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

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

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.

Study Overview

• Status: Terminated
• Conditions: Neuroblastoma; Solid Tumors; Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)
• Intervention / Treatment: Drug: Idasanutlin; Drug: Venetoclax; Drug: Cyclophosphamide; Drug: Topotecan; Drug: Intrathecal Chemotherapy; Drug: Fludarabine; Drug: Cytarabine

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
• France
  • Lyon CEDEX 08, France, 69373
    • Centre Léon Bérard
  • Paris, France, 75005
    • Institut Curie
• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Prinses Maxima Centrum
• Spain
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Niño Jesús
  • Barcelona
    • Esplugues De Llobregas, Barcelona, Spain, 08950
      • Hospital Sant Joan de Deu
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
  • Surrey, United Kingdom, SM2 5PT
    • Royal Marsden Hospital; Pediatric Unit
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital Research Institute
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology
  • Florida
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hosp-Children
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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: ABT-199; GDC-0199; RG7601
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: ABT-199; GDC-0199; RG7601; 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: 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.; 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.
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: ABT-199; GDC-0199; RG7601; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	CBR was defined as the percentage of participants achieving confirmed CR, PR, or stable disease (SD) on 2 consecutive occasions ≥4 weeks apart during the total study period. Per RECIST, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference smallest sum on study. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants who had neuroblastoma were assessed by INRC. CR and PR per INRC were defined as outlined in the description for Part 1b: ORR outcome measure (OM).	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	CBR=percentage of participants with CR, PR, or SD on 2 consecutive occasions ≥ 4 weeks apart per INRC. Primary tumor: CR=residual soft tissue at primary site is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in longest diameter (LD) of primary site, with stable/improved MIBG/FDG-PET uptake; SD=Insufficient shrinkage for PR/increase for PD. PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. 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; PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site; SD=no sufficient change in non-primary lesions. Bone marrow: CR=no tumor infiltration on reassessment; PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration; SD=persistent infiltration at >5% without meeting other criteria.	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	CBR=percentage of participants with CR, PR, or SD on 2 consecutive occasions ≥ 4 weeks apart per INRC. Primary tumor: CR=residual soft tissue at primary site is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in longest diameter (LD) of primary site, with stable/improved MIBG/FDG-PET uptake; SD=Insufficient shrinkage for PR or increase for PD. PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. 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; PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site; SD=no sufficient change in non-primary lesions. Bone marrow: CR=no tumor infiltration on reassessment; PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration; SD=persistent infiltration at >5% without meeting other criteria.	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	DOR was defined as the time from the first tumor assessment that supports a participant's objective response (CR or PR) to the time of PD or death from any cause (whichever occurs first), as determined by the investigator using RECIST v1.1 or INRC. Per PRECIST, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants who had neuroblastoma were assessed by INRC. CR/PR/PD were defined per INRC as outlined in the description for the Part 1b: CBR OM.	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	DOR=time from the first tumor assessment that supports a participant's objective response (CR or PR) to the time of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: CR=residual soft tissue at primary site is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved; PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. 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; PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: CR=no tumor infiltration on reassessment; PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration.	From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Part 1b: DOR in in Participants With TP53 WT Neuroblastoma Assessed According to INRC	DOR=time from the first tumor assessment that supports a participant's objective response (CR or PR) to the time of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: CR=residual soft tissue at primary site is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved; PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. 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; PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: CR=no tumor infiltration on reassessment; PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration.	From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC	PFS was defined as the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using RECIST or INRC. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants who had neuroblastoma were assessed by INRC. PD per INRC: Primary tumor = >20% increase in LD from smallest sum & minimum 5 mm increase in LD; Soft tissue & bone metastases = new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site; Bone marrow = new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration.	From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC	PFS was defined as the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. Soft tissue & bone metastases: PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration.	From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC	PFS was defined as the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. Soft tissue & bone metastases: PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration.	From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Parts 1a and 1b: Overall Survival (OS) in SE Population	OS was defined as the time from initiation of the study drug to death from any cause. Estimates for median OS were computed using Kaplan-Meier methodology	Up to approximately 29 months
Part 1b: OS in Participants With TP53 WT Neuroblastoma	OS was defined as the time from initiation of the study drug to death from any cause. Estimates for median OS were computed using Kaplan-Meier methodology	Up to approximately 29 months
Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC	ORR was defined as the percentage of participants with CR or PR at any time during study treatment, on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1 or INRC. Per RECIST, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. Participants who had neuroblastoma were assessed by INRC. Per INRC, 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.	From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population 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. Percentages have been rounded off to nearest decimal point.	From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy		Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax		Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy		Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)		Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin		Cycle 1: Predose on Days 2 and 5, 4 and 6 hours post dose on Days 1 and 5 (1 cycle = 28 days)
Parts 1, 2 and 3: Number of Participants With Leukemia Receiving Transplant After Study Treatment		Up to approximately 29 months
Parts 1, 2 and 3: Duration of Objective Response in Participants With Leukemia	DOR, defined as the time from the first tumor assessment that supports the participant's objective response (CR, CRp, CRi) to the time of relapse, or death from any cause, whichever occurs first. 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/L [1000µL]; 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). Relapse=participants who achieved a CR/CRp/CRi & subsequently developed: Bone marrow blasts ≥5%; reappearance of blasts in the blood ≥1%; or development of extra-medullary disease.	Up to approximately 29 months
Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants With Leukemia	EFS=time 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. CR=Bone marrow blasts <5% (AML) & no evidence of circulating blasts, must be <1% (ALL); absence of blasts with Auer rods (AML); absence of extramedullary disease; ANC >1.0*10^9/L [1000µL]; platelet count > 100*10^9/L (100,000/µL); no transfusions for a minimum of 1 week (AML & 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 & 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). Relapse=participants who achieved a CR/CRp/CRi & subsequently developed: Bone marrow blasts ≥5%; reappearance of blasts in blood ≥1%; or development of extra-medullary disease.	Up to approximately 29 months
Parts 1, 2 and 3: OS in Participants With Leukemia	OS was defined as the time from initiation of study drug to death from any cause.	Up to approximately 29 months
Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Status in Participants With Leukemia	CRR was defined as the percentage of participants with CR, CRi, or 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/L [1000/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 approximately 29 months
Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL	MRD - negative rate was defined as defined as the percentage of participants with AML who are MRD negative within 2 cycles of study treatment.	Up to approximately 29 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2020
• Primary Completion (Actual): May 6, 2024
• Study Completion (Actual): May 6, 2024

Study Registration Dates

• First Submitted: July 19, 2019
• First Submitted That Met QC Criteria: July 19, 2019
• First Posted (Actual): July 23, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neoplasms, Glandular and Epithelial; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Leukemia, Myeloid; Leukemia, Lymphoid; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Leukemia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neuroblastoma; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Venetoclax; Cyclophosphamide; Fludarabine; Cytarabine; Topotecan
• Other Study ID Numbers: GO40871; 2018-004579-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No