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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 : Not yet recruiting
First Posted : July 23, 2019
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Neuroblastoma Solid Tumors Drug: Idasanutlin Drug: Venetoclax Drug: Cyclophosphamide Drug: Topotecan Drug: Fludarabine Drug: Cytarabine Drug: Intrathecal Chemotherapy Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : October 26, 2019
Estimated Primary Completion Date : May 16, 2024
Estimated Study Completion Date : May 16, 2024


Arm Intervention/treatment
Experimental: Dose Escalation: Solid Tumors: Idasanutlin Single Agent Drug: Idasanutlin
Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.
Other Name: RG7388

Experimental: Neuroblastoma: Idasanutlin + Venetoclax 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

Experimental: Neuroblastoma: Idasanutlin + Cyclophosphamide/Topotecan 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: 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.

Experimental: AML: Idasanutlin + Venetoclax 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: 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.

Experimental: AML: Idasanutlin + Fludarabine/Cytarabine 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: 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.

Experimental: ALL: Idasanutlin + Venetoclax 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: 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.




Primary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. Number of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (one cycle is 28 days) ]
  4. 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).

  5. 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).

  6. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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) ]
  6. 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) ]
  7. 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.

  8. 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) ]
  9. 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).

  10. 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) ]
  11. 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) ]
  12. 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04029688


Contacts
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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

Locations
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United States, Arkansas
Arkansas Children's Hospital Research Institute Not yet recruiting
Little Rock, Arkansas, United States, 72202
Spain
Hospital Sant Joan De Deu Not yet recruiting
Esplugues De Llobregas, Barcelona, Spain, 08950
Hospital Infantil Universitario Nino Jesus Not yet recruiting
Madrid, Spain, 28009
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04029688     History of Changes
Other Study ID Numbers: GO40871
2018-004579-11 ( EudraCT Number )
First Posted: July 23, 2019    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Venetoclax
Leukemia
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neuroblastoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cytarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Topotecan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating