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A5481092 - Phase 1/2 Study to Evaluate Palbociclib (IBRANCE(Registered)) in combination with Irinotecan and Temozolomide and/or in combination with Topotecan and Cyclophosphamide in Pediatric Patients with Recurrent or Refractory Solid Tumors

Studio Clinico

Patologia: Sarcomi dei tessuti molli e gist

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico


Fase di studio: II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Non applicabile

Criteri di inclusione: 

  • Histologically confirmed Ewing sarcoma. Histopathology confirmation of EWSR1-ETS or FUS-ETS rearrangement is required or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or refractory disease with no known bone marrow metastases and at least evaluable disease.
  • Age ≥2 and <21 years at the time of study entry.
  • 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.
  • Adequate bone marrow function.
  • Absolute neutrophil count ≥1000/mm3;
  • Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
  • Hemoglobin ≥8.5 g/dL (transfusion allowed).
  • Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
  • 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 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 INRC for neuroblastoma. 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).
  • 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.
  • Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.
  • Evidence of a personally signed and dated informed consent document indicating that the patient or a legally acceptable representative/parent(s)/legal guardian of minors, has been informed of all pertinent aspects of the study. Minor study patients also must provide age appropriate assent according to the local guidelines, where applicable.
  • Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.

Criteri di esclusione: 

  • Prior treatment with a CDK4/6 inhibitor or prior treatment with an IRN and/or TMZ-containing regimen.
  • 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.
  • Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. 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.)
  • Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry.
  • Radiation therapy within 14 days before study entry.
  • Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
  • Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1.
  • Prior irradiation to >50% of the bone marrow (see Appendix 9).
  • Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
  • Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
  • For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, IRN and/or TMZ.
  • For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
  • 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.
  • 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.
  • Hereditary bone marrow failure disorder.Phase 2 portion patients with bone marrow involvement are excluded.
    QTc >470 msec.
  • 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%.
  • Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
  • 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.
  • Other 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.
  • 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.
  • Fertile male patients and female patients of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 after the last dose of investigational product.

Schema di trattamento: 

Arm A: Palbociclib (oral) at 75 mg/m2 on days 1-14 of a 21-day cycle + 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle
Arm B: Temozolomide 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle. Irinotecan 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle

Trattamento sperimentale: 

Palbociclib + irinotecan + temozolomide

Trattamento di controllo: 

Temozolomide, Irinotecan

Obiettivi primari dello studio: 

The main purpose of phase 2 portion is to compare the efficacy of palbociclib in combination with irinotecan and temozolomide vs irinotecan and temozolomide alone in the treatment of children, adolescents, and young adults with recurrent or refractory Ewing sarcoma (EWS). Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.

Centri partecipanti

Centro Italia

Ospedale Pediatrico Bambin Gesù
Piazza Sant Onofrio 4 - 00165 Roma - RM

Informazioni Generali


Numero di iscrizione a registro: 2021-003444-25 / NCT03709680

Data di inserimento: 05.07.2023





Principal Investigator ITALIA

Ospedale Bambin Gesù, Roma

Riferimento: Dr. Informazione non disponibile

Telefono: 00000


Localita: Roma


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