Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors

• Palbociclib (Drug), also known as Ibrance: Phase 1: Administered (oral) at 55 mg/m2, 75 mg/m2, or 40 mg/m2, or 95 mg/m2 or 115 mg/m2 on days 1-14 of a 21-day cycle Phase 1 Tumor specific cohort-Neuroblastoma and Phase 2 : Administered (oral) at 75 mg/m2 on days 1-14 of a 21-day cycle
• Temozolomide (Drug), also known as Temodar: Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle
• Irinotecan (Drug), also known as Campto: Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
• Topotecan (Drug), also known as Hycamtin: Phase 1 only : Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
• Cyclophosphamide (Drug), also known as Cytoxan: Phase 1 only: Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle

Primary outcomes

• Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) [Cycle 1 (21 days)]: DLT was an adverse event (AE) occurring in the first cycle of treatment which were attributable to at least one of the agents in the combination that met the defined criteria of study per Sponsor. An AE we defined as any untoward medical occurrence in a study participant who received study drug without regard to possibility of causal relationship. AEs determined as DLT were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
• Phase 1, Dose Expansion Cohorts and TSC: Number of Participants With Treatment-emergent AEs, Treatment-emergent Serious AEs (SAEs), Treatment Related AEs, Treatment Related SAEs and AEs of Maximum Grade 3 or 4 and 5 [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs: AEs that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect or other important medical event. Treatment-emergent AEs: AEs that occurred on or after the first dose of study treatment and up to 35 days after last dose of study treatment. AEs related to study drug as judged by the investigator were considered as treatment-related TEAEs. Severity of AEs were graded according to CTCAE version 4.03 as: Grade 3= severe, Grade 4= life threatening, and Grade 5= death related to AE.
• Phase 1, Dose Expansion Cohorts and TSC: Number of Participants With Maximum CTCAE Grade in Hematology Parameters [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: Hematology parameters included activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, lymphocyte count decreased and increased, neutrophil count decreased, platelet count decreased. Grades by CTCAE version 4.03: Grade 1= mild, Grade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening and Grade 5= death related to AE; Grade 0= non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter.
• Phase 1, Dose Expansion Cohorts and TSC: Number of Participants With Maximum CTCAE Grade in Chemistry Parameters [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: Clinical chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, gamma glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia and hypophosphatemia. According to CTCAE version 4.03: Grade 1=mild, Grade 2=moderate, Grade 3=severe and Grade 4= life-threatening; Grade 0: non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter.
• Phase 1, Dose Expansion Cohorts and TSC: Number of Participants With Post-Baseline and Maximum Change From Baseline in Electrocardiogram (ECG) Parameters [Baseline (pre-treatment) up to Cycle 3 (63 days)]: ECG parameters included PR interval, QRS complex, QT interval, Bazett's correction QT (QTcB) interval and Fridericia's correction (QTcF) interval. In this outcome measure number of participants with post-baseline values and with maximum change from baseline values in ECG parameters were recorded.
• Phase 1, Dose Expansion Cohorts and TSC: Maximum Change From Baseline in Vital Signs Parameter- Blood Pressure [Baseline (pre-treatment) up to end of study treatment (maximum up to approximately 24.2 months)]: Blood pressure evaluation included systolic blood pressure (SBP) and diastolic blood pressure (DBP). SBP and DBP were measured in the sitting position after participant had been in the supine position for approximately 2 minutes.
• Phase 1, Dose Expansion Cohorts and TSC: Maximum Change From Baseline in Vital Signs Parameter- Pulse Rate [Baseline (pre-treatment) up to end of study treatment (maximum up to approximately 25 months)]: Pulse rate was measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions.
• Phase 1, Dose Expansion Cohorts and TSC: Number of Participants With Clinically Significant Changes in Glycosylated Hemoglobin (HbA1c) [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: HbA1c is a form of hemoglobin which was measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Clinical significance was determined based on investigator
• Phase 1, Dose Expansion Cohorts: Objective Response (OR) Rate Based on Investigator Assessment [First dose of study treatment (Day 1) up to maximum of approximately 25 months]: OR: best overall response(BOR) of confirmed complete response(CR) or partial response(PR) per response evaluation criteria in solid tumors(RECIST)v1.1 (CR:complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size(short axis<10 mm),no new lesion;PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions,no new lesion) or modified revised assessment for neuro-oncology(RANO) for central nervous system malignancies (CR:disappearance of all target lesions,no new lesion;PR:>=50% decrease in sum of products of 2 perpendicular diameters of target lesions, compared to baseline value,no new lesion);international neuroblastoma response criteria(INRC)for neuroblastoma also included minor response(MR)(Per protocol different criteria for following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow). OR rate:percentage of participants with BOR of CR or PR;CR or PR or MR.
• TSC: OR Rate Based on Investigator Assessment [First dose of study treatment (Day 1) up to maximum of approximately 25 months]: OR: BOR of confirmed CR or PR or MR assessed by investigator per INRC for neuroblastoma. There were different criteria for CR and PR as specified in protocol for the following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow. Overall CR: All components met criteria for CR; PR: PR in at least 1 component and all other components were either CR, minimal disease (MD) \[bone marrow\], PR (soft tissue or bone) or not involved; no component with progressive disease (PD) and MR: PR or CR in at least one component but at least one other component with stable disease (SD); no component with PD. OR rate was presented as percentage of participants with BOR of CR or PR or MR.
• Phase 2: Event Free Survival (EFS) Based on Investigator Assessment [From date of randomization up to objective PD, diagnosis of secondary malignancy or death, whichever occurred first (maximum of approximately 14 months)]: EFS: time from date of randomization to the date of first documentation of any of the following events based on investigator assessment: objective PD per RECIST v.1.1 (including PD without achieving a response or recurrence following a response), diagnosis of secondary malignancy, death due to any cause. PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Kaplan-Meier method was used for evaluation.

