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

NCT04029688 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GO408712018-004579-11
• Study Type: interventional
• Target: 38
• Locations: 6 countries
• Sites: 14

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.

Conditions

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

Outcome Measures

Primary Outcomes (6)

• Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)

  An AE is any untoward medical occurrence in participant administered a pharmaceutical product \& regardless of causal relationship with this treatment. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether or not considered related to investigational product. AEs were graded as per NCI CTCAE v5.0. Grade 1=Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated; Grade 2=Moderate; minimal, local or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3=Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living; Grade 4=Life-threatening consequences/urgent intervention indicated; Grade 5=Death related to adverse event.

  From screening up to 30 days after study treatment discontinuation (approximately 7 months)

• Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs)

  DLTs were assessed for single-agent idasanutlin and idasanutlin in combination with chemotherapy or venetoclax. A DLT was defined as any AE that occurred during the DLT assessment window and was assessed by the investigator as related or possibly related to idasanutlin. An AE is an untoward medical occurrence in participant administered a pharmaceutical product \& regardless of causal relationship with this treatment. Following events were considered to be DLTs: any treatment-related death; elevation of serum hepatic transaminase; severe liver injury, in the absence of cholestasis or other causes of hyperbilirubinemia; any non-hematologic toxicity Grade ≥3; nausea, vomiting, and/or diarrhea if Grade 3 severity lasts \> than 24 hours after initiation of supportive care measures or if Grade 4 or higher; hematologic toxicity; any related event that results in a dose delay beyond Day 42.

  Cycle 1 (one cycle is 28 days)

• Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild-Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC)

  ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) at any time during study treatment, on 2 consecutive occasions ≥ 4 weeks apart, as determined by the investigator per INRC. Primary tumor: CR = \<10 millimeters (mm) residual soft tissue at primary site and complete resolution of meta-iodobenzylguanidine (MIBG) or fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake at primary site. PR = ≥ 30% decrease in longest diameter of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved. Soft tissue \& bone metastases: CR = resolution of all disease sites; PR = ≥30% decrease in sum of non-primary target lesions, with no new lesions or ≥50% reduction in MIBG score or in number of FDG-PET-avid bone lesions; Bone marrow: CR = no tumor infiltration on reassessment.

  From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

• Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

  ORR was defined as the percentage of participants with CR or PR at any time during study treatment, on 2 consecutive occasions ≥ 4 weeks apart, as determined by the investigator per INRC. Primary tumor: CR = \<10 mm residual soft tissue at primary site and complete resolution of MIBG or FDG-PET uptake at primary site. PR = ≥ 30% decrease in longest diameter of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved. Soft tissue \& bone metastases: CR = resolution of all disease sites; PR = ≥30% decrease in sum of non-primary target lesions, with no new lesions or ≥50% reduction in MIBG score or in number of FDG-PET-avid bone lesions; Bone marrow: CR = no tumor infiltration on reassessment.

  Up to approximately 29 months

• Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia

  CRR was defined as the percentage of participants with morphologic complete remission (CR), complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet count recovery (CRp) within 2 cycles of study treatment. CR=Bone marrow blasts \<5% (AML) and no evidence of circulating blasts, must be \<1% (ALL); absence of blasts with Auer rods (AML); absence of extramedullary disease; absolute neutrophil count (ANC) \>1.0\*10\^9/liter (L) \[1000/microliter (µL)\]; platelet count \> 100\*10\^9/L (100,000/µL); independence of transfusions for a minimum of 1 week (AML and ALL). CRi= All CR criteria except for ANC \<1.0\*10\^9/L\[1000/µL\] or insufficient recovery of platelet count \<100\* 10\^9/L \[100,000/µL\] (AML and ALL). CRp=All CR criteria except for ANC \>1.0\*10\^9/L\[1000/µL\]) or but with insufficient recovery of platelet (\<100\* 10\^9/L \[100,000/µL\]) (ALL).

  Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)

• Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL

  MRD - negative rate was defined as percentage of participants with ALL who have an MRD value \< 0.01%, as measured by next-generation sequencing (NGS), within 2 cycles of study treatment.

  Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)

Secondary Outcomes (24)

• Part 1a: Clinical Benefit Rate (CBR) in Participants With Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC

  From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

• Part 1b: CBR in Participants With Neuroblastoma From SE Population Assessed According to INRC

  From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

• Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

  From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

• Part 1a: Duration of Response (DOR) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC

  From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

• Part 1b: DOR in Participants With Neuroblastoma From SE Population Assessed According to INRC

  From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Study Arms (6)

Dose Escalation: Solid Tumors: Idasanutlin Single Agent

EXPERIMENTAL

Drug: Idasanutlin

Neuroblastoma: Idasanutlin + Venetoclax

EXPERIMENTAL

Drug: Idasanutlin; Drug: Venetoclax

Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan

EXPERIMENTAL

Drug: Idasanutlin; Drug: Cyclophosphamide; Drug: Topotecan

AML: Idasanutlin + Venetoclax

EXPERIMENTAL

Drug: Idasanutlin; Drug: Venetoclax; Drug: Intrathecal Chemotherapy

AML: Idasanutlin + Fludarabine + Cytarabine

EXPERIMENTAL

Drug: Idasanutlin; Drug: Fludarabine; Drug: Cytarabine; Drug: Intrathecal Chemotherapy

ALL: Idasanutlin + Venetoclax

EXPERIMENTAL

Drug: Idasanutlin; Drug: Venetoclax; Drug: Intrathecal Chemotherapy

Interventions

Idasanutlin DRUG

Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

Also known as: RG7388

ALL: Idasanutlin + Venetoclax; AML: Idasanutlin + Fludarabine + Cytarabine; AML: Idasanutlin + Venetoclax; Dose Escalation: Solid Tumors: Idasanutlin Single Agent; Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan; Neuroblastoma: Idasanutlin + Venetoclax

Venetoclax DRUG

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.

Also known as: RG7601, GDC-0199, ABT-199

ALL: Idasanutlin + Venetoclax; AML: Idasanutlin + Venetoclax; Neuroblastoma: Idasanutlin + Venetoclax

Cyclophosphamide DRUG

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.

Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan

Topotecan DRUG

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.

Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan

Fludarabine DRUG

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.

AML: Idasanutlin + Fludarabine + Cytarabine

Cytarabine DRUG

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.

AML: Idasanutlin + Fludarabine + Cytarabine

Intrathecal Chemotherapy DRUG

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.

ALL: Idasanutlin + Venetoclax; AML: Idasanutlin + Fludarabine + Cytarabine; AML: Idasanutlin + Venetoclax

Eligibility Criteria

• Age: 0 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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
• 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
• Bone marrow with ≥5% lymphoblasts by morphologic assessment at screening
• Available bone marrow aspirate or biopsy from screening

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (14)

Arkansas Children's Hospital Research Institute

Little Rock, Arkansas, 72202, United States

Location

Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology

Palo Alto, California, 94304, United States

Location

Arnold Palmer Hosp-Children

Orlando, Florida, 32806, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Alberta Children'S Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Centre Leon Berard

Lyon, 69373, France

Location

Institut Curie

Paris, 75005, France

Location

Prinses Maxima Centrum

Utrecht, 3584 CS, Netherlands

Location

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, 08950, Spain

Location

Hospital Infantil Universitario Nino Jesus

Madrid, 28009, Spain

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Royal Marsden Hospital; Pediatric Unit

Surrey, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Rubio-San-Simon A, Marshall LV, Doz F, Mora J, Bielamowicz K, Corradini N, Langevin AM, Narendran A, Smith AA, Zwaan CM, Gho D, Cardenas A, Fowler S, Guizani C, Breton V, Wulff B, Bernardi R, Trippett T, Campbell-Hewson Q. Idasanutlin in Combination with Chemotherapy or Venetoclax in Pediatric and Young Adult Patients with Relapsed/Refractory Solid Tumors (iMATRIX Idasa): Results of a Phase I/II, Multicenter, Multi-arm Study. Target Oncol. 2025 Dec 11. doi: 10.1007/s11523-025-01186-w. Online ahead of print.

  PMID: 41379293 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neuroblastoma

Interventions

RG7388; venetoclax; Cyclophosphamide; Topotecan; fludarabine; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; 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

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2019
• First Posted: July 23, 2019
• Study Start: January 27, 2020
• Primary Completion: May 6, 2024
• Study Completion: May 6, 2024
• Last Updated: December 20, 2024
• Results First Posted: December 20, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

FR (2); GB (3); ES (2); NL (1); US (5); CA (1)