Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Neuroblastoma, Solid Tumors
Conditions
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.
Interventions
DRUGIdasanutlin
Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle.
DRUGVenetoclax
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.
DRUGCyclophosphamide
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.
DRUGTopotecan
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.
DRUGFludarabine
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.
DRUGCytarabine
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.
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 30 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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) | 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) | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1a: Progression Free Survival (PFS) 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) | 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. |
| Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC | From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days) | 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. |
| Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC | From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days) | 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. |
| Parts 1a and 1b: Overall Survival (OS) in SE Population | Up to approximately 29 months | 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 |
| Part 1b: OS in Participants With TP53 WT Neuroblastoma | Up to approximately 29 months | 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 |
| Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days) | 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. |
| Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population According to INRC | From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days) | 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. |
| 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: 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) | 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). |
| 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 | Up to approximately 29 months | 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. |
| Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants With Leukemia | Up to approximately 29 months | 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. |
| Parts 1, 2 and 3: OS in Participants With Leukemia | Up to approximately 29 months | OS was defined as the time from initiation of study drug to death from any cause. |
| Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Status in Participants With Leukemia | Up to approximately 29 months | 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). |
| Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL | Up to approximately 29 months | MRD - negative rate was defined as defined as the percentage of participants with AML who are MRD negative within 2 cycles of study treatment. |
| 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: 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| Part 1b: DOR in in Participants With TP53 WT Neuroblastoma Assessed According to INRC | From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days) | 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. |
Countries
Canada, France, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants with relapsed/refractory solid tumors took part in the study across 12 investigative sites in 6 countries (United States, Spain, United Kingdom, France, Canada, and Netherlands) from January 27, 2020 to May 6, 2024.
Pre-assignment details
Study was divided into 3 parts. Part 1a: Single agent idasanutlin dose escalation in pediatric participants with solid tumors. Part 1b: Combination safety run-in in participants with neuroblastoma/acute leukemia. Part 2: Early efficacy in participants with neuroblastoma/acute leukemia. Part 3: Expansion cohorts in participants with neuroblastoma/acute leukemia. Leukemia cohorts in Part 1b & all cohorts in Part 2 & Part 3 were never initiated due to early termination of the study by the sponsor.
Participants by arm
| Arm | Count |
|---|---|
| Part 1a: Idasanutlin 2 mg/kg Participants with solid tumors received idasanutlin 2 mg/kg QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 8 |
| Part 1a: Idasanutlin 3 mg/kg Participants with solid tumors received idasanutlin 3 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 3 |
| Part 1a: Idasanutlin 4.5 mg/kg Participants with solid tumors received idasanutlin 4.5 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 6 |
| Part 1a: Idasanutlin 6.4 mg/kg Participants with solid tumors received idasanutlin 6.4 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 3 |
| Part 1a: Idasanutlin 8 mg/kg Participants with solid tumors received idasanutlin 8 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 6 |
| Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy Participants with neuroblastoma received idasanutlin 2.8 mg/kg orally in combination with cyclophosphamide 200 mg/m\^2 and topotecan 0.6 mg/m\^2 as an IV infusion QD on Days 1-5 of each 28-day cycle. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 3 |
| Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy Participants with neuroblastoma received idasanutlin, 3.6 mg/kg orally, in combination with cyclophosphamide 250 mg/m\^2 and topotecan 0.75 mg/m\^2 as an IV infusion QD on Days 1-5 of each 28-day cycle. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 3 |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax Participants with neuroblastoma (first 3) received idasanutlin, 3.6 mg/kg orally QD on Days 1-5, in combination with venetoclax 400 mg adult dose equivalent (adjusted by body weight) on Days 1-28 of each 28-day cycle. After the first three participants were treated, the schedule was modified as idasanutlin, 3.6 mg/kg orally QD on Days 1-5 and venetoclax 400 mg (adult dose equivalent) on Days 1-14 of a each 28-day cycle for the next 3 participants enrolled in this arm. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first. | 6 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 8 | 3 | 6 | 2 | 5 | 0 | 2 | 3 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1a: Idasanutlin 2 mg/kg | Part 1a: Idasanutlin 3 mg/kg | Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Idasanutlin 8 mg/kg | Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy | Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy | Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 7.6 years STANDARD_DEVIATION 5 | 11.3 years STANDARD_DEVIATION 3.2 | 7.3 years STANDARD_DEVIATION 3.9 | 15.0 years STANDARD_DEVIATION 1.7 | 11.5 years STANDARD_DEVIATION 5 | 15.0 years STANDARD_DEVIATION 11.4 | 5.3 years STANDARD_DEVIATION 1.2 | 8.0 years STANDARD_DEVIATION 3.8 | 9.5 years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 3 Participants | 14 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 21 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 8 | 3 / 3 | 6 / 6 | 2 / 3 | 5 / 6 | 0 / 3 | 2 / 3 | 3 / 6 |
| other Total, other adverse events | 8 / 8 | 3 / 3 | 6 / 6 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 6 / 8 | 3 / 3 | 4 / 6 | 2 / 3 | 6 / 6 | 2 / 3 | 3 / 3 | 4 / 6 |
Outcome results
Primary
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.
