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

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

A study to learn about safety and find out maximum tolerable dose of palbociclib given in combination with chemotherapy (temozolomide with irinotecan or topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors (phase 1). Neuroblastoma tumor specific cohort to further evaluate antitumor activity of palbociclib in combination with topotecan and cyclophosphamide in children, adolescents, and young adults with recurrent or refractory neuroblastoma. Phase 2 to learn about the efficacy of palbociclib in combination with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the treatment of children, adolescents, and young adults with recurrent or refractory Ewing sarcoma (EWS).

Study Overview

• Status: Active, not recruiting
• Conditions: Ewing Sarcoma; Medulloblastoma; Rhabdoid Tumor; Neuroblastoma; Solid Tumors; Rhabdomyosarcoma; Diffuse Intrinsic Pontine Glioma
• Intervention / Treatment: Drug: Temozolomide; Drug: Irinotecan; Drug: Topotecan; Drug: Cyclophosphamide; Drug: Palbociclib

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 20230-130
    • Instituto Nacional de Cancer - INCa
  • São Paulo, Brazil, 08270-070
    • Hospital Santa Marcelina
  • Paraná
    • Curitiba, Paraná, Brazil, 80250-060
      • Hospital Pequeno Principe / A ssociacao Hospitalar de Protecao a Infancia
    • Curitiba, Paraná, Brazil, 80250-060
      • Hospital Pequeno Principe
  • RIO Grande DO SUL
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90410000
      • Hospital de Clinicas de Porto Alegre
  • SÃO Paulo
    • Barretos, SÃO Paulo, Brazil, 14784400
      • Fundação Pio XII - Hospital de Câncer de Barretos
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • Stollery Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • CHU Sainte-Justine
• Czechia
  • Brno-město
    • Brno, Brno-město, Czechia, 613 00
      • Detska nemocnice FN Brno
  • Praha 5
    • Praha, Praha 5, Czechia, 150 06
      • Fakultni nemocnice v Motole
• France
  • Marseille, France, 13385
    • Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone
  • Aquitaine
    • Bordeaux, Aquitaine, France, 33076
      • Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest
  • Rhône-alpes
    • Lyon, Rhône-alpes, France, 69008
      • Centre Leon Berard
    • Lyon, Rhône-alpes, France, 69373 CEDEX 08
      • Centre Leon Berard
  • Val-de-marne
    • Villejuif, Val-de-marne, France, 94800
      • Gustave Roussy
• Germany
  • Nordrhein-westfalen
    • Essen, Nordrhein-westfalen, Germany, 45122
      • Universitätsklinikum Essen
• India
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences
    • New Delhi, Delhi, India, 110085
      • Rajiv Gandhi Cancer Institute And Research Centre
  • Haryana
    • Gurugram, Haryana, India, 122001
      • Artemis Hospital
• Korea, Republic of
  • Kyǒnggi-do
    • Goyang-si, Kyǒnggi-do, Korea, Republic of, 10408
      • National Cancer Center
  • Seoul-teukbyeolsi [seoul]
    • Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 05505
      • Asan Medical Center
    • Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 03080
      • Seoul National University Hospital
    • Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 06351
      • Samsung Medical Center
• Poland
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 01-211
      • Instytut Matki i Dziecka
• Slovakia
  • Banska Bystrica, Slovakia, 974 09
    • Detska fakultna nemocnica s poliklinikou Banska Bystrica
  • Bratislava, Slovakia, 83340
    • Narodny ustav detskych chorob
• Spain
  • Barcelona [barcelona]
    • Barcelona, Barcelona [barcelona], Spain, 08035
      • Hospital Universitari Vall d'Hebron
  • Madrid, Comunidad DE
    • Madrid, Madrid, Comunidad DE, Spain, 28009
      • Hospital Infantil Universitario Nino Jesus
• Sweden
  • Västra Götalands LÄN [se-14]
    • Gothenburg, Västra Götalands LÄN [se-14], Sweden, 416 50
      • Sahlgrenska Universitetssjukhuset Östra
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe Universite Hastaneleri
  • İ̇zmir
    • İzmir, İ̇zmir, Turkey, 35100
      • Ege Universitesi Hastanesi
• United Kingdom
  • Leeds, United Kingdom, LS1 3EX
    • Leeds General Infirmary
  • London, United Kingdom, NW1 2PG
    • University College London Hospital, NHS Foundation Trust
  • England
    • Newcastle upon Tyne, England, United Kingdom, NE1 4LP
      • Royal Victoria Infirmary
  • Scotland
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Royal Hospital For Children
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham/Children's of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Long Beach, California, United States, 90806
      • MemorialCare Health System - Long Beach Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital
    • San Francisco, California, United States, 94158
      • UCSF Medical Center
    • San Francisco, California, United States, 94158
      • University of California San Francisco,
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
    • Gainesville, Florida, United States, 32610
      • UF Health Shands Hospital
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Outpatient Care Center
    • Tampa, Florida, United States, 33612
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta at Scottish Rite
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta, Medical Office Building
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Children's Hospital
    • Louisville, Kentucky, United States, 40202
      • Novak Center for Children's Health
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center, Fairview
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Masonic Children's Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson University Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Buffalo, New York, United States, 14203
      • John R. Oishei Childrens Hospital
    • New Hyde Park, New York, United States, 11040
      • Cohen Children's Medical Center
    • New York, New York, United States, 10032
      • Morgan Stanley Children's Hospital of New York-Presbyetrian Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Liberty Township, Ohio, United States, 45044
      • Cincinnati Children's Liberty Campus
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital and Penn State Health Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • Buerger Center for Advanced Pediatric Care
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center
    • Austin, Texas, United States, 78723
      • Children's Blood and Cancer Center
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Grapevine, Texas, United States, 76051
      • Cook Children's H/O Infusion Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Plano, Texas, United States, 75024
      • Children's Medical Center Plano
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital Outpatient Services
    • Salt Lake City, Utah, United States, 84113
      • Intermountain - Primary Children's Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23219
      • Children's Hospital of Richmond at VCU
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2 Arm A; Palbociclib in combination with irinotecan and temozolomide.	Drug: Temozolomide; Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle; Other Names: Temodar; Drug: Irinotecan; Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Campto; Drug: Palbociclib; 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; Other Names: Ibrance
