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

NCT ID: NCT04029688

Last Updated: 2024-12-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-27
• Study Completion Date: 2024-05-06

Brief Summary

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.

Conditions

Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Neuroblastoma; Solid Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation: Solid Tumors: Idasanutlin Single Agent

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Neuroblastoma: Idasanutlin + Venetoclax

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Venetoclax

Intervention Type: DRUG

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.

Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Cyclophosphamide

Intervention Type: DRUG

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.

Topotecan

Intervention Type: DRUG

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.

AML: Idasanutlin + Venetoclax

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Venetoclax

Intervention Type: DRUG

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.

Intrathecal Chemotherapy

Intervention Type: DRUG

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.

AML: Idasanutlin + Fludarabine + Cytarabine

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Fludarabine

Intervention Type: DRUG

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.

Cytarabine

Intervention Type: DRUG

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.

Intrathecal Chemotherapy

Intervention Type: DRUG

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.

ALL: Idasanutlin + Venetoclax

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Venetoclax

Intervention Type: DRUG

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.

Intrathecal Chemotherapy

Intervention Type: DRUG

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.

Interventions

Idasanutlin

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Intervention Type: DRUG

Venetoclax

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.

Intervention Type: DRUG

Cyclophosphamide

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.

Intervention Type: DRUG

Topotecan

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.

Intervention Type: DRUG

Fludarabine

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.

Intervention Type: DRUG

Cytarabine

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.

Intervention Type: DRUG

Intrathecal Chemotherapy

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.

Intervention Type: DRUG

Other Intervention Names

RG7388; RG7601; GDC-0199; ABT-199

Eligibility Criteria

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

• 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

• 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

• Minimum Eligible Age: 0 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Arkansas Children's Hospital Research Institute

Little Rock, Arkansas, United States

Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology

Palo Alto, California, United States

Arnold Palmer Hosp-Children

Orlando, Florida, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Alberta Children'S Hospital

Calgary, Alberta, Canada

Centre Leon Berard

Lyon, , France

Institut Curie

Paris, , France

Prinses Maxima Centrum

Utrecht, , Netherlands

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, Spain

Hospital Infantil Universitario Nino Jesus

Madrid, , Spain

Birmingham Children's Hospital

Birmingham, , United Kingdom

The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit

Newcastle upon Tyne, , United Kingdom

Royal Marsden Hospital; Pediatric Unit

Surrey, , United Kingdom

Countries

United States; Canada; France; Netherlands; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2018-004579-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GO40871

Identifier Type: -

Identifier Source: org_study_id