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.
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
Drug | Synonyms | Arms |
---|
Idasanutlin | RG7388 | ALL: Idasanutlin + Venetoclax |
Venetoclax | RG7601, GDC-0199, ABT-199 | ALL: Idasanutlin + Venetoclax |
Cyclophosphamide | | Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan |
Topotecan | | Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan |
Fludarabine | | AML: Idasanutlin + Fludarabine + Cytarabine |
Cytarabine | | AML: Idasanutlin + Fludarabine + Cytarabine |
Intrathecal Chemotherapy | | ALL: 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
Name | Type | Description | Interventions |
---|
Dose Escalation: Solid Tumors: Idasanutlin Single Agent | Experimental | | |
Neuroblastoma: Idasanutlin + Venetoclax | Experimental | | |
Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan | Experimental | | - Idasanutlin
- Cyclophosphamide
- Topotecan
|
AML: Idasanutlin + Venetoclax | Experimental | | - Idasanutlin
- Venetoclax
- Intrathecal Chemotherapy
|
AML: Idasanutlin + Fludarabine + Cytarabine | Experimental | | - Idasanutlin
- Fludarabine
- Cytarabine
- Intrathecal Chemotherapy
|
ALL: Idasanutlin + Venetoclax | Experimental | | - Idasanutlin
- Venetoclax
- Intrathecal Chemotherapy
|
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
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
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, Severity Graded 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) |
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: | Recruiting |
Lead Sponsor: | Hoffmann-La Roche |
Last Updated
August 17, 2021