A 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 Participants With Relapsed/Refractory Acute Le

• Status: Recruiting
• Trial end date: 2024-05-16
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Hoffmann-La Roche
• Treatments: Cyclophosphamide; Cytarabine; Fludarabine; Fludarabine phosphate; Topotecan; Venetoclax

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

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