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

Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03709680
• Other study ID #: A5481092
• Secondary ID: 2021-003444-25
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: May 24, 2019
• Est. completion date: February 25, 2025

Study information

• Verified date: June 2024
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 128
• Est. completion date: February 25, 2025
• Est. primary completion date: August 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 20 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Ewing Sarcoma
• Medulloblastoma
• Neoplasms
• Neuroblastoma
• Rhabdoid Tumor
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing
• Solid Tumors

Intervention

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
• Temozolomide
Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle
• Irinotecan
Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
• Topotecan
Phase 1 only : Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
• Cyclophosphamide
Phase 1 only: Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle

Locations

Country	Name	City	State
Argentina	Hospital Universitario Austral	Pilar	Buenos Aires
Belgium	Cliniques universitaires Saint-Luc	Brussels	Bruxelles-capitale, Région DE
Belgium	Antwerp University Hospital	Edegem	Antwerpen
Belgium	UZ Gent	Gent	Oost-vlaanderen
Belgium	UZ Leuven	Leuven	Vlaams-brabant
Brazil	Fundação Pio XII - Hospital de Câncer de Barretos	Barretos	SÃO Paulo
Brazil	Hospital Pequeno Príncipe	Curitiba	Paraná
Brazil	Hospital Pequeno Principe / A ssociacao Hospitalar de Protecao a Infancia	Curitiba	Parana
Brazil	Hospital Pequeno Principe / A ssociacao Hospitalar de Protecao a Infancia	Curitiba	Paraná
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RIO Grande DO SUL
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RIO Grande DO SUL
Brazil	Instituto Nacional de Câncer - INCA	Rio de Janeiro
Brazil	Hospital Santa Marcelina	São Paulo
Bulgaria	UMHAT Tsaritsa Yoanna-ISUL EAD	Sofia
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Stollery Children's Hospital	Edmonton	Alberta
Canada	CHU Sainte-Justine	Montreal	Quebec
Canada	The Hospital for Sick Children	Toronto	Ontario
Czechia	Detska nemocnice FN Brno	Brno	Brno-mesto
Czechia	Fakultni nemocnice v Motole	Praha	Praha 5
France	Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest	Bordeaux	Aquitaine
France	Centre Leon Berard	Lyon	Rhône-alpes
France	Centre Leon Berard	Lyon	Rhône-alpes
France	Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone	Marseille
France	Gustave Roussy	Villejuif	Val-de-marne
Germany	Universitaetsklinikum Erlangen	Erlangen	Bayern
Germany	Universitätsklinikum Essen	Essen	Nordrhein-westfalen
Hungary	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház	Miskolc	Borsod-abaúj-zemplén
Hungary	Pecsi Tudomanyegyetem Klinikai Kozpont	Pecs
India	Artemis hospital	Gurugram	Haryana
India	All India Institute of Medical Sciences	New Delhi	Delhi
India	Rajiv Gandhi Cancer Institute And Research Centre	New Delhi	Delhi
Israel	Tel-Aviv Sourasky Medical Center Dana-Dwek Children's Hospital	Tel Aviv	Tell Abib
Italy	A.O.Universitaria Meyer	Firenze	Toscana
Italy	Ospedale Pediatrico Bambino Gesù IRCCS	Rome	Roma
Korea, Republic of	National Cancer Center	Goyang-si	Kyonggi-do
Korea, Republic of	Asan Medical Center	Seoul	Seoul-teukbyeolsi [seoul]
Korea, Republic of	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [seoul]
Korea, Republic of	Seoul National University Hospital	Seoul	Seoul-teukbyeolsi [seoul]
Netherlands	Prinses Maxima Centrum voor Kinderoncologie	Utrecht
Poland	Instytut Matki i Dziecka	Warsaw	Mazowieckie
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Slovakia	Detska Fakultna nemocnica s poliklinikou Banska Bystrica	Banska Bystrica
Slovakia	Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska Bystrica, Oddelenie radiologie	Banska Bystrica
Slovakia	Institut nuklearnej a molekularnej mediciny	Banska Bystrica
Slovakia	BIONT, a.s.	Bratislava
Slovakia	Narodny ustav detskych chorob	Bratislava
Slovakia	Narodny ustav detskych chorob	Bratislava
Spain	Hospital Universitari Vall d'Hebron	Barcelona	Barcelona [barcelona]
Spain	Hospital Sant Joan de Déu	Esplugues de Llobregat	Barcelona [barcelona]
Spain	Hospital Infantil Universitario Niño Jesús	Madrid	Madrid, Comunidad DE
Spain	Hospital Universitario Virgen Del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	València
Sweden	Sahlgrenska Universitetssjukhuset Östra	Gothenburg	Västra Götalands LÄN [se-14]
Sweden	Astrid Lindgrens Barnsjukhus	Stockholm
Turkey	Hacettepe Universite Hastaneleri	Ankara
Turkey	Ege Universitesi Hastanesi	Izmir	I?zmir
United Kingdom	Royal Hospital for Children	Glasgow	Scotland
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	University College London Hospital	London	London, CITY OF
United Kingdom	University College London Hospital, NHS Foundation Trust	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	The Christie NHS Foundation Trust	Manchester	Greater Manchester
United Kingdom	Royal Victoria Infirmary	Newcastle upon Tyne	England
United Kingdom	Royal Victoria Infirmary	Newcastle upon Tyne	England
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia
United States	Children's Healthcare of Atlanta at Scottish Rite	Atlanta	Georgia
United States	Children's Healthcare of Atlanta, Medical Office Building	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's Blood and Cancer Center	Austin	Texas
United States	Dell Children's Medical Center	Austin	Texas
United States	Johns Hopkins University	Baltimore	Maryland
United States	Children's of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham/Children's of Alabama	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	John R. Oishei Childrens Hospital	Buffalo	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Carolinas Medical Center/Levine Children's Hospital	Charlotte	North Carolina
United States	Torrence E. Hemby Jr. Pediatric Hematology & Oncology Center	Charlotte	North Carolina
United States	Torrey Hemby Center for Cancer and Blood Disorders	Charlotte	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center Dallas	Dallas	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	UF Health Shands Hospital	Gainesville	Florida
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Cook Children's H/O Infusion Center	Grapevine	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital and Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Texas Children's Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Cincinnati Children's Liberty Campus	Liberty Township	Ohio
United States	MemorialCare Health System - Long Beach Medical Center	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Novak Center for Children's Health	Louisville	Kentucky
United States	Children's Wisconsin	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	University of Minnesota Masonic Children's Hospital	Minneapolis	Minnesota
United States	University of Minnesota Medical Center, Fairview	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Cohen Children's Medical Center	New Hyde Park	New York
United States	Columbia University Medical Center - Herbert Irving Pavilion	New York	New York
United States	Morgan Stanley Children's Hospital of New York-Presbyetrian Hospital	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Lucile Packard Children's Hospital	Palo Alto	California
United States	University of Illinois College of Medicine at Peoria	Peoria	Illinois
United States	Buerger Center for Advanced Pediatric Care	Philadelphia	Pennsylvania
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Children's Medical Center Plano	Plano	Texas
United States	Oregon Health & Science University	Portland	Oregon
United States	Children's Hospital of Richmond at VCU	Richmond	Virginia
United States	Children's Hospital of Richmond at VCU	Richmond	Virginia
United States	Mayo Clinic in Rochester, Minnesota	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Johns Hopkins All Children's Outpatient Care Center	Saint Petersburg	Florida
United States	Intermountain - Primary Children's Hospital	Salt Lake City	Utah
United States	Primary Children's Hospital Outpatient Services	Salt Lake City	Utah
United States	UCSF Medical Center	San Francisco	California
United States	University of California San Francisco,	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Johns Hopkins All Children's Hospital	Tampa	Florida
United States	Children's National Hospital	Washington	District of Columbia
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Children's Oncology Group (COG)

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Slovakia,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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)
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.

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