A Study Evaluating the Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in Treatment of Pediatric and Young Adult Participants With Relapsed/Refractory Acute Leukemias or Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin, administered as a single agent or in combination with chemotherapy or venetoclax, in pediatric and young adult participants with acute leukemias or solid tumors. This study is divided into three parts: Part 1 will begin with dose escalation of idasanutlin as a single agent in pediatric participants with relapsed or refractory solid tumors to identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and to characterize dose-limiting toxicities (DLTs). Following MTD/MAD identification, three separate safety run-in cohorts in neuroblastoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) will be conducted to identify the recommended Phase 2 dose (RP2D) of idasanutlin in each combination, with chemotherapy or venetoclax. Part 2 will evaluate the safety and early efficacy of idasanutlin in combination with chemotherapy or venetoclax in newly enrolled pediatric and young adult participants in neuroblastoma, AML,and ALL cohorts at idasanutlin RP2D. Part 3 will potentially be conducted as an additional expansion phase of the idasanutlin combination cohorts in neuroblastoma, AML, or ALL for further response and safety assessment.

Official Title
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A Phase I/II, Multicenter, Open-Label, Multi-Arm Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in the Treatment of Pediatric and Young Adult Patients With Relapsed/Refractory Acute Leukemias or Solid Tumors

Conditions
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Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Neuroblastoma, Solid Tumors

Intervention / Treatment
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* Drug: Idasanutlin
* Drug: Venetoclax
* Drug: Cyclophosphamide
* Drug: Topotecan
* Drug: Fludarabine
* Drug: Cytarabine
* Drug: Intrathecal Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participants ages are < 18 for part 1a, < 30 for Parts 1b. 2 and 3 Study Part 1 (single-agent therapy dose escalation): histologically confirmed diagnosis of neuroblastoma or other solid tumor that has progressed or recurred despite standard therapy, and for which there is no therapy proven to prolong survival with an acceptable quality of life Study Part 1 (combination safety run-in), Study Part 2 (initial expansion), and Study Part 3 (additional expansion): histologically confirmed diagnosis of neuroblastoma, AML, or precursor-B ALL that has progressed or recurred despite, or is refractory to, standard therapy Adequate performance status: Participants <16 years of age: Lansky greater than or equal to (≥)50%; Patients ≥16 years of age: Karnofsky ≥50% Adequate end-organ function, as defined in the protocol For females of childbearing potential: agreement to remain abstinent, use contraception, agreement to refrain from donating eggs. Females must remain abstinent or use two methods of contraception with a failure rate of <1% per year during the treatment and follow-up period (variable depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception For males: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, with a female partner of childbearing potential or pregnant female partner, males must remain abstinent or use a condom during the treatment period and for follow-up period (variable, depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception Additional Inclusion Criteria for Participants with Solid Tumors (including Neuroblastoma) At least one evaluable or measurable radiological site of disease as defined by standard criteria for the participant's tumor type, or measurable bone marrow disease by morphology Adequate hematologic end-organ function, as defined in the protocol Tumor tissue from relapsed disease Additional Inclusion Criteria for Patients with Leukemia Bone marrow with ≥5% lymphoblasts by morphologic assessment at screening Available bone marrow aspirate or biopsy from screening Exclusion Criteria: Primary Central Nervous System (CNS) tumors Symptomatic CNS metastases that result in a neurologically unstable clinical state or require increasing doses of corticosteroids or local CNS-directed therapy to control the CNS disease CNS3 leukemia Acute promyelocytic leukemia White blood cell count >50 × 10^9 cells/Liter (L) Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome Burkitt-type acute lymphoblastic leukemia T-cell lymphoblastic leukemia Prior treatment with a MDM2 antagonist Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm) Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant Any uncontrolled