Secondary outcomes

• Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Treatment Emergent AEs, Treatment Emergent SAEs, Treatment Related AEs, and Maximum Grade 3 or 4 and 5 AEs by CTCAE v4.03 [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs: AEs that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect or other important medical event. Treatment-emergent AEs: AEs that occurred on or after the first dose of study treatment and up to 35 days after last dose of study treatment. AEs related to study drug as judged by the investigator were considered as treatment-related TEAEs. Severity of AEs were graded according to CTCAE version 4.03 as: Grade 3= severe, Grade 4= life threatening, and Grade 5= death related to AE.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Maximum CTCAE Grade in Hematology Parameters [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: Hematology parameters included activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, lymphocyte count decreased and increased, neutrophil count decreased, platelet count decreased. Grades by CTCAE version 4.03: Grade 1= mild, Grade 2= moderate, Grade 3= severe AE, Grade 4= life-threatening and, Grade 5= death related to AE; Grade 0= non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter. Only those parameters are reported which had at least 1 participant for any reporting group.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Maximum CTCAE Grade in Chemistry Parameters [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 25 months)]: Clinical chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, GGT increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia and hypophosphatemia. According to CTCAE version 4.03: Grade 1=mild, Grade 2=moderate, Grade 3=severe and, Grade 4= life-threatening; Grade 0: non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter. Only those parameters are reported which had at least 1 participant for any reporting group.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Post-Baseline and Maximum Change From Baseline in ECG Parameters [Baseline (pre-treatment) up to Cycle 3 (63 days)]: ECG parameters included RR interval, PR interval, QRS complex, QT interval, QTc interval, QTcB interval and QTcF interval. In this outcome measure number of participants with post-baseline values and with maximum change from baseline values in ECG parameters are recorded.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Maximum Change From Baseline in Vital Signs Parameter- Blood Pressure [Baseline (pre-treatment) up to end of study treatment (maximum up to approximately 25 months)]: Blood pressure evaluation included SBP and DBP. SBP and DBP were measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Maximum Change From Baseline in Vital Signs Parameter- Pulse Rate [Baseline (pre-treatment) up to end of study treatment (maximum up to approximately 25 months)]: Pulse rate was measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions.
• Phase 1: Maximum Plasma Concentration (Cmax) at Steady-State of Palbociclib, TMZ, IRN, SN-38, CTX and TOPO [Palbociclib: PRD C1D5: and C1D5 2, 4, 6, 8 & 24 hrs post dose (PTD) IRN, SN-38, TOPO, CTX: PRD C1D5; PTI C1D5; and 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5; 1, 4, 8 PTD C1D5; TMZ IV PRD C1D5; PTI C1D5; and 4, 8 PTD C1D5]: Cmax was observed directly from data. Active metabolite of IRN is 7-Ethyl-10-hydroxycamptothecin (SN-38). In this outcome measure, Cmax was reported for Phase 1: based on dose-level and combination, dose escalation and dose expansion cohorts were combined/pooled, wherever applicable and Phase 1: TSC. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 1: Time to Reach Cmax (Tmax) of Palbociclib, TMZ, IRN SN-38, CTX and TOPO [Palbociclib: PRD C1D5: and C1D5 2, 4, 6, 8 & 24 hrs post dose (PTD) IRN, SN-38, TOPO, CTX: PRD C1D5; PTI C1D5; and 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5; 1, 4, 8 PTD C1D5; TMZ IV PRD C1D5; PTI C1D5; and 4, 8 PTD C1D5]: Tmax was defined as time for Cmax. Active metabolite of IRN is SN-38. In this outcome measure, Tmax was reported for Phase 1: based on dose-level and combination, dose escalation and dose expansion cohorts were combined/pooled, wherever applicable and Phase 1: TSC. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI. As pre-specified in protocol, time points in time frame could have a window of +/- 20% of the sampling time.
• Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau at Steady-State (AUCtau,ss) of Palbociclib, TMZ, IRN SN-38, CTX and TOPO [Palbociclib: PRD C1D5: and C1D5 2, 4, 6, 8 & 24 hrs post dose (PTD) IRN, SN-38, TOPO, CTX: PRD C1D5; PTI C1D5; and 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5; 1, 4, 8 PTD C1D5; TMZ IV PRD C1D5; PTI C1D5; and 4, 8 PTD C1D5]: Area under the concentration-time profile from time zero to the time tau. AUCtau was determined using the linear/log trapezoidal method. Active metabolite of IRN is SN-38. In this outcome measure, AUCtau was reported for Phase 1: based on dose-level and combination, dose escalation and dose expansion cohorts were combined/pooled, wherever applicable and Phase 1: TSC. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 1: Pre-dose Plasma Concentration (Ctrough) at Steady-State of Palbociclib, TMZ, IRN SN-38, CTX and TOPO [Palbociclib: PRD C1D2/D5/D14, C2D5/D14; IRN, SN-38, TOPO, CTX: PRD C1D2/D5, C2D5; TMZ Oral- PRD C1D5, C2D5 or TMZ IV- PRD C1D5, C2D5]: Ctrough was defined as pre-dose plasma concentration during multiple dosing and observed directly from data. Active metabolite of IRN is SN-38. In this outcome measure, Ctrough was reported for Phase 1: based on dose-level and combination, dose escalation and dose expansion cohorts were combined/pooled, wherever applicable and Phase 1: TSC. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D.
• Phase 1: Clearance of Palbociclib, TMZ, IRN SN-38, CTX and TOPO [Palbociclib: PRD C1D2/D5/D14, C2D5/D14; 2, 4, 6, 8 & 24 hrs PTD C1D5; IRN, SN-38, TOPO, CTX: PRD C1D2/D5, C2D5; PTI C1D5, C2D5; 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5, C2D5; 1, 4, 8 & 24 hrs PTD C1D5; 1 hr PTD C2D5 or TMZ IV- PRD, PTI C1D5, C2D5]: Clearance of a drug is a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Active metabolite of IRN is SN-38. In this outcome measure, clearance was reported for Phase 1: based on dose-level and combination, dose escalation and dose expansion cohorts were combined/pooled, wherever applicable and Phase 1: TSC. For IV administration CL/F was reported while for oral CL was reported. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 1, Dose Escalation/Dose Determination Cohorts: OR Rate Based on Investigator Assessment [First dose of study treatment (Day 1) up to maximum of approximately 25 months]: OR: BOR of confirmed CR or PR per RECIST v1.1 \[CR: complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size(short axis<10 mm), no new lesion;PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions, no new lesion\]or RANO for central nervous system malignancies\[CR: disappearance of all target lesions, no new lesion; PR:>=50% decrease in sum of products of 2 perpendicular diameters of target lesions, compared to baseline value, no new lesion\]; INRC for neuroblastoma also included MR \[per protocol different criteria for following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow\]. OR rate: percentage of participants with BOR of CR or PR per RECIST or RANO; BOR of CR or PR or MR per INRC for neuroblastoma.
• Phase 1, Dose Escalation/Dose Determination Cohorts: Duration of Response (DOR) Based on Investigator Assessment [From first documentation of OR to PD or death, whichever occurred earlier (maximum of approximately 25 months)]: DOR was defined for participants with OR:time from the date of first documentation of OR to the date of first documentation of PD or death due to any cause. OR: BOR of confirmed CR or PR per RECIST v1.1\[CR: complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size(short axis<10 mm),no new lesion; PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions, no new lesion\] or RANO for central nervous system malignancies \[CR: disappearance of all target lesions, no new lesion; PR:>=50% decrease in sum of products of 2 perpendicular diameters of target lesions, compared to baseline value, no new lesion\]; INRC for neuroblastoma also included MR \[per protocol different criteria for following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow\]. OR rate: % participants with BOR of CR or PR per RECIST or RANO; BOR of CR or PR or MR per INRC for neuroblastoma.
• Phase 1, Dose Expansion Cohorts and TSC: DOR Based on Investigator Assessment [From first documentation of OR to PD or death, whichever occurred earlier (maximum of approximately 25 months)]: DOR for participants with OR: time from the date of first documentation of OR to the date of first documentation of PD or death due to any cause. OR: BOR of confirmed CR or PR per RECIST v1.1 \[CR: complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis<10 mm), no new lesion; PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions, no new lesion\] or RANO for central nervous system malignancies \[CR: disappearance of all target lesions, no new lesion; PR:>=50% decrease in sum of products of 2 perpendicular diameters INRC for neuroblastoma also included MR \[per protocol different criteria for following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow\]. of target lesions, compared to baseline value, no new lesion\]; OR rate: % participants with BOR of CR or PR per RECIST or RANO; BOR of CR or PR or MR per INRC for neuroblastoma.
• Phase 1, Dose Expansion Cohorts and TSC: Progression-Free Survival (PFS) Based on Investigator Assessment [First dose of study treatment (Day 1) up to objective PD or death due to any cause, whichever occurred first (maximum of approximately 25 months)]: PFS: time from date of first dose of study treatment to the date of the first documentation of objective PD or death due to any cause, whichever occurred first. Per RECIST, PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Per RANO, PD: >=25% increase in the product of perpendicular diameters of any target lesion, taking as reference the smallest product; the appearance of one or more new lesions, worsening neurologic status not explained by causes unrelated to tumor progression; any increase in tumor cross-sectional area (tumor volume). Per INRC for neuroblastoma as specified in protocol different PD criteria for following components: soft tissue at primary site, metastatic soft tissue and bone sites, and bone marrow; overall PD was when any component fulfilled criteria of PD. Kaplan-Meier method was used for evaluation.
• Phase 1, Dose Expansion Cohorts and TSC: Overall Survival (OS) [First dose of study treatment (Day 1) up to death due to any cause (maximum of approximately 25 months)]: OS: time from date of first dose of study treatment to the date of death due to any cause. Kaplan-Meier method was used for evaluation.
• Phase 2: Event-Free Survival (EFS) Based on Blinded Independent Review Committee (BIRC) Assessment [First date of randomization to the date of first objective PD, diagnosis of secondary malignancy, death due to any cause (maximum of approximately 14 months)]: EFS: time from date of randomization to the date of first documentation of any of the following events based on investigator assessment: objective PD per RECIST v.1.1 (including PD without achieving a response or recurrence following a response), diagnosis of secondary malignancy, death due to any cause. PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Kaplan-Meier method was used for evaluation.
• Phase 2: OR Rate Based on Investigator Assessment [First dose of study treatment (Day 1) up to maximum of approximately 14 months]: OR: BOR of CR or PR per RECIST v1.1. CR: complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis<10 mm), no new lesion; PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions, no new lesion. OR rate was percentage of participants with BOR of CR or PR.
• Phase 2: Comparison of Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET) Assessment With Magnetic Resonance Imaging (MRI)/ Computed Tomography (CT) Assessment for OR [Cycle 4]: CR or PR per RECIST v1.1. CR: complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis<10 mm), no new lesion; PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions, no new lesion. PD per RECIST v.1.1 (including PD without achieving a response or recurrence following a response), diagnosis of secondary malignancy, death due to any cause. PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD= stable disease, NE= Not Evaluable.