Experimental: Phase 1; Palbociclib in combination with temozolomide and irinotecan and/or with topotecan and cyclophosphamide.	Drug: Temozolomide; Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle; Other Names: Temodar; Drug: Irinotecan; Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Campto; Drug: Topotecan; Phase 1 only : Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Hycamtin; Drug: Cyclophosphamide; Phase 1 only: Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Cytoxan; Drug: Palbociclib; 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; Other Names: Ibrance
Active Comparator: Phase 2 Arm B; Irinotecan and temozolomide alone.	Drug: Temozolomide; Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle; Other Names: Temodar; Drug: Irinotecan; Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Campto
Experimental: Phase 1 Tumor specific cohort - Neuroblastoma; Palbociclib in combination with topotecan and cyclophosphamide.	Drug: Topotecan; Phase 1 only : Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Hycamtin; Drug: Cyclophosphamide; Phase 1 only: Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle; Other Names: Cytoxan; Drug: Palbociclib; 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; Other Names: Ibrance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2 open-label, randomized: Event-free survival (EFS) based on Investigator assessment.	EFS is defined as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence).	Baseline to Month 24.
Phase 1: First Cycle Dose-Limiting Toxicities (DLT)	For Dose Escalation/Determination Part: DLT defined as any of the following events occurring during the first treatment cycle and considered at least possibly-related to study medication:Grade 4 neutropenia lasting greater than 7 days;Grade 4 thrombocytopenia lasting greater than 7 days or need for platelet transfusion for a platelet count of < 20,000 per cubic millimeters twice within a 7-day period;greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia;Grade 3 or greater non-hematologic toxicities despite optimal treatment;any Grade 2 or greater non-hematologic toxicity requiring discontinuation or interruption of palbociclib for 7 or more consecutive days during the first cycle or any grade non-hematologic toxicity that delays the start of Cycle 2 by more than 14 days;clinically significant non-hematologic laboratory test abnormality Grade 3 or greater not resolving to Grade 1 or baseline within 7 days.	First cycle (cycle length is approximately 21 days)
Phase 1: Dose Expansion Parts: Frequency of adverse events	For Dose Expansion and Tumor-Specific Expansion Parts: Adverse events to be reported during treatment and for at least 28 days after last dose.	At least 28 days after last dose
Phase 1: Dose Expansion Parts: Percentage of Participants With Complete Response or Partial Response	For Dose Expansion and Tumor-Specific Expansion Parts: patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies, or International Neuroblastoma Response Criteria (INRC) for neuroblastoma, during study treatment, assessed approximately every 2 to 4 cycles (each cycle is approximately 21 days).	Through the end of treatment (up to at least 28 days after last dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 and Phase 2: Frequency of adverse events	Adverse events to be reported during treatment and for at least 28 days after last dose.	At least 28 days after last dose
Phase 1 and Phase 2: Percentage of participants with laboratory abnormalities	Magnesium, Calcium, Creatinine, Albumin, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Phosphorus, Total Bilirubin, Blood urea nitrogen, Alkaline phosphatase, Sodium, Potassium, Chloride, Platelet Count, White Blood Cell Count (differential), hemoglobin, INR or prothrombin Time, HbA1c	At least 28 days after last dose
Phase 1 and Phase 2: Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings	Clinically significant ECG findings included: corrected QT (QTc) > 450 ms, QTc >500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.	At least 28 days after last dose
Phase 1 and Phase 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs	systolic and diastolic blood pressure, pulse	At least 28 days after last dose
Phase 2 open-label, randomized: Event-free survival (EFS) assessed by an independent review committee.	EFS is defined as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence).	Baseline to Month 24.
Phase 1 and Phase 2: Percentage of Participants With Complete Response or Partial Response	Patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies, or International Neuroblastoma Response Criteria (INRC) for neuroblastoma, during study treatment, assessed approximately every 2 to 4 cycles (each cycle is approximately 21 days).	Through the end of treatment (up to at least 28 days after last dose)
Phase 1 and Phase 2: Duration of response (DoR) for Participants Who Achieved Complete Response or Partial Response	DoR defined as time from date of first response (Complete Response or Partial Response) in responders to date of progression or death	Up to 2 years
Phase 1 and Phase 2: Progression Free Survival (PFS)	PFS defined as time from date of enrollment to earliest date of the death or progressive disease	Up to 2 years
Phase 1 and Phase 2: Overall Survival (OS)	OS defined as the time from enrollment to date of death due to any cause.	Up to 2 years
Phase 2 : comparison of PET-CT response assessment to objective response on CT/MRI.	PET-CT response assessment will be compared to objective response on MRI/CT, as data permit.	up to completion of Cycle 4 ( 12 weeks of therapy)
Phase 2: the impact of the combination of palbociclib with TMZ and IRN treatment on the quality of life (QoL) of patients with refractory or recurrent EWS.	Results of QoL reported by patient at baseline and after 2 and 4 cycles using age-appropriate PROMIS tools will be summarized for both treatment arms, as data permit. Days of hospitalization will be compared in both treatment arms.	Up to Cycle 5 (completion of 12 weeks of treatment)
Phase 1 and Phase 2:Palbociclib Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Maximum plasma concentration time (Tmax)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2,5, 6,14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Oral plasma clearance (CL/F)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Maximum plasma concentration time (Tmax)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Oral plasma clearance (CL/F)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Irinotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Topotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Cyclophosphamide Pharmacokinetics, Oral plasma clearance (CL/F)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Cyclophosphamide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Cyclophosphamide Pharmacokinetics, Maximum plasma concentration time (Tmax)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Cyclophosphamide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Phase 1: Cyclophosphamide Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)	Multiple Dose (assuming steady state is achieved), as data permit	PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Children's Oncology Group
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2019
• Primary Completion (Actual): August 26, 2024
• Study Completion (Estimated): October 18, 2025