medical condition or other identified abnormality that precludes the patient's safe participation in and completion of the study Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to initiation of study treatment Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy for anti-neoplastic intent within 30 days prior to initiation of study treatment I-131 meta-iodobenzylguanidine (MIBG) therapy within 6 weeks prior to initiation of study treatment Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of study treatment initiation Radiotherapy within 3 weeks prior to study treatment initiation Specific restrictions are applicable for patients treated with drugs interacting with CYP2C8, CYP3A4, OATP1B1/B3, and P-gp Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study treatment initiation Underwent major surgical procedure within 21 days of study treatment initiation, or anticipate need for major surgical procedure during the course of the study

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Solid Tumors: Idasanutlin Single Agent<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;|
| Experimental: Neuroblastoma: Idasanutlin + Venetoclax<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;Drug: Venetoclax<br>* Venetoclax will be administered orally at the adult dose equivalent (adjusted by body weight) of 400 milligrams (mg) in participants with neuroblastoma and the adult dose equivalent of 600 mg in participants with leukemia.<br>* Other names: ABT-199;|
| Experimental: Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered once daily on Days 1-5 of each 28-day cycle at 250 milligrams per meter squared of body surface area (mg/m^2) as an intravenous (IV) infusion.<br>Drug: Topotecan<br>* Topotecan will be administered once daily on Days 1-5 of each 28-day cycle at 0.75 mg/m^2 as an IV infusion.<br>|
| Experimental: AML: Idasanutlin + Venetoclax<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;Drug: Venetoclax<br>* Venetoclax will be administered orally at the adult dose equivalent (adjusted by body weight) of 400 milligrams (mg) in participants with neuroblastoma and the adult dose equivalent of 600 mg in participants with leukemia.<br>* Other names: ABT-199;Drug: Intrathecal Chemotherapy<br>* All participants with leukemia, irrespective of arm, will receive intrathecal chemotherapy on Day 1 of each 28-day treatment cycle. Intrathecal chemotherapy will consist of either single-agent cytarabine or methotrexate, or a combination of methotrexate, cytarabine, and hydrocortisone, at appropriate age-based dosing as specified in the protocol.<br>|
| Experimental: AML: Idasanutlin + Fludarabine + Cytarabine<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;Drug: Fludarabine<br>* Fludarabine will be administered once daily on Days 1-5 of each 28-day treatment cycle at 30 mg/m^2 as an IV infusion.<br>Drug: Cytarabine<br>* Cytarabine will be administered once daily on Days 1-5 of each 28-day treatment cycle at 2000 mg/m^2 as an IV infusion.<br>Drug: Intrathecal Chemotherapy<br>* All participants with leukemia, irrespective of arm, will receive intrathecal chemotherapy on Day 1 of each 28-day treatment cycle. Intrathecal chemotherapy will consist of either single-agent cytarabine or methotrexate, or a combination of methotrexate, cytarabine, and hydrocortisone, at appropriate age-based dosing as specified in the protocol.<br>|
| Experimental: ALL: Idasanutlin + Venetoclax<br> | Drug: Idasanutlin<br>* Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.<br>* Other names: RG7388;Drug: Venetoclax<br>* Venetoclax will be administered orally at the adult dose equivalent (adjusted by body weight) of 400 milligrams (mg) in participants with neuroblastoma and the adult dose equivalent of 600 mg in participants with leukemia.<br>* Other names: ABT-199;Drug: Intrathecal Chemotherapy<br>* All participants with leukemia, irrespective of arm, will receive intrathecal chemotherapy on Day 1 of each 28-day treatment cycle. Intrathecal chemotherapy will consist of either single-agent cytarabine or methotrexate, or a combination of methotrexate, cytarabine, and hydrocortisone, at appropriate age-based dosing as specified in the protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with at Least One Adverse Event, Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) |  | From Baseline until 30 days after study treatment discontinuation (approximately 1 year) | 
| Number of Participants with Dose-Limiting Toxicities (DLTs) |  | Cycle 1 (one cycle is 28 days) | 