• Phase 2: PFS Based on Investigator Assessment [First dose of study treatment (Day 1) up to PD or death due to any cause, whichever occurred (maximum of approximately 14 months)]: PFS: time from date of first dose of study treatment to the date of the first documentation of PD or death due to any cause. Per RECIST v1.1, PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Kaplan-Meier method was used for evaluation.
• Phase 2: OS [First dose of study treatment (Day 1) up to date of death due to any cause (maximum of approximately 76 months)]: OS: time from date of first dose of study treatment to the date of death due to any cause. Kaplan-Meier method was used for evaluation.
• Phase 2: Number of Participants With Treatment Emergent AEs, Treatment Emergent SAEs, Treatment Related AEs, Treatment Related SAEs and AEs of Maximum Grade 3 or 4 and 5 [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 9.5 months)]: An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs: AEs that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect or other important medical event. Treatment-emergent AEs: AEs that occurred on or after the first dose of study treatment and up to 35 days after last dose of study treatment. AEs related to study drug as judged by the investigator were considered as treatment-related TEAEs. Severity of AEs were graded according to CTCAE version 4.03 as: Grade 3= severe, Grade 4= life threatening, and Grade 5= death related to AE.
• Phase 2: Cmax at Steady-State of Palbociclib, TMZ, IRN and SN-38 [Palbociclib: PRD C1D5: and C1D5 2, 4, 6, 8 & 24 hrs post dose (PTD) IRN, SN-38, TOPO, CTX: PRD C1D5; PTI C1D5; and 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5; 1, 4, 8 PTD C1D5; TMZ IV PRD C1D5; PTI C1D5; and 4, 8 PTD C1D5]: Cmax was observed directly from data. Active metabolite of IRN is SN-38. In this outcome measure, Cmax was reported only for Phase 2 reporting group Palbociclib 75 mg/m\^2 + IRN + TMZ and not for reporting group IRN + TMZ, as pre-specified objective was to evaluate PK data of palbociclib, TMZ and IRN when given in combination. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 2: Tmax of Palbociclib, TMZ, IRN and SN-38 [Palbociclib: PRD C1D5: and C1D5 2, 4, 6, 8 & 24 hrs post dose (PTD) IRN, SN-38, TOPO, CTX: PRD C1D5; PTI C1D5; and 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5; 1, 4, 8 PTD C1D5; TMZ IV PRD C1D5; PTI C1D5; and 4, 8 PTD C1D5]: Tmax was defined as time for Cmax. Active metabolite of IRN is SN-38. In this outcome measure, Tmax was reported only for Phase 2: reporting group Palbociclib 75 mg/m\^2 + IRN + TMZ and not for reporting group IRN + TMZ, as pre-specified objective was to evaluate PK data of palbociclib, TMZ and IRN when given in combination. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 2: AUCtau,ss of Palbociclib, TMZ, IRN and SN-38 [Palbociclib: PRD C1D2/D5/D14, C2D5/D14; 2, 4, 6, 8 & 24 hrs PTD C1D5; IRN, SN-38 : PRD C1D2/D5, C2D5; PTI C1D5, C2D5; 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5, C2D5; 1, 4, 8 & 24 hrs PTD C1D5; 1 hr PTD C2D5 or TMZ IV- PRD, PTI C1D5, C2D5]: Area under the concentration-time profile from time zero to the time tau. AUCtau was determined using the linear/log trapezoidal method. Active metabolite of IRN is SN-38. In this outcome measure, AUCtau was reported for Phase 2 reporting group Palbociclib 75 mg/m\^2 + IRN + TMZ and not for reporting group IRN + TMZ, as pre-specified objective was to evaluate PK data of palbociclib, TMZ and IRN when given in combination. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 2: Ctrough at Steady-State of Palbociclib, TMZ, IRN and SN-38 [Palbociclib: PRD C1D2/D5/D14, C2D5/D14; IRN, SN-38 : PRD C1D2/D5, C2D5; TMZ Oral- PRD C1D5, C2D5; or TMZ IV- PRD C1D5, C2D5]: Ctrough was defined as pre-dose plasma concentration during multiple dosing and observed directly from data. Active metabolite of IRN is SN-38. In this outcome measure, Ctrough was reported for Phase 2 reporting group Palbociclib 75 mg/m\^2 + IRN + TMZ and not for reporting group IRN + TMZ, as pre-specified objective was to evaluate PK data of palbociclib, TMZ and IRN when given in combination. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D.
