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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

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ClinicalTrials.gov Identifier: NCT04029688
Recruitment Status : Recruiting
First Posted : July 23, 2019
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE July 19, 2019
First Posted Date  ICMJE July 23, 2019
Last Update Posted Date December 6, 2019
Estimated Study Start Date  ICMJE December 26, 2019
Estimated Primary Completion Date May 16, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2019)
  • 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) ]
  • Number of Participants with at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) [ Time Frame: From Baseline until 30 days after study treatment discontinuation (approximately 1 year) ]
  • Number of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (one cycle is 28 days) ]
  • Parts 2 and 3: Percentage of Participants with TP53 Wild-Type (WT) Neuroblastoma Achieving an Objective Response [ Time Frame: 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) ]
    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).
  • Parts 2 and 3: Complete Remission Rate Within 2 Cycles of Study Treatment in Participants with TP53 WT Leukemia [ 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) ]
    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).
  • Parts 2 and 3: Percentage of Participants with TP53 WT ALL who are Minimal Residual Disease (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) ]
    MRD-negative is defined as ALL with <0.01% leukemic blasts in bone marrow identifiable by flow cytometry.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT04029688 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2019)
  • 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) ]
    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.
  • 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) ]
    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.
  • 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) ]
    Progression-free survival as determined by the investigator using INRC for neuroblastoma or RECIST v1.1 for other solid tumors.
  • 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) ]
    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.
  • 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) ]
  • 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) ]
  • 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) ]
    Objective response is defined as achieving CR, CRi, or CRp.
  • 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) ]
  • 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) ]
    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).
  • 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) ]
  • 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) ]
  • 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) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphoblastic Leukemia (ALL)
  • Neuroblastoma
  • Solid Tumors
Intervention  ICMJE
  • Drug: Idasanutlin
    Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.
    Other Name: RG7388
  • 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.
    Other Names:
    • RG7601
    • GDC-0199
    • ABT-199
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Study Arms  ICMJE
  • Experimental: Dose Escalation: Solid Tumors: Idasanutlin Single Agent
    Intervention: Drug: Idasanutlin
  • Experimental: Neuroblastoma: Idasanutlin + Venetoclax
    Interventions:
    • Drug: Idasanutlin
    • Drug: Venetoclax
  • Experimental: Neuroblastoma: Idasanutlin + Cyclophosphamide/Topotecan
    Interventions:
    • Drug: Idasanutlin
    • Drug: Cyclophosphamide
    • Drug: Topotecan
  • Experimental: AML: Idasanutlin + Venetoclax
    Interventions:
    • Drug: Idasanutlin
    • Drug: Venetoclax
    • Drug: Intrathecal Chemotherapy
  • Experimental: AML: Idasanutlin + Fludarabine/Cytarabine
    Interventions:
    • Drug: Idasanutlin
    • Drug: Fludarabine
    • Drug: Cytarabine
    • Drug: Intrathecal Chemotherapy
  • Experimental: ALL: Idasanutlin + Venetoclax
    Interventions:
    • Drug: Idasanutlin
    • Drug: Venetoclax
    • Drug: Intrathecal Chemotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 19, 2019)
220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 16, 2024
Estimated Primary Completion Date May 16, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 end-organ function, as defined in the protocol
  • 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: GO40871 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. Only) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Canada,   France,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04029688
Other Study ID Numbers  ICMJE GO40871
2018-004579-11 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP