Bone tumor cancer
Conditions
Interventions
Combination of 75mg/m2 palbociclib with 2 chemotherapy agents,50mg/m2
irinotecan (IRN) and 100mg/m2 temozolomide (TMZ) in comparison to treatment
with 50mg/m2 IRN and 100mg/m2 TMZ alone.
Sponsors
Pfizer
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed relapsed or refractory solid tumor as follows: • 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 FUSETS 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 =50% 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 be less than or equal to the following maximum upper limits 6. Adequate liver function, including: •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =8 years of age) negative at screening and at the baseline visit.
Exclusion criteria
Exclusion criteria: 1. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZcontaining 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 for IRN and TMZ plus/minus palbociclib combinations 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 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 4. Systemic anticancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 5. Prior irradiation to >50% of the bone marrow (see ATTACHMENTS). 6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 halflives, 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 postradiation and 4 weeks postsurgery 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 <
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Event-free survival (EFS) based on investigator assessment. Assessment of response in phase 2 of the study in Ewing sarcoma patients will be made using RECIST 1.1 criteria as per Appendix 5. The primary outcome measure of event-free survival (EFS) is defined in the Protocol (section 9.6.1) as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence. RECIST 1.1 criteria will be applied to define progression and/or recurrence following response. | — |
Secondary
| Measure | Time frame |
|---|---|
| * Event-free survival (EFS) assessed by an independent review committee. * Objective response (OR), as assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. * PET-CT response after cycle 4 compared to objective response on MRI/CT. * Progression free survival (PFS) based on investigator assessment * Overall survival (OS). * Adverse Events (AEs) as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse events [CTCAE] version 4.03) * Pharmacokinetic parameters of palbociclib, TMZ, IRN: - Palbociclib PK: MD (assuming steady state is achieved) - Css,max, Tmax, AUCss, Css,trough, and CL/F, as data permit. - TMZ PK: MD - Css,max, Tmax, AUCss,*, Css,trough, and CL/F, as data permit. - IRN (and active metabolite, SN-38) PK: MD - Css,max, Tmax, AUCss,*, Css,trough, and CL/F, as data permit. * QoL reported by patient at baseline and after 2 and 4 cycles using age-appropriate tools. * Days of hospitalization. | — |
Countries
Netherlands
Outcome results
None listed