• Phase 2: Clearance of Palbociclib, TMZ, IRN and SN-38 [Palbociclib: PRD C1D2/D5/D14, C2D5/D14; 2, 4, 6, 8 & 24 hrs PTD C1D5; IRN, SN-38 : PRD C1D2/D5, C2D5; PTI C1D5, C2D5; 4, 8 & 24 hrs PTD C1D5; TMZ Oral- PRD C1D5, C2D5; 1, 4, 8 & 24 hrs PTD C1D5; 1 hr PTD C2D5 or TMZ IV- PRD, PTI C1D5, C2D5]: Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Active metabolite of IRN is SN-38. In this outcome measure, clearance was reported for Phase 2 reporting group Palbociclib 75 mg/m\^2 + IRN + TMZ and not for reporting group IRN + TMZ, as pre-specified objective was to evaluate PK data of palbociclib, TMZ and IRN when given in combination. For IV administration CL/F was reported while for oral administration CL was reported. In below time frame few abbreviations have been used, where hour = hr, pre-dose = PRD, Cycle = C, Day = D, post-dose = PTD and post-infusion = PTI.
• Phase 2: Change From Baseline of Patient Reported Outcomes (PROMIS) Parent Proxy Profile v2.0 - Profile-25 Scale Score for Age >=5 to <=17 Years at Cycles 2 and 4 [Baseline, Cycles 2 and 4]: PROMIS Parent Proxy Profile V2.0 - Profile-25 instrument in this outcome measure was intended for parents serving as proxy reporters for their child (youth ages 5-17). The Profile-25 was a collection of short forms containing 4 items from six PROMIS domains (depressive symptoms, anxiety, physical function-mobility, pain interference, fatigue, and peer relationships with scores ranged from 20 to 80; where 20 = better health and 80 = worse health and for peer relationship 80 to 20; where 80 = better health and 20 = worse health along with a single item on pain intensity with 11 levels of responses from 0 (no pain) to 10 (worst pain you can think of).
• Phase 2: Change From Baseline of PROMIS Pediatric Profile v2.0 - Profile-25 Scale Score for Age >=8 to <=17 Years at Cycles 2 and 4 [Baseline, Cycles 2 and 4]: PROMIS Parent Proxy Profile V2.0 - Profile-25 instrument in this outcome measure was intended for parents serving as proxy reporters for their child (youth ages 5-17). The Profile-25 was a collection of short forms containing 4 items from six PROMIS domains (depressive symptoms, anxiety, physical function-mobility, pain interference, fatigue, and peer relationships with each item having 5 levels of responses (1=Never, 2=Almost never, 3=Sometimes, 4=Often, and 5=Almost always) along with a single item on pain intensity with 11 levels of responses from 0 (No pain) to 10 (Worst pain you can think of).
• Phase 2: Change From Baseline of PROMIS-29 Profile v2.1 Scale Score for Age >=18 Years at Cycles 2 and 4 [Baseline, Cycles 2 and 4]: PROMIS Profile-29 had eight domains (ability to participate in social roles, anxiety, depression, fatigue, pain Intensity, pain Interference, physical function, sleep disturbance). There were four items for each domain except pain intensity which had only 1 item. All items (except pain intensity) had a score of 1 to 5, when scores from each item was summed, it resulted to score ranged from 4 to 20, (except for pain intensity, where it is 1 to 10, highest score = worst pain), where for physical function highest score = without any difficulty and lowest score = unable to do; anxiety, depression, fatigue highest score = always and lowest score = never; sleep disturbance highest score = not at all, lowest score = very much; ability to participate in social roles and activities (trouble) highest score = never and lowest score = always; pain interference highest score = very much and lowest score = not at all.
• Phase 2: Average Days of Hospitalization [First dose of study treatment (Day 1) up to maximum of approximately 25 months]: Hospitalization included planned and unplanned inpatient admissions regardless the reason.

