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

• ClinicalTrials.gov Identifier: NCT03709680
• Recruitment Status: Active, not recruiting
• First Posted: October 17, 2018
• Last Update Posted: March 26, 2024
• Sponsor: Pfizer
• Collaborator: Children's Oncology Group (COG)
• Information provided by (Responsible Party): Pfizer

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Ewing Sarcoma; Solid Tumors; Rhabdoid Tumor; Rhabdomyosarcoma; Neuroblastoma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma	Drug: Palbociclib; Drug: Temozolomide; Drug: Irinotecan; Drug: Topotecan; Drug: Cyclophosphamide	Phase 1; Phase 2

Expanded Access : Pfizer has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Phase 1 portion: The palbociclib plus irinotecan and temozolomide combination part of the study will comprise of a dose escalation cohort (following a rolling 6 design), a dose expansion cohort.

The palbociclib plus topotecan and cyclophosphamide will comprise of a dose determination cohort(following a modified rolling 6 design), a dose expansion cohort, and Neuroblastoma tumor -specific cohort.

Phase 2 open-label, randomized portion of the study will randomize patients in a 2:1 ratio to receive either palbociclib in combination with irinotecan and temozolomide (Arm A) or irinotecan and temozolomide chemotherapy alone (Arm B). Randomization will be stratified using block randomization by type and time of current disease recurrence (primary refractory or 1st recurrence < 2 years versus 1st recurrence ≥ 2 years or 2nd or greater recurrence).

• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 24, 2019
• Estimated Primary Completion Date: June 24, 2024
• Estimated Study Completion Date: February 25, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Phase 2 open-label, randomized: Event-free survival (EFS) based on Investigator assessment. [ Time Frame: Baseline to Month 24. ]
   EFS is defined as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence).
2. Phase 1: First Cycle Dose-Limiting Toxicities (DLT) [ Time Frame: First cycle (cycle length is approximately 21 days) ]
   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.
3. Phase 1: Dose Expansion Parts: Frequency of adverse events [ Time Frame: At least 28 days after last dose ]
   For Dose Expansion and Tumor-Specific Expansion Parts: Adverse events to be reported during treatment and for at least 28 days after last dose.
4. Phase 1: Dose Expansion Parts: Percentage of Participants With Complete Response or Partial Response [ Time Frame: Through the end of treatment (up to at least 28 days after last dose) ]
   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).

Secondary Outcome Measures :

1. Phase 1 and Phase 2: Frequency of adverse events [ Time Frame: At least 28 days after last dose ]
   Adverse events to be reported during treatment and for at least 28 days after last dose.
2. Phase 1 and Phase 2: Percentage of participants with laboratory abnormalities [ Time Frame: At least 28 days after last dose ]
   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
3. Phase 1 and Phase 2: Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings [ Time Frame: At least 28 days after last dose ]
   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.
4. Phase 1 and Phase 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: At least 28 days after last dose ]
   systolic and diastolic blood pressure, pulse
5. Phase 2 open-label, randomized: Event-free survival (EFS) assessed by an independent review committee. [ Time Frame: Baseline to Month 24. ]
   EFS is defined as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence).
6. Phase 1 and Phase 2: Percentage of Participants With Complete Response or Partial Response [ Time Frame: Through the end of treatment (up to at least 28 days after last dose) ]
   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).
7. Phase 1 and Phase 2: Duration of response (DoR) for Participants Who Achieved Complete Response or Partial Response [ Time Frame: Up to 2 years ]
   DoR defined as time from date of first response (Complete Response or Partial Response) in responders to date of progression or death
8. Phase 1 and Phase 2: Progression Free Survival (PFS) [ Time Frame: Up to 2 years ]
   PFS defined as time from date of enrollment to earliest date of the death or progressive disease
9. Phase 1 and Phase 2: Overall Survival (OS) [ Time Frame: Up to 2 years ]
   OS defined as the time from enrollment to date of death due to any cause.
10. Phase 2 : comparison of PET-CT response assessment to objective response on CT/MRI. [ Time Frame: up to completion of Cycle 4 ( 12 weeks of therapy) ]
    PET-CT response assessment will be compared to objective response on MRI/CT, as data permit.
11. 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. [ Time Frame: Up to Cycle 5 (completion of 12 weeks of treatment) ]

    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.

12. Phase 1 and Phase 2:Palbociclib Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: 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. ]
    Multiple Dose (assuming steady state is achieved), as data permit
13. Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: 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. ]
    Multiple Dose (assuming steady state is achieved), as data permit
14. Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: 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. ]
    Multiple Dose (assuming steady state is achieved), as data permit
15. 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) [ Time Frame: 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. ]
    Multiple Dose (assuming steady state is achieved), as data permit
16. Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: 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. ]
    Multiple Dose (assuming steady state is achieved), as data permit
17. Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
18. Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
19. Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
20. 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) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
21. Phase 1 and Phase 2: Temozolomide Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
22. Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
23. Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
24. 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) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
25. 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) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
26. Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
27. Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
28. 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) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
29. Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
30. Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
31. Phase 1: Topotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
32. Phase 1: Cyclophosphamide Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
33. Phase 1: Cyclophosphamide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
34. Phase 1: Cyclophosphamide Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
35. Phase 1: Cyclophosphamide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit
36. Phase 1: Cyclophosphamide Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

Children's of Alabama

Birmingham, Alabama, United States, 35233

University of Alabama at Birmingham/Children's of Alabama

Birmingham, Alabama, United States, 35233

United States, Arizona

Phoenix Children's Hospital

Phoenix, Arizona, United States, 85016

United States, California

MemorialCare Health System - Long Beach Medical Center

Long Beach, California, United States, 90806

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

Children's Hospital and Research Center at Oakland

Oakland, California, United States, 94609

Children's Hospital of Orange County

Orange, California, United States, 92868

Lucile Packard Children's Hospital

Palo Alto, California, United States, 94304

UCSF Medical Center

San Francisco, California, United States, 94158

University of California San Francisco,

San Francisco, California, United States, 94158

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Connecticut

Connecticut Children's Medical Center

Hartford, Connecticut, United States, 06106

United States, District of Columbia

Children's National Hospital

Washington, District of Columbia, United States, 20010

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Florida

UF Health Shands Hospital

Gainesville, Florida, United States, 32610

University of Florida College of Medicine

Gainesville, Florida, United States, 32610

Arnold Palmer Hospital for Children

Orlando, Florida, United States, 32806

Johns Hopkins All Children's Hospital

Saint Petersburg, Florida, United States, 33701

Johns Hopkins All Children's Outpatient Care Center

Saint Petersburg, Florida, United States, 33701

Johns Hopkins All Children's Hospital

Tampa, Florida, United States, 33612

United States, Georgia

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, United States, 30322

Children's Healthcare of Atlanta at Scottish Rite

Atlanta, Georgia, United States, 30342

Children's Healthcare of Atlanta, Medical Office Building

Atlanta, Georgia, United States, 30342

United States, Hawaii

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii, United States, 96826

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States, 60611

University of Illinois College of Medicine at Peoria

Peoria, Illinois, United States, 61605

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202-5225

United States, Kentucky

Norton Children's Hospital

Louisville, Kentucky, United States, 40202

Novak Center for Children's Health

Louisville, Kentucky, United States, 40202

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

University of Michigan Health System

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

University of Minnesota Masonic Children's Hospital

Minneapolis, Minnesota, United States, 55454

University of Minnesota Medical Center, Fairview

Minneapolis, Minnesota, United States, 55455

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States, 55455

University of Minnesota

Minneapolis, Minnesota, United States, 55455

Mayo Clinic in Rochester, Minnesota

Rochester, Minnesota, United States, 55905

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

Robert Wood Johnson University Hospital

New Brunswick, New Jersey, United States, 08901

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

John R. Oishei Childrens Hospital

Buffalo, New York, United States, 14203

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Cohen Children's Medical Center

New Hyde Park, New York, United States, 11040

Columbia University Medical Center - Herbert Irving Pavilion

New York, New York, United States, 10032

Morgan Stanley Children's Hospital of New York-Presbyetrian Hospital

New York, New York, United States, 10032

SUNY Upstate Medical University

Syracuse, New York, United States, 13210

United States, North Carolina

Carolinas Medical Center/Levine Children's Hospital

Charlotte, North Carolina, United States, 28203

Torrence E. Hemby Jr. Pediatric Hematology & Oncology Center

Charlotte, North Carolina, United States, 28203

Torrey Hemby Center for Cancer and Blood Disorders

Charlotte, North Carolina, United States, 28203

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States, 44106

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

Nationwide Children's Hospital

Columbus, Ohio, United States, 43215

Cincinnati Children's Liberty Campus

Liberty Township, Ohio, United States, 45044

United States, Oklahoma

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73104

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Penn State Children's Hospital and Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 17033-0850

Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Buerger Center for Advanced Pediatric Care

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

Children's Blood and Cancer Center

Austin, Texas, United States, 78723

Dell Children's Medical Center

Austin, Texas, United States, 78723

Children's Medical Center Dallas

Dallas, Texas, United States, 75235

Cook Children's Medical Center

Fort Worth, Texas, United States, 76104

Cook Children's H/O Infusion Center

Grapevine, Texas, United States, 76051

Texas Children's Hospital

Houston, Texas, United States, 77030

Children's Medical Center Plano

Plano, Texas, United States, 75024

United States, Utah

Intermountain - Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

Primary Children's Hospital Outpatient Services

Salt Lake City, Utah, United States, 84113

United States, Virginia

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States, 23507

Children's Hospital of Richmond at VCU

Richmond, Virginia, United States, 23219

Children's Hospital of Richmond at VCU

Richmond, Virginia, United States, 23298

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

United States, Wisconsin

Children's Wisconsin

Milwaukee, Wisconsin, United States, 53226

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Argentina

Hospital Universitario Austral

Pilar, Buenos Aires, Argentina, 1629

Belgium

Antwerp University Hospital

Edegem, Antwerpen, Belgium, 2650

Cliniques universitaires Saint-Luc

Brussels, Bruxelles-capitale, Région DE, Belgium, 1200

UZ Gent

Gent, Oost-vlaanderen, Belgium, 9000

UZ Leuven

Leuven, Vlaams-brabant, Belgium, 3000

Brazil

Hospital Pequeno Principe / A ssociacao Hospitalar de Protecao a Infancia

Curitiba, Parana, Brazil, 80250-060

Hospital Pequeno Principe / A ssociacao Hospitalar de Protecao a Infancia

Curitiba, Paraná, Brazil, 80250-060

Hospital Pequeno Príncipe

Curitiba, Paraná, Brazil, 80250-060

Hospital de Clinicas de Porto Alegre

Porto Alegre, RIO Grande DO SUL, Brazil, 90035-903

Hospital de Clinicas de Porto Alegre

Porto Alegre, RIO Grande DO SUL, Brazil, 90410000

Fundação Pio XII - Hospital de Câncer de Barretos

Barretos, SÃO Paulo, Brazil, 14784400

Instituto Nacional de Câncer - INCA

Rio de Janeiro, Brazil, 20230-130

Hospital Santa Marcelina

São Paulo, Brazil, 08270-070

Bulgaria

UMHAT Tsaritsa Yoanna-ISUL EAD

Sofia, Bulgaria, 1527

Canada, Alberta

Alberta Children's Hospital

Calgary, Alberta, Canada, T3B 6A8

Stollery Children's Hospital

Edmonton, Alberta, Canada, T6G 2B7

Canada, Ontario

The Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

Canada, Quebec

CHU Sainte-Justine

Montreal, Quebec, Canada, H3T 1C5

Czechia

Detska nemocnice FN Brno

Brno, Brno-město, Czechia, 613 00

Fakultni nemocnice v Motole

Praha, Praha 5, Czechia, 150 06

France

Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest

Bordeaux, Aquitaine, France, 33076

Centre Leon Berard

Lyon, Rhône-alpes, France, 69008

Centre Leon Berard

Lyon, Rhône-alpes, France, 69373 CEDEX 08

Gustave Roussy

Villejuif, Val-de-marne, France, 94800

Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone

Marseille, France, 13385

Germany

Universitaetsklinikum Erlangen

Erlangen, Bayern, Germany, 91054

Universitätsklinikum Essen

Essen, Nordrhein-westfalen, Germany, 45122

Hungary

Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház

Miskolc, Borsod-abaúj-zemplén, Hungary, 3526

Pecsi Tudomanyegyetem Klinikai Kozpont

Pecs, Hungary, 7623

India

All India Institute of Medical Sciences

New Delhi, Delhi, India, 110029

Rajiv Gandhi Cancer Institute And Research Centre

New Delhi, Delhi, India, 110085

Artemis hospital

Gurugram, Haryana, India, 122001

Israel

Tel-Aviv Sourasky Medical Center Dana-Dwek Children's Hospital

Tel Aviv, Tell Abīb, Israel, 6423906

Italy

Ospedale Pediatrico Bambino Gesù IRCCS

Rome, Roma, Italy, 00165

A.O.Universitaria Meyer

Firenze, Toscana, Italy, 50139

Korea, Republic of

National Cancer Center

Goyang-si, Kyǒnggi-do, Korea, Republic of, 10408

Seoul National University Hospital

Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 03080

Asan Medical Center

Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 05505

Samsung Medical Center

Seoul, Seoul-teukbyeolsi [seoul], Korea, Republic of, 06351

Netherlands

Prinses Maxima Centrum voor Kinderoncologie

Utrecht, Netherlands, 3584 CS

Poland

Instytut Matki i Dziecka

Warsaw, Mazowieckie, Poland, 01-211

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu

Wroclaw, Poland, 50-556

Slovakia

Detska Fakultna nemocnica s poliklinikou Banska Bystrica

Banska Bystrica, Slovakia, 974 09

Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska Bystrica, Oddelenie radiologie

Banska Bystrica, Slovakia, 975 17

Institut nuklearnej a molekularnej mediciny

Banska Bystrica, Slovakia, 97517

Narodny ustav detskych chorob

Bratislava, Slovakia, 833 40

Narodny ustav detskych chorob

Bratislava, Slovakia, 83340

BIONT, a.s.

Bratislava, Slovakia, 842 29

Spain

Hospital Universitari Vall d'Hebron

Barcelona, Barcelona [barcelona], Spain, 08035

Hospital Sant Joan de Déu

Esplugues de Llobregat, Barcelona [barcelona], Spain, 08950

Hospital Infantil Universitario Niño Jesús

Madrid, Madrid, Comunidad DE, Spain, 28009

Hospital Universitario Virgen Del Rocio

Sevilla, Spain, 41013

Hospital Universitari i Politecnic La Fe

València, Spain, 46026

Sweden

Sahlgrenska Universitetssjukhuset Östra

Gothenburg, Västra Götalands LÄN [se-14], Sweden, 416 50

Astrid Lindgrens Barnsjukhus

Stockholm, Sweden, 17165

Turkey

Ege Universitesi Hastanesi

İzmir, İ̇zmir, Turkey, 35100

Hacettepe Universite Hastaneleri

Ankara, Turkey, 06100

United Kingdom

Royal Victoria Infirmary

Newcastle upon Tyne, England, United Kingdom, NE1 4LP

Royal Victoria Infirmary

Newcastle upon Tyne, England, United Kingdom, NE1 4PL

The Christie NHS Foundation Trust

Manchester, Greater Manchester, United Kingdom, M20 4BX

University College London Hospital

London, London, CITY OF, United Kingdom, NW1 2PG

Royal Hospital for Children

Glasgow, Scotland, United Kingdom, G51 4TF

Leeds General Infirmary

Leeds, United Kingdom, LS1 3EX

University College London Hospital, NHS Foundation Trust

London, United Kingdom, NW1 2PG

Royal Manchester Children's Hospital

Manchester, United Kingdom, M13 9WL

Sponsors and Collaborators

Pfizer

Children's Oncology Group (COG)

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

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

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03709680
• Other Study ID Numbers: A5481092; 2021-003444-25 ( EudraCT Number )
• First Posted: October 17, 2018
• Last Update Posted: March 26, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• 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

Keywords provided by Pfizer:

Ewing Sarcoma; EWS; Neuroblastoma; Recurrent Neuroblastoma; Solid Tumor; Recurrent Solid Tumors; Refractory Solid Tumors; Bone Cancer; Bone Tumor; Bone Sarcoma; Soft Tissue Cancer; Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Refractory Ewing Sarcoma; Relapsed Ewing Sarcoma; Pediatric Cancer; Childhood Cancer; Ewing Sarcoma Treatment; Palbociclib; CDK4/6 Inhibitor; Irinotecan; Temozolomide; Topotecan; Cyclophosphamide

Additional relevant MeSH terms:

Neoplasms; Sarcoma; Neuroblastoma; Rhabdomyosarcoma; Sarcoma, Ewing; Medulloblastoma; Diffuse Intrinsic Pontine Glioma; Rhabdoid Tumor; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Glioma; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases