A Study Evaluating the Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in Treatment of Pediatric and Young Adult Participants With Relapsed/Refractory Acute Leukemias or Solid Tumors

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04029688

Collaborator

(none)

183

Enrollment

Locations

Arms

51.6

Anticipated Duration (Months)

9.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

183 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

Actual Study Start Date :

Jan 27, 2020

Anticipated Primary Completion Date :

May 16, 2024

Anticipated Study Completion Date :

May 16, 2024

Arms and Interventions

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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

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) [From Baseline until 30 days after study treatment discontinuation (approximately 1 year)]
Number of Participants with Dose-Limiting Toxicities (DLTs) [Cycle 1 (one cycle is 28 days)]
Parts 2 and 3: Percentage of Participants with TP53 Wild-Type (WT) Neuroblastoma Achieving an Objective Response [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 [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 [Baseline, once on Day 28 of Cycles 1 and 2, and every second cycle thereafter until study treatment discontinuation (one cycle is 28 days)]

Secondary Outcome Measures

Clinical Benefit Rate (CBR) in Participants with Solid Tumors (Including Neuroblastoma) [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) [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) [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 [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 [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 [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 [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 [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 [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 [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 [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 [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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	Arkansas Children's Hospital Research Institute	Little Rock	Arkansas	United States	72202
3	Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology	Palo Alto	California	United States	94304
4	Arnold Palmer Hosp-Children	Orlando	Florida	United States	32806
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
6	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
7	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
8	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
9	Huntsman Cancer Institute at The University of Utah	Salt Lake City	Utah	United States	84112
10	Alberta Children'S Hospital	Calgary	Alberta	Canada	T3B 6A8
11	Centre Leon Berard	Lyon CEDEX 08		France	69373
12	Institut Curie	Paris		France	75005
13	CHU de Brabois	Vandoeuvre Les Nancy		France	54511
14	Gustave Roussy	Villejuif CEDEX		France	94800
15	Hospital Sant Joan De Deu	Esplugues De Llobregas	Barcelona	Spain	08950
16	Hospital Infantil Universitario Nino Jesus	Madrid		Spain	28009
17	Birmingham Children's Hospital	Birmingham		United Kingdom	B4 6NH
18	The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit	Newcastle Upon Tyne		United Kingdom	NE1 4LP
19	Royal Marsden Hospital; Pediatric Unit	Surrey		United Kingdom	SM2 5PT