Other outcomes

• Phase 1 TSC: Number of Participants With Maximum CTCAE Grade in Chemistry Parameters - Upto Study Completion Date [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 24.2 months)]: Clinical chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, gamma glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia and hypophosphatemia. According to CTCAE version 4.03: Grade 1=mild, Grade 2=moderate, Grade 3=severe and Grade 4= life-threatening; Grade 0: non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter.
• Phase 1 TSC: Number of Participants With Post-Baseline and Maximum Change From Baseline in ECG Parameters - Upto Study Completion Date [First dose of study treatment (Day 1) up to 35 days after last dose of study treatment (maximum up to approximately 24.2 months)]: ECG parameters included PR interval, QRS interval, QT interval, Bazett's correction QT (QTcB) interval and Fridericia's correction (QTcF) interval. In this outcome measure number of participants with post-baseline values and with maximum change from baseline values in ECG parameters were recorded.
• Phase 1 TSC: Maximum Change From Baseline in Vital Signs Parameter- Blood Pressure (Upto Study Completion Date) [Baseline (pre-treatment) up to end of study treatment (maximum up to approximately 24.2 months)]: Blood pressure evaluation included systolic blood pressure (SBP) and diastolic blood pressure (DBP). SBP and DBP were measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions.
• Phase 1, Dose Expansion Cohorts and TSC: Overall Survival (OS) - Upto Study Completion Date [First dose of study treatment (Day 1) up to death due to any cause (maximum of approximately 26 months)]: OS: time from date of first dose of study treatment to the date of death due to any cause. Kaplan-Meier method was used for evaluation.
• Phase 2: OS - Upto Study Completion Date [First dose of study treatment (Day 1) up to date of death due to any cause (maximum up to 76 months of treatment exposure)]: OS: time from date of first dose of study treatment to the date of death due to any cause. Kaplan-Meier method was used for evaluation.

Sex: All, ages: 2 Years to 20 Years

Inclusion:

1. Histologically confirmed relapsed or refractory solid tumor as follows:

   * For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
   * For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
   * For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging.
2. Age ≥2 and <21 years at the time of study entry.
3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.

   * Absolute neutrophil count ≥1000/mm3;
   * Platelet count ≥75,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
   * Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
6. Adequate liver function, including:

   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

     ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
   * Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome.Patients with documented Gilbert's syndrome are eligible if direct bilirubin is within normal ranges (≤ULN).
7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or at least evaluable disease by INRC for neuroblastoma.

   The eligible patients with neuroblastoma must have at least one of the following at the time of study entry:
   * Measurable tumor by CT or MRI that is avid on MIBG scan or demonstrates increased FDG uptake on PET scan;
   * Avid lesion on MIBG scan with positive uptake at a minimum of one site;
   * For disease that is not avid by MIBG-scan, at least one lesion that demonstrates increased FDG uptake on PET scan AND viable neuroblastoma confirmed by current or prior biopsy;
   * bone marrow involvement with more than 5% neuroblastoma cells in at least one sample from bilateral bone marrow biopsies;
   * In non MIBG-avid refractory soft tissue disease that does not demonstrate increased FDG uptake; lesion biopsy is required to document the presence of viable neuroblastoma, unless patient has a new soft tissue lesion (radiographic evidence of disease progression).

   Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.

Exclusion:

1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. For patients enrolled in the UK, any contraindication for IRN and/or TMZ treatment, as per the local SmPC.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within 12 days of study entry. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.)
4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
5. Prior irradiation to >50% of the bone marrow (see Appendix 9).
6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease, including:

    * History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
    * Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    * Diagnosed or suspected congenital or acquired prolonged QT syndrome;
    * Need for medications known to prolong the QT interval;
    * Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
    * Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
15. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. Screening for viral hepatitis and HIV is under discretion of investigator unless required by local regulation.
16. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
17. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
18. Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements.
19. Pregnant or breastfeeding women.

• Study Protocol (PDF, 2023-05-31)
• Statistical Analysis Plan (PDF, 2023-08-25)

• Pfizer CT.gov Call Center, Study director, Pfizer