Time frame: From screening up to 30 days after study treatment discontinuation (approximately 7 months)
Population: Safety evaluable (SE) population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Grade 5 | 0 Participants |
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Any Grade | 8 Participants |
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Grade 1 | 1 Participants |
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Grade 2 | 0 Participants |
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Grade 4 | 5 Participants |
| Part 1a: Idasanutlin 2 mg/kg | 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) | AEs, Grade 3 | 2 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Grade 2 | 0 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Any Grade | 3 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Grade 3 | 1 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Grade 5 | 0 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Grade 1 | 0 Participants |
| Part 1a: Idasanutlin 3 mg/kg | 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) | AEs, Grade 4 | 2 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Grade 4 | 3 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Grade 2 | 0 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Grade 1 | 0 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Grade 3 | 3 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Grade 5 | 0 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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) | AEs, Any Grade | 6 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Grade 4 | 1 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Any Grade | 3 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Grade 1 | 0 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Grade 2 | 0 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Grade 3 | 2 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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) | AEs, Grade 5 | 0 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Grade 4 | 5 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Grade 1 | 0 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Grade 5 | 0 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Any Grade | 6 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Grade 3 | 1 Participants |
| Part 1a: Idasanutlin 8 mg/kg | 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) | AEs, Grade 2 | 0 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Grade 2 | 0 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Grade 3 | 0 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Grade 1 | 0 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Grade 4 | 3 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Any Grade | 3 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | 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) | AEs, Grade 5 | 0 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Grade 3 | 0 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Grade 4 | 3 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Any Grade | 3 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Grade 2 | 0 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Grade 5 | 0 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | 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) | AEs, Grade 1 | 0 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Grade 3 | 3 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Grade 2 | 1 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Grade 5 | 1 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Grade 4 | 1 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Any Grade | 6 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | 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) | AEs, Grade 1 | 0 Participants |
Primary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild-Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC) | 0 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild-Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC) | 33.3 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild-Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC) | 0 percentage of participants |
Primary
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.
Time frame: Cycle 1 (one cycle is 28 days)
Population: DLT-evaluable population included all participants enrolled in Part 1 who either completed at least 80% of the prescribed dose of idasanutlin and the DLT observation window in Cycle 1 OR have experienced a DLT in Cycle 1 of the dose-escalation phase.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part 1a: Idasanutlin 3 mg/kg | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| Part 1a: Idasanutlin 6.4 mg/kg | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part 1a: Idasanutlin 8 mg/kg | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 4 Participants |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 2 Participants |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Primary
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).
Time frame: Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Primary
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.
Time frame: Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Primary
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.
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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).
Time frame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | 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 | 12.5 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | 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 | 33.3 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | 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 | 0 percentage of participants |
| Part 1a: Idasanutlin 6.4 mg/kg | 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 | 66.7 percentage of participants |
| Part 1a: Idasanutlin 8 mg/kg | 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 | 0 percentage of participants |
Secondary
Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy
Time frame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Population: PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. One participant assigned to the 6.4 mg/kg dose level received a dose of 3.8 mg/kg due to the maximum absolute dose cap of 300 mg/day in protocol v3 and earlier. Hence this participant has been reported in a separate arm for PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 129 ng/mL | Geometric Coefficient of Variation 63 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 436 ng/mL | Geometric Coefficient of Variation 73 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 184 ng/mL | Geometric Coefficient of Variation 39 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 419 ng/mL | Geometric Coefficient of Variation 23 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 72 ng/mL | — |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 345 ng/mL | — |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 340 ng/mL | Geometric Coefficient of Variation 60 |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 820 ng/mL | Geometric Coefficient of Variation 76 |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 542 ng/mL | Geometric Coefficient of Variation 153 |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 1865 ng/mL | Geometric Coefficient of Variation 197 |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 1 | 575 ng/mL | Geometric Coefficient of Variation 148 |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy | Cycle 1 Day 5 | 1511 ng/mL | Geometric Coefficient of Variation 201 |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. DOR was only evaluated in participants who achieved an objective response (CR or PR).
Secondary
Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy
Time frame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Population: Pharmacokinetic (PK)-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. One participant assigned to the 6.4 mg/kg dose level received a dose of 3.8 mg/kg due to the maximum absolute dose cap of 300 mg/day in protocol v3 and earlier. Hence this participant has been reported in a separate arm for PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 1429 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 36 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 2548 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 21 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 2110 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 27 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 2784 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 27 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 1560 ng/mL(nanograms/millilitres) | — |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 2940 ng/mL(nanograms/millilitres) | — |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 3174 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 25 |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 4892 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 53 |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 7748 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 81 |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 4474 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 90 |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 5 | 6298 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 67 |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy | Cycle 1 Day 1 | 5102 ng/mL(nanograms/millilitres) | Geometric Coefficient of Variation 67 |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | 0 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | 0 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | 0 percentage of participants |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | 0 percentage of participants |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC | 0 percentage of participants |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC | 0.8 months |
| Part 1a: Idasanutlin 3 mg/kg | Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC | 0.9 months |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC | 0.8 months |
| Part 1a: Idasanutlin 6.4 mg/kg | Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC | 3.5 months |
| Part 1a: Idasanutlin 8 mg/kg | Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC | 1.9 months |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: CBR in Participants With Neuroblastoma From SE Population Assessed According to INRC | 33.3 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: CBR in Participants With Neuroblastoma From SE Population Assessed According to INRC | 33.3 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: CBR in Participants With Neuroblastoma From SE Population Assessed According to INRC | 0 percentage of participants |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 50.0 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 33.3 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 0 percentage of participants |
Secondary
Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax
Time frame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Population: PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 5 | 2393 ng/mL | Geometric Coefficient of Variation 32 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 1 | 2834 ng/mL | Geometric Coefficient of Variation 31 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 1 | 1540 ng/mL | Geometric Coefficient of Variation 11 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 5 | 2110 ng/mL | Geometric Coefficient of Variation 72 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 1 | 2131 ng/mL | Geometric Coefficient of Variation 43 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax | Cycle 1 Day 5 | 2272 ng/mL | Geometric Coefficient of Variation 32 |
Secondary
Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)
Time frame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
Population: PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 1 | 229 ng/mL | Geometric Coefficient of Variation 56 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 5 | 442 ng/mL | Geometric Coefficient of Variation 148 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 1 | 214 ng/mL | Geometric Coefficient of Variation 72 |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 5 | 524 ng/mL | Geometric Coefficient of Variation 97 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 1 | 213 ng/mL | Geometric Coefficient of Variation 67 |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) | Cycle 1 Day 5 | 369 ng/mL | Geometric Coefficient of Variation 58 |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. DOR was only evaluated in participants who achieved an objective response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: DOR in in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 4.5 months |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. DOR was only evaluated in participants who achieved an objective response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: DOR in Participants With Neuroblastoma From SE Population Assessed According to INRC | 4.5 months |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population According to INRC | 0 percentage of participants |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population According to INRC | 33.3 percentage of participants |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population According to INRC | 0 percentage of participants |
Secondary
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
Time frame: Up to approximately 29 months
Population: Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: OS in Participants With TP53 WT Neuroblastoma | NA months |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: OS in Participants With TP53 WT Neuroblastoma | 3.2 months |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: OS in Participants With TP53 WT Neuroblastoma | NA months |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC | 1.9 months |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC | 1.8 months |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC | 1.7 months |
Secondary
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.
Time frame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
Population: Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC | NA months |
| Part 1a: Idasanutlin 3 mg/kg | Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 1.8 months |
| Part 1a: Idasanutlin 4.5 mg/kg | Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC | 1.7 months |
Secondary
Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin
Time frame: Cycle 1: Predose on Days 2 and 5, 4 and 6 hours post dose on Days 1 and 5 (1 cycle = 28 days)
Population: PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 1, Post dose 4 Hours | 693 ng/mL | Geometric Coefficient of Variation 44 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 1, Post dose 6 Hours | 669 ng/mL | Geometric Coefficient of Variation 86 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 2, Predose | 202 ng/mL | Geometric Coefficient of Variation 109 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 5, Predose | 221 ng/mL | Geometric Coefficient of Variation 108 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 5, Post dose 4 Hours | 1145 ng/mL | Geometric Coefficient of Variation 45 |
| Part 1a: Idasanutlin 2 mg/kg | Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin | Cycle 1 Day 5, Post dose 6 Hours | 968 ng/mL | Geometric Coefficient of Variation 39 |
Secondary
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).
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Part 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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.
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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.
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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.
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
Parts 1, 2 and 3: Number of Participants With Leukemia Receiving Transplant After Study Treatment
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Parts 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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.
Time frame: Up to approximately 29 months
Population: The study was terminated before initiation of Part 2 and 3 as per sponsor's decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.
Secondary
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
Time frame: Up to approximately 29 months
Population: SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: Idasanutlin 2 mg/kg | Parts 1a and 1b: Overall Survival (OS) in SE Population | 5.6 months |
| Part 1a: Idasanutlin 3 mg/kg | Parts 1a and 1b: Overall Survival (OS) in SE Population | 12.5 months |
| Part 1a: Idasanutlin 4.5 mg/kg | Parts 1a and 1b: Overall Survival (OS) in SE Population | 3.6 months |
| Part 1a: Idasanutlin 6.4 mg/kg | Parts 1a and 1b: Overall Survival (OS) in SE Population | 16.4 months |
| Part 1a: Idasanutlin 8 mg/kg | Parts 1a and 1b: Overall Survival (OS) in SE Population | 5.4 months |
| Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy | Parts 1a and 1b: Overall Survival (OS) in SE Population | NA months |
| Part 1b: Idasanutlin (3.6mg/kg) +Chemotherapy | Parts 1a and 1b: Overall Survival (OS) in SE Population | 3.2 months |
| Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax | Parts 1a and 1b: Overall Survival (OS) in SE Population | NA months |