (determined at the investigator's discretion).
• Antitumor therapy or investigational therapy, within 2 weeks of dosing. For certain types of radiation (craniospinal, total abdominal, whole lung [spot irradiation to skull-based metastases is not considered craniospinal radiation for the purposes of this study]), at least 3 months must have elapsed. No washout is required for palliative focal radiation. NOTE: Patients participating in non-interventional clinical trials (i.e., non-drug) are allowed to participate in this trial
• Patients previously treated with iodine-131 (131I)-MIBG who have already received a cumulative I-131 dose > 54 mCi/kg or who would exceed 54 mCi/kg by participating in this trial, are not eligible.

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Study Description

Brief Summary:

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

Detailed Description:

ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumors. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumor patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected.

Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.

Phase I Secondary Objectives

• To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
• To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
• To estimate the antitumor activity of Onivyde plus talazoparib and Onivyde plus temozolomide.

Phase I Exploratory Objectives

• To describe the relationship between UGT1A1 genotype status with toxicity and response.
• To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumors.
• To measure ctDNA at different time points and evaluate its relationship with response to therapy.
• To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
• To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase II Primary Objectives

• To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.

Phase II Secondary Objectives

• To describe the toxicity of the treatment regimens.
• To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
• To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.

Phase II Exploratory Objectives

• To describe the relationship between UGT1A1 genotype status with toxicity and response.
• To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
• To describe ctDNA at different time points and the relationship with response to therapy.
• To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumors who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation.

Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation.

Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumor cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumors (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.

Inclusion Criteria

Patients must be > 12 months and < 30 years at the time of enrollment on study.

Phase I

• Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment are eligible. Patients must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Patients eligible for the expansion cohort, A2, will include non-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a CLIA-approved (or equivalent) facility.

Phase II

• Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Refractory disease is defined as progression during first line treatment or within 12 weeks of completion of first line treatment. Recurrent disease includes patients who received first line treatment and experienced disease progression at any time point >12 weeks from the completion of first line therapy.
• Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated for enrollment.

Disease status

• Patients must have either measurable or evaluable disease (see Section 7.0 for definitions). Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the OR endpoint.
• Performance level: Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Prior therapy

Phase I Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible.

Phase II

• Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse).
• Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
• Patients with solid tumors not metastatic to bone marrow:
• Peripheral absolute neutrophil count (ANC) >1,000/mm3 (1x109/L)
• Platelet count > 75,000/mm3 (75x109/L) (no transfusion within 7 days of enrollment)
• Hemoglobin > 9 g/dL (with or without support)

In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as <30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity.

• Adequate renal function defined as: Creatinine clearance or radioisotope GFR > 60ml/min/1.73m2 or a serum creatinine maximum based on age/sex: age 6months to <1 year, creatinine 0.4; 1 to < 2 years, creatinine 0.6; 2 < 6 years, creatinine 0.8; 6 < 10 years, creatinine 1; 10 to <13 years, creatinine 1.2; 13 to < 16 years creatinine 1.5 (males) or 1.4 (females); > 16 years, creatinine 1.7 (males) 1.4 (females)
• Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration <5x the institutional ULN, a total bilirubin concentration <2x the institutional ULN for age, and serum albumin > 2g/dL.
• Adequate pulmonary function defined as no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.
• Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
• Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy).
• 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.
• Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
• Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment.
• Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal RT, 131I-mIBG therapy or substantial bone marrow irradiation (e.g., >50% pelvis irradiation).
• Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study.
• Female or male participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment.

Exclusion Criteria

Pregnant or breastfeeding

• Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose.
• Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).

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Study Description

This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, 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. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Inclusion Criteria

• Patients must be newly diagnosed and have:

  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:

    • Classical histologic type (non LC/A) WNT medulloblastoma
    • Positive nuclear beta-catenin by immunohistochemistry (IHC)
    • Positive for CTNNB1 mutation
    • Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology
  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status; patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated; patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1; patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with gadolinium must be performed
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (day 0)
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions)
• 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:
  • 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)
  • 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
  • 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
  • 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)
  • >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
    • The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L
• Central nervous system function defined as:
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and neurocognitive assessments; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted
• All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids
• Pregnancy and Breast Feeding
  • Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
• Patients with a history of moderate to profound intellectual disability (i.e., intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team.

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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.

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Study Description

This is a phase 1/2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study.

Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN.

This study includes four groups:

All patients except patients with PN must have failed at least one line of treatment.

The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway.rmore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

Inclusion Criteria

1. Signed written informed consent Prior to study participation, written informed consent from participants, or in the case of minors, written permission (informed consent) from parents, guardians, or legally acceptable representatives must be obtained according to local laws and regulations.
2. Assent Assent from minor participants should be obtained per local laws and regulations and should be documented in accordance with local requirements.
3. Study activities compliance. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast-enhanced MRI.
4. Age Patient must be aged ≥ 1 month (corrected age) to ≤ 25 years at the time of study enrollment
5. Study group Participants must belong to one of the following groups to be eligible. Group 1: NF1 with progressing/refractory LGG Group 2: NF1 with PN Group 3: Progressing/refractory LGG with KIAA 1549-BRAF fursion Group 4: Progressing/refractory glioma with activation of the MAPK/ERK pathway who do not meet criteria for other study groups
6. Tumor Tissue Sample Tumor tissue will be required for all patients (fresh tissue recommended when available). Patients with NF1 and LGG or PN can still be enrolled without tissue if no surgery or biopsy was conducted.

7 Previous MRI At least two previous MRIS fro Group 1, 3, 4 and one previous MRI for Group 2 must be available for central review.

8. Prior therapy Participants must have failed at least one line of treatment including chemotherapy and/or radiation therapy except for plexiform neurofibroma (since there is no recognized standard treatment for his tumor).

9. Prior therapy toxicity Patients must have recovered to grade ≤ 1 from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to enrollment. Toxicities will be graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

10. Prior therapy timeline Participants having previously received a chemotherapy agent(s) and/or radiation must conform to the timeline described below. There is no limitation on the number of previous treatments or cycles received.

• An interval of at least 28 days after the last dose of a myelosuppressive chemotherapy, and at least 42 days after the last dose of Nitrosoureas is required prior to starting trametinib.
• An interval of at least 28 days after the last dose of any biologic agents including monoclonal antibody treatment, immunotherapy, viral therapy and other investigational agent is required prior to starting trametinib.
• An interval of at least 84 days after the end of the radiation therapy is required prior to starting trametinib.

• An interval of at least 48 hours for short-acting colony stimulating factor agents and 10 days interval for long-acting colony stimulating factor agents are required prior to starting trametinib.

  11. Life expectancy Patients must have a life expectancy of greater than 6 months.

  12. Performance level Patients must have a performance status corresponding to a Lansky/Karnofsky score ≥50.

  13. Organ Function Requirements

Participants must have normal organ and marrow function as defined below:

• Total leukocytes ≥ 3,000/µL
• Absolute neutrophil count (ANC) ≥ 1, 000/µL
• Hemoglobin > 80 g/l (transfusion independent within last 2 weeks)
• Platelet count ≥ 100,000/µL (transfusion independent within last 2 weeks)
• Total bilirubin ≤ 1.5 times the ULN within normal institutional limits for age
• Alanine Aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)*
• Creatinine serum within normal institutional limits for age OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
• Creatine phosphokinase ≤ 2x ULN
• A cardiac function defined as Corrected QT (QTcB) interval < 480 msec and LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO).

• Blood pressure must be smaller or equal to the 95th percentile for patient's age, height and gender.

  • For uniformity reasons, the ULN for ALT will be 45 U/L in this study

    14. Reproductive status Children of childbearing and child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males and females treated or enrolled in this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration. Furthermore, females of childbearing potential (older than 10 years old for this study) must have a negative serum pregnancy test within 7 days prior to the start of study drug. A urine pregnancy test will be done according to evaluation calendar at at 30 days and at 6 months following the last does of study medications.

    15. Administration of oral medication Patients must be able to ingest and retain enterally (per os, nasogastric tube or gastrostomy) administered medication and be free of any clinically significant gastrointestinal abnormalities limiting the absorption of the medication. Tablets cannot be crushed. If the patient cannot swallow tablets, the liquid form should then be used.

SPECIFIC INCLUSION CRITERIA

Participants must belong to one of the following groups to be eligible.

• Group 1: NF1 with Progressing/Refractory LGG (42 patients).
• Group 2: NF1 with Progressing/Refractory PN (46 patients).
• Group 3: Progressing/Refractory LGG with KIAA1549-BRAF fusion (42 patients).
• Group 4: Progressing/Refractory CNS Glioma with activation of the MAPK/ERK pathway who do not meet criteria of other study groups (20 patients).

Exclusion Criteria

1. Other investigational agents Patients who are receiving any other investigational agents.
2. Cardiac exclusion criteria Patients who have an ejection fraction inferior to the institution LLN, a QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 39% are not eligible for enrolment.
3. Presence of another malignancy Patient has any other malignancy except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
4. Previous MEK inhibitor treatment Participants previously treated with a MEK inhibitor who showed less than stable disease during treatment.
5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation.
6. Other uncontrollable medical disease Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, chronic renal disease or active uncontrolled infection), has a chronic liver disease (i.e., chronic active hepatitis and cirrhosis), 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.
7. Known HIV infection Patient has a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
8. Previous surgery Patients who had major surgery within 2 weeks prior to study entry.
9. Allergy History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib.
10. Previous history of non-compliance Patients with a previous significant history of non-compliance to their treatment or medical regimen.
11. Pregnant or breastfeeding patients Pregnant or breastfeeding female patients are not eligible for this study.

Publications

Perreault S, Larouche V, Tabori U, Hawkin C, Lippé S, Ellezam B, Décarie JC, Théoret Y, Métras MÉ, Sultan S, Cantin É, Routhier MÈ, Caru M, Legault G, Bouffet É, Lafay-Cousin L, Hukin J, Erker C, Jabado N. A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC Cancer. 2019 Dec 27;19(1):1250. doi: 10.1186/s12885-019-6442-2.

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Centres

Study Description

Brief Summary:

FIREFLY-1 is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma harboring a known BRAF alteration.

Detailed Description:

Approximately 60 pediatric patients will be treated with DAY101, an oral pan-RAF inhibitor, for a planned period of 26 cycles will be treated with DAY101 for a planned period of 26 cycles (approximately 24 months).

DAY101 will be administered at the recommended Phase 2 dose (RP2D) of 420 mg/m2 (not to exceed 600 mg) orally once weekly (QW) for each 28-day treatment cycle.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle. Patients will continue on DAY101 until radiographic evidence of disease progression by RANO criteria as determined by treating investigator, unacceptable toxicity, patient withdrawal of consent, or death.

Patients who have radiographic evidence of disease progression may be allowed to continue DAY101 if, in the opinion of the investigator and approval by the Sponsor, the patient is deriving clinical benefit from continuing study treatment. Disease assessments for patients being treated beyond progression should continue as per regular schedule.

DAY101 is an oral pan-RAF inhibitor administered as an oral tablet at 420 mg/m2 (not to exceed 600 mg).

Inclusion Criteria

• Age 6 months to 25 years with a relapsed or progressive LGG or solid tumor with known activating RAF alteration (BRAF or CRAF/RAF1 fusion or BRAF V600 mutations (LGG only))
• Confirmation of histopathologic diagnosis of LGG or solid tumor and molecular diagnosis of activating RAF alteration (BRAF or CRAF/RAF1 fusion or BRAF V600 mutations (LGG only))
• Must have received at least one line of systemic therapy and have evidence of radiographic progression
• Must have at least 1 measurable lesion as defined by RANO criteria

Exclusion Criteria

• Patient's tumor has additional previously-known activating molecular alterations
• Patient has symptoms of clinical progression in the absence of radiographic progression
• Known or suspected diagnosis of neurofibromatosis type 1 (NF-1)
• Other inclusion/exclusion criteria as stipulated by protocol may apply

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Centres

Study Description

This phase III trial compares the effect of vinorelbine with vincristine, dactinomycin, and cyclophosphamide (VAC) followed by vinorelbine and cyclophosphamide versus VAC followed by vinorelbine and cyclophosphamide for the treatment of high risk rhabdomyosarcoma. Chemotherapy drugs, such as vinorelbine, vincristine, dactinomycin, and cyclophosphamide, 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. Giving vinorelbine and VAC may kill more tumor cells. Adding maintenance therapy (vinorelbine and cyclophosphamide) after VAC therapy, with or without vinorelbine, may help get rid of the cancer and/or lower the chance that the cancer comes back.

PRIMARY OBJECTIVE:

I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS) treated with vinorelbine, dactinomycin and cyclophosphamide (VINO AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patients treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by 24 weeks of VINO-CPO maintenance therapy.

SECONDARY OBJECTIVES:

I. To assess the safety and feasibility of administering VINO-AC in newly diagnosed patients with HR-RMS.

II. To describe the toxicity experience of patients with HR-RMS treated with VINO-AC compared to VAC.

III. To compare overall survival (OS) of patients with HR-RMS treated with VINO AC followed by 24 weeks of VINO-CPO maintenance therapy to that of patients treated with VAC followed by 24 weeks of VINO-CPO maintenance therapy.

IV. To compare objective radiologic response rates at week 12 between patients with HR-RMS treated with VINO-AC to those treated with VAC.

V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFS in patients with HR-RMS when compared to historical controls.

EXPLORATORY OBJECTIVE:

I. To collect serial blood samples and tumor tissue for banking at baseline, during treatment, at the end of therapy, and at the time of progression for future tumor and liquid biopsy studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

• ARM A: Patients receive vincristine sulfate intravenously (IV) on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.
• ARM B: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

MAINTENANCE: All patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide orally (PO) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for years 2-3, and every 6 months for year 4.

Inclusion Criteria

• Patients must be =< 50 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification are eligible to enroll on the study based upon Stage, Group, and age, as below. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) Classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants
  • ERMS
    • Stage 4, group IV, >= 10 years of age
  • ARMS
    • Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study
• 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:
  • 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
  • If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x ULN for age
• 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

Additional inclusion and exclusion criteria may apply 

Exclusion Criteria

• Patients with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed
• Patients with central nervous system involvement of RMS as defined below:
  • Malignant cells detected in cerebrospinal fluid
  • Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed).
  • Diffuse leptomeningeal disease
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment.
  • Note: the following exception:
    • Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Additional inclusion and exclusion criteria may apply