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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 Leukemias or Solid Tumors

NCT04029688

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • B-Cell Acute Lymphoblastic Leukemia
  • Malignant Solid Tumor
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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 Leukemias or Solid Tumors
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: GO40871
  • SECONDARY ID: 2018-004579-11
  • NCT ID: NCT04029688

Conditions

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

Interventions

DrugSynonymsArms
IdasanutlinRG7388Dose Escalation: Solid Tumors: Idasanutlin Single Agent
VenetoclaxRG7601, GDC-0199, ABT-199Neuroblastoma: Idasanutlin + Venetoclax
CyclophosphamideNeuroblastoma: Idasanutlin + Cyclophosphamide/Topotecan
TopotecanNeuroblastoma: Idasanutlin + Cyclophosphamide/Topotecan
FludarabineAML: Idasanutlin + Fludarabine/Cytarabine
CytarabineAML: Idasanutlin + Fludarabine/Cytarabine
Intrathecal ChemotherapyAML: Idasanutlin + Venetoclax

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: Solid Tumors: Idasanutlin Single AgentExperimental
  • Idasanutlin
Neuroblastoma: Idasanutlin + VenetoclaxExperimental
  • Idasanutlin
  • Venetoclax
Neuroblastoma: Idasanutlin + Cyclophosphamide/TopotecanExperimental
  • Idasanutlin
  • Cyclophosphamide
  • Topotecan
AML: Idasanutlin + VenetoclaxExperimental
  • Idasanutlin
  • Venetoclax
  • Intrathecal Chemotherapy
AML: Idasanutlin + Fludarabine/CytarabineExperimental
  • Idasanutlin
  • Fludarabine
  • Cytarabine
  • Intrathecal Chemotherapy
ALL: Idasanutlin + VenetoclaxExperimental
  • Idasanutlin
  • Venetoclax
  • Intrathecal Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          -  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 hematologic and end-organ function

          -  Able to swallow tablets or liquid

          -  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 function

          -  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, and OATP1B1/B3

          -  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
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with at Least One Adverse Event, Including Non-Serious and Serious Adverse Events
Time Frame:From Baseline (Screening Days -28 to -1) until 30 days after study treatment discontinuation (approximately 1 year)
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Clinical Benefit Rate (CBR) in Participants with Solid Tumors (Including Neuroblastoma)
Time Frame: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)
Safety Issue:
Description: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.
Measure:Duration of Objective Response in Participants with Solid Tumors (Including Neuroblastoma)
Time Frame: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)
Safety Issue:
Description: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.
Measure:Progression-Free Survival in Participants with Solid Tumors (Including Neuroblastoma)
Time Frame:From initiation of study drug to the first documented occurrence of disease progression or death from any cause, whichever occurs first (approximately 1 year)
Safety Issue:
Description:Progression-free survival as determined by the investigator using INRC for neuroblastoma or RECIST v1.1 for other solid tumors.
Measure:Percentage of Participants with Solid Tumors (Including Neuroblastoma) Achieving an Objective Response Irrespective of TP53 Mutation Status
Time Frame: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)
Safety Issue:
Description: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.
Measure:Overall Survival
Time Frame:From initiation of study drug to death from any cause or end of study, whichever occurs first (up to 5 years)
Safety Issue:
Description:
Measure:Number of Participants with Leukemia Receiving Transplant After Study Treatment
Time Frame:Every 3 months from study treatment discontinuation until death or end of study, whichever occurs first (up to 5 years)
Safety Issue:
Description:
Measure:Duration of Objective Response in Participants with Leukemia
Time Frame: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)
Safety Issue:
Description:Objective response is defined as achieving CR, CRi, or CRp.
Measure:Event-Free Survival in Participants with Leukemia
Time Frame: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)
Safety Issue:
Description:
Measure:Complete Remission Rate in Participants with Leukemia Irrespective of TP53 Mutation Status
Time Frame:Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days)
Safety Issue:
Description: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).
Measure:Percentage of Participants with TP53 WT AML who are MRD-Negative Within 2 Cycles of Study Treatment
Time Frame:Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days)
Safety Issue:
Description:
Measure:Plasma Concentration of Idasanutlin Over Time, as a Single Agent and in Combination with Chemotherapy or Venetoclax
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of Venetoclax Over Time
Time Frame: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)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

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