Health Condition 1: C419- Malignant neoplasm of bone and articular cartilage, unspecified
Conditions
Interventions
Intervention1: Experimental: Phase 2 Arm A
Palbociclib in combination with irinotecan and temozolomide.: Drug: Palbociclib
Administered (oral) at 75 mg/m2 on days 1-14 of a 21-day cycle
Drug: Temozo
Sponsors
Pfizer Inc
Eligibility
Inclusion criteria
Inclusion criteria: (1) Histologically confirmed relapsed or refractory solid tumor: For randomized Phase 2 part: 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. (2) Age above 2 and lower than 21 years at the time of study entry. (3) Lansky performance status more than 50% for patients less than 16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients above 16 years of age. (4) Adequate bone marrow function. (5) Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits. (6) Adequate liver function, including: (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 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). (8) Recovered to CTCAE Grade less than 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 above 8 years of age) negative at screening and at the baseline visit. (10) 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. (11) Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
Exclusion criteria
Exclusion criteria: 1. 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. 2. 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.) 3. Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry. 4. Radiation therapy within 14 days before study entry. 5. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 6. Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1. 7. Prior irradiation to >50% of the bone marrow (see Appendix 9). 8. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 9. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 10. 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. 11. 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. 12. 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. 13. Hereditary bone marrow failure disorder. Phase 2 portion patients with bone marrow involvement are excluded. 14. QTc >470 msec. 15. 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 16. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 17. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 2 open-label, randomized: Event-free survival (EFS) in irinotecan and temozolomide with palbociclib treatment arm will be compared to EFS in treatment with irinotecan and temozolomide alone treatment armTimepoint: Through the end of treatment (up to at least 28 days after last dose) | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 1 and Phase 2: Duration of response (DoR) for Participants Who Achieved Complete Response or Partial ResponseTimepoint: Up to 2 years;Phase 1 and Phase 2: Frequency of adverse eventsTimepoint: At least 28 days after last dose;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)Timepoint: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days;Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)Timepoint: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days;Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax)Timepoint: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days;Phase 1 and Phase 2: Irinotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F)Timepoint: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days;Phase 1 and Phase 2: Irinotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)Timepoint: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.;Phase 1 and Phase 2: Number of Participants With Clinically Significant Change From Baseline in Vital SignsTimepoint: At least 28 days after last dose;Phase 1 and Phase 2: Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) FindingsTimepoint: At least 28 days after last dose;Phase 1 and Phase 2: Overall Survival (OS)Timepoint: Up to 2 years;Phase 1 and Phase 2: Palbociclib Pharmacokinetics, Area under the concentration-time | — |
Countries
Bulgaria, Canada, Hungary, India, Israel, Poland, Republic of Korea, Russian Federation, Slovakia, Sweden, Turkey, Ukraine, United States of America
Contacts
Public ContactDr Seema Pai
Pfizer Limited
Outcome results
None listed