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

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)

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

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.

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

时间窗: Cycle 1 (one cycle is 28 days)

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.

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

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

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.

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

时间窗: Up to approximately 29 months

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.

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

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

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).

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

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

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.