Study Registration Dates

• First Submitted: October 9, 2018
• First Submitted That Met QC Criteria: October 15, 2018
• First Posted (Actual): October 17, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 13, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Temozolomide; Cyclophosphamide; Topotecan; Pediatric Cancer; Childhood Cancer; Solid Tumor; Irinotecan; Ewing Sarcoma; Soft Tissue Cancer; Soft Tissue Sarcoma; Neuroblastoma; EWS; Refractory Solid Tumors; Palbociclib; Bone Tumor; Bone Cancer; Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma; Recurrent Neuroblastoma; CDK4/6 Inhibitor; Recurrent Solid Tumors; Bone Sarcoma; Recurrent Ewing Sarcoma; Ewing Sarcoma Treatment
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neoplasms, Connective and Soft Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Central Nervous System Neoplasms; Neoplasms, Muscle Tissue; Neoplasms, Complex and Mixed; Myosarcoma; Brain Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Neoplasms; Neuroblastoma; Sarcoma, Ewing; Sarcoma; Rhabdomyosarcoma; Medulloblastoma; Rhabdoid Tumor; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Protein Kinase Inhibitors; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Temozolomide; Irinotecan; Cyclophosphamide; Palbociclib; Topotecan
• Other Study ID Numbers: A5481092; 2024-511975-14-00 (Registry Identifier: CTIS (EU))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes