PHASE 1/2 STUDY TO EVALUATE PALBOCICLIB (IBRANCE® ) IN COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE OR IN COMBINATION WITH TOPOTECAN AND CYCLOPHOSPHAMIDE IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS

INTERVENTION: Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Palbociclib CAS Number: 571190‐30‐2 Current Sponsor code: PD‐0332991 Other descriptive name: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Palbociclib CAS Number: 571190‐30‐2 Current Sponsor code: PD‐0332991 Other descriptive name: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Palbociclib CAS Number: 571190‐30‐2 Current Sponsor code: PD‐0332991 Other descriptive name: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Oral solution INN or Proposed INN: Palbociclib CAS Number: 571190‐30‐2 Current Sponsor code: PD‐0332991 Other descriptive name: PD‐0332991 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 25‐ Trade Name: Temozolomide Product Name: Temozolomide Pharmaceutical Form: Capsule, hard INN or Proposed INN: Temozolomide CAS Number: 85622‐93‐1 Current Sponsor code: ‐ Other descriptive name: ‐ Concentration unit: mg milligram(s) Concentration type: not less then Concentration number: 5‐ Trade Name: Temozolomide Product Name: Temozolomide Product Code: ‐ Pharmaceutical Form: Capsule, hard INN or Proposed INN: Temozolomide CAS Number: 85622‐93‐1 Current Sponsor code: ‐ Other descriptive name: ‐ Concentration unit: mg milligram(s) Concentration type: equal Concentration number: CONDITION: recurrent/refractory Ewing sarcoma ; MedDRA version: 20.0 Level: PT Classification code 10015560 Term: Ewing's sarcoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): • Objective response (OR), as assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ; • PET‐CT response after cycle 4 compared to objective response on MRI/CT. ; • Progression free survival (PFS) based on investigator assessment. ; • Overall survival (OS). ; • Adverse Events (AEs) as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version 4.03. ; • Pharmacokinetic parameters of palbociclib, TMZ, IRN: ; • Palbociclib PK: MD (assuming steady state is achieved) ‐ Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit. ; • TMZ PK: MD ‐ Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit. ; • IRN (and active metabolite, SN‐38) PK: MD ‐ Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit. ; • QoL reported by patient at baseline and after 2 and 4 cycles using age‐appropriate tools. ; • Days of hospitalization. Timepoint(s) of evaluation of this end point: at baseline and after 2 and 4 cycles INCLUSION CRITERIA: 1. Histologically confirmed relapsed or refractory solid tumor as follows: 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 =100,000/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/g PRIMARY OUTCOME: Main Objective: ‐ To compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone in the treatment of children, adolescents, and young adults with recurrent or refractory EWS. Primary end point(s): • Event‐free survival (EFS) based on investigator assessment. Secondary Objective: ‐ To further compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone.; ‐ To characterize the toxicity and safety of the combination of TMZ and IRN plus or minus palbociclib.; ‐ To describe the PK of palbociclib, TMZ, and IRN in children, adolescents, and young adults with recurrent or refractory EWS when given in combination.; ‐ To assess the impact of the combination of palbociclib with TMZ and IRN treatment on the quality of life (QoL) of patients with; refractory and recurrent EWS. Timepoint(s) of evaluation of this end point: time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence). • For randomized Phase 2 part: Histologically confirmed Ewing sarcoma. Histopathology confirmation of EWSR1‐ETS or FUS‐ETS rearrangement is required or availability of formalin‐fixed paraffin‐embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or refractory disease with no known bone marrow metastases and at least evaluable disease.