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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

Hospitalization included planned and unplanned inpatient admissions regardless the reason.