| Parts 2 and 3: Percentage of Participants with TP53 Wild-Type (WT) Neuroblastoma Achieving an Objective Response | Objective response is defined as complete response or partial response at any time during study treatment, on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to International Neuroblastoma Response Criteria (INRC). | Baseline, once between Days 22-28 of Cycles 2, 4, 6, 8, and then every fourth cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Parts 2 and 3: Complete Remission Rate Within 2 Cycles of Study Treatment in Participants with TP53 WT Leukemia | The complete remission rate is defined as the percentage of participants with morphologic complete remission (CR), CR with incomplete hematological recovery (CRi), or CR with incomplete platelet count recovery (CRp). | Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Parts 2 and 3: Percentage of Participants with TP53 WT ALL who are Minimal Residual Disease (MRD)-Negative Within 2 Cycles of Study Treatment |  | Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) in Participants with Solid Tumors (Including Neuroblastoma) | CBR is defined as the percentage of participants achieving confirmed complete response, partial response, or stable disease on two consecutive occasions ≥4 weeks apart during the total study period, using INRC for neuroblastoma or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for other solid tumors. | Baseline, once between Days 22-28 of either Cycles 1, 3, 5, and 7 or Cycles 2, 4, 6, 8, and then every fourth cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Duration of Objective Response in Participants with Solid Tumors (Including Neuroblastoma) | Objective response is defined as complete response or partial response at any time during study treatment, on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to INRC or RECIST v1.1 for other solid tumors. | From the first tumor assessment that supports an objective response to the time of disease progression or death from any cause, whichever occurs first (approximately 1 year) | 
| Progression-Free Survival in Participants with Solid Tumors (Including Neuroblastoma) | Progression-free survival as determined by the investigator using INRC for neuroblastoma or RECIST v1.1 for other solid tumors. | From initiation of study drug to the first documented occurrence of disease progression or death from any cause, whichever occurs first (approximately 1 year) | 
| Percentage of Participants with Solid Tumors (Including Neuroblastoma) Achieving an Objective Response Irrespective of TP53 Mutation Status | Objective response is defined as complete response or partial response at any time during study treatment, on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to INRC or RECIST v1.1 for other solid tumors. | Baseline, once between Days 22-28 of either Cycles 1, 3, 5, and 7 or Cycles 2, 4, 6, 8, and then every fourth cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Overall Survival |  | From initiation of study drug to death from any cause or end of study, whichever occurs first (up to 5 years) | 
| Number of Participants with Leukemia Receiving Transplant After Study Treatment |  | Every 3 months from study treatment discontinuation until death or end of study, whichever occurs first (up to 5 years) | 
| Duration of Objective Response in Participants with Leukemia | Objective response is defined as achieving CR, CRi, or CRp. | From the first tumor assessment that supports an objective response to the time of disease progression or death from any cause, whichever occurs first (approximately 1 year) | 
| Event-Free Survival in Participants with Leukemia |  | From initiation of study drug to first documented occurrence of M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi after Cycle 2, disease progression, relapse after achieving CR/CRp/CRi, or death from any cause, whichever occurs first (about 1 year) | 
| Complete Remission Rate in Participants with Leukemia Irrespective of TP53 Mutation Status | The complete remission rate is defined as the percentage of participants with morphologic complete remission (CR), CR with incomplete hematological recovery (CRi), or CR with incomplete platelet count recovery (CRp). | Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Percentage of Participants with TP53 WT AML who are MRD-Negative Within 2 Cycles of Study Treatment |  | Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Plasma Concentration of Idasanutlin Over Time, as a Single Agent and in Combination with Chemotherapy or Venetoclax |  | Days 1, 2, 5, 8, 15, and 22 of Cycle 1; Day 1 of Cycles 2, 3, 8, 12, 16, and every 8 cycles thereafter until study treatment discontinuation (one cycle is 28 days) | 
| Plasma Concentration of Venetoclax Over Time |  | Days 1, 2, 5, and 15 of Cycle 1; Day 1 of Cycles 2, 3, 8, 12, 16, and every 8 cycles thereafter until study treatment discontinuation (one cycle is 28 days) |