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

Phase 1

• Conditions: recurrent/refractory Ewing sarcoma; MedDRA version: 20.0Level: PTClassification code 10015560Term: Ewing's sarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-003444-25-SE
• Lead Sponsor: Pfizer Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-11-08
• Last Update Posted: 26 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 75

Inclusion Criteria

Patients must meet all the following inclusion criteria to be eligible for enrollment in the study:
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 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.
•For 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.
• 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 <21 years at the time of study entry. Refer to Section 4.3 for reproductive criteria for male and female participants.
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 be less than or equal to the following maximum upper limits as shown in Table 10:
Table 10. Maximum Allowed Creatinine Levels
Age Maximum Serum Creatinine (mg/dL)
Male Female
2 to <6 years 0.8 0.8
6 to <10 years 1.0 1.0
10 to <13 years 1.2 1.2
13 to <16 years 1.5 1.4
16 to <21 years 1.7 1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular filtration rate utilizing child length and stature data published by the CDC.
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 RA

Exclusion Criteria

Patients with any of the following characteristics/conditions will not be included in the study:
1. Phase 1 portion 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 thesemedications 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 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
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 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 eff

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified