|Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
|PHASE 1 STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF PALBOCICLIB (IBRANCE(REGISTERED)) IN COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE AND IN COMBINATION WITH TOPOTECAN AND CYCLOPHOSPHAMIDE IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS
|This study will evaluate palbociclib in combination with chemotherapy (temozolomide with irinotecan and topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors. The main purpose of this study is to evaluate the safety of palbociclib in combination with chemotherapy in order to estimate the maximum tolerated dose. Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.
Intervention Model: Sequential Assignment
Intervention Model Description:
Masking: None (Open Label)
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, EWS tumor specific cohort and if applicable, other solid tumor-specific cohorts.
The palbociclib plus topotecan and cyclophosphamide will comprise of a dose determination cohort(following a modified rolling 6 design), a dose expansion cohort, and if applicable, other solid tumor-specific cohorts.
Primary Purpose: Treatment
- Solid Tumors
- Ewing Sarcoma
- Rhabdoid Tumor
- Diffuse Intrinsic Pontine Glioma
- Drug: Palbociclib
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
Other Name: Ibrance
- Drug: Temozolomide
Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle
- Drug: Irinotecan
Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
- Drug: Topotecan
Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
- Drug: Cyclophosphamide
Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle
|Experimental: Single Arm
Palbociclib in combination with temozolomide and irinotecan Palbociclib in combination with topotecan and cyclophosphamide
- Drug: Palbociclib
- Drug: Temozolomide
- Drug: Irinotecan
- Drug: Topotecan
- Drug: Cyclophosphamide
|January 13, 2025
|November 29, 2021 (Final data collection date for primary outcome measure)
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.
- 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);
- 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.
- Measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma.
- 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.
- 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.
- Prior intolerability to IRN and/or TMZ, for palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for palbociclib with 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.
- Known or suspected hypersensitivity to palbociclib, IRN and/or TMZ.
- 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.
- 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.
|Sexes Eligible for Study:||All|
|2 Years to 20 Years (Child, Adult)
|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|
|Plan to Share IPD:||No|
|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/d….|
|Study Director:||Pfizer CT.gov Call Center||Pfizer|