A Study Evaluating the Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in Treatment of Pediatric and Young Adult Participants With Relapsed/Refractory Acute Leukemias or Solid Tumors
- Conditions
- Acute Lymphoblastic Leukemia (ALL)Acute Myeloid Leukemia (AML)Solid TumorsNeuroblastoma
- Interventions
- Drug: Intrathecal Chemotherapy
- Registration Number
- NCT04029688
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 38
- 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
- Primary Central Nervous System (CNS) tumors
- Symptomatic CNS metastases that result in a neurologically unstable clinical state or require increasing doses of corticosteroids or local CNS-directed therapy to control the CNS disease
- CNS3 leukemia
- Acute promyelocytic leukemia
- White blood cell count >50 × 10^9 cells/Liter (L)
- Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome
- Burkitt-type acute lymphoblastic leukemia
- T-cell lymphoblastic leukemia
- Prior treatment with a MDM2 antagonist
- Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm)
- Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant
- Any uncontrolled medical condition or other identified abnormality that precludes the patient's safe participation in and completion of the study
- Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to initiation of study treatment
- Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy for anti-neoplastic intent within 30 days prior to initiation of study treatment
- I-131 meta-iodobenzylguanidine (MIBG) therapy within 6 weeks prior to initiation of study treatment
- Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation
- Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of study treatment initiation
- Radiotherapy within 3 weeks prior to study treatment initiation
- Specific restrictions are applicable for patients treated with drugs interacting with CYP2C8, CYP3A4, OATP1B1/B3, and P-gp
- Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study treatment initiation
- Underwent major surgical procedure within 21 days of study treatment initiation, or anticipate need for major surgical procedure during the course of the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Escalation: Solid Tumors: Idasanutlin Single Agent Idasanutlin - AML: Idasanutlin + Fludarabine + Cytarabine Fludarabine - Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan Topotecan - AML: Idasanutlin + Fludarabine + Cytarabine Intrathecal Chemotherapy - ALL: Idasanutlin + Venetoclax Idasanutlin - AML: Idasanutlin + Venetoclax Intrathecal Chemotherapy - AML: Idasanutlin + Fludarabine + Cytarabine Cytarabine - ALL: Idasanutlin + Venetoclax Intrathecal Chemotherapy - Neuroblastoma: Idasanutlin + Venetoclax Venetoclax - Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan Cyclophosphamide - AML: Idasanutlin + Venetoclax Idasanutlin - AML: Idasanutlin + Venetoclax Venetoclax - ALL: Idasanutlin + Venetoclax Venetoclax - Neuroblastoma: Idasanutlin + Venetoclax Idasanutlin - Neuroblastoma: Idasanutlin + Cyclophosphamide + Topotecan Idasanutlin - AML: Idasanutlin + Fludarabine + Cytarabine Idasanutlin -
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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).
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.
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.
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: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy Days 1 and 5 of Cycle 1 (cycle length = 28 days) Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) Days 1 and 5 of Cycle 1 (cycle length = 28 days) Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin Cycle 1: Predose on Days 2 and 5, 4 and 6 hours post dose on Days 1 and 5 (1 cycle = 28 days) Parts 1, 2 and 3: Number of Participants With Leukemia Receiving Transplant After Study Treatment Up to approximately 29 months Parts 1, 2 and 3: Duration of Objective Response in Participants With Leukemia 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: 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.
Trial Locations
- Locations (14)
Arkansas Children's Hospital Research Institute
🇺🇸Little Rock, Arkansas, United States
Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology
🇺🇸Palo Alto, California, United States
Arnold Palmer Hosp-Children
🇺🇸Orlando, Florida, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Alberta Children'S Hospital
🇨🇦Calgary, Alberta, Canada
Centre Leon Berard
🇫🇷Lyon CEDEX 08, France
Institut Curie
🇫🇷Paris, France
Prinses Maxima Centrum
🇳🇱Utrecht, Netherlands
Hospital Sant Joan De Deu
🇪🇸Esplugues De Llobregas, Barcelona, Spain
Hospital Infantil Universitario Nino Jesus
🇪🇸Madrid, Spain
Birmingham Children's Hospital
🇬🇧Birmingham, United Kingdom
The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
🇬🇧Newcastle Upon Tyne, United Kingdom
Royal Marsden Hospital; Pediatric Unit
🇬🇧Surrey, United Kingdom