Phase 1/2 Study to Evaluate Palbociclib (Ibrance®) in Combination with Irinotecan and Temozolomide or in Combination with Topotecan and Cyclophosphamide in Pediatric Patients with Recurrent or Refractory Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 May 2022 → 7 Aug 2025

Decision date (initial)

2024-08-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc

External identifiers

EU CT number

2024-511975-14-00

EudraCT number

2021-003444-25

ClinicalTrials.gov

NCT03709680

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Therapy, Pharmacodynamic

To compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone in the treatment of children, adolescents, and young adults with recurrent or refractory EWS.
Tumor-Specific Cohorts:
• To evaluate the safety, and confirm the RP2D for the combination of palbociclib, TMZ, and IRN at the MTD in children, adolescents and young adults with recurrent or refractory solid tumors that are known to be sensitive to a CDK4/6 inhibitor.
• To evaluate the safety, and confirm the RP2D for the combination palbociclib, CTX, and TOPO in children, adolescents and young adults with recurrent or refractory solid tumors that are known to be sensitive to a CDK4/6 inhibitor.
• To evaluate the preliminary antitumor activity of palbociclib combined with TMZ and IRN.
• To evaluate the preliminary antitumor activity of palbociclib combined with TOPO and CTX.

Secondary objectives 5

1. To further compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone.
2. To characterize the toxicity and safety of the combination of TMZ and IRN plus or minus Palbociclib.
3. To describe the PK of palbociclib, TMZ, and IRN in children, adolescents, and young adults with recurrent or refractory EWS when given in combination.
4. To assess the impact of the combination of palbociclib with TMZ and IRN treatment on the quality of life (QoL) of patients with refractory and recurrent EWS.
5. Tumor-Specific Cohorts: -To evaluate other efficacy parameters of palbociclib combined with TOPO and CTX. - To describe the PK of palbociclib, TMZ, and IRN in children, adolescents, and young adults with recurrent or refractory solid tumors when given in combination. - To describe the PK of palbociclib, TOPO, and CTX in children, adolescents, and young adults with recurrent or refractory solid tumors when given in combination.

Conditions and MedDRA coding

recurrent/refractory Ewing sarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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.
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
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 RANO criteria for CNS disease or at least evaluable disease by INRC for neuroblastoma.The eligible patients with neuroblastoma must have at least one of the following at the time of study entry: •Measurable tumor by CT or MRI that is avid on MIBG scan or demonstrates increased FDG uptake on PET scan; •Avid lesion on MIBG scan with positive uptake at a minimum of one site; •For disease that is not avid by MIBG-scan, at least one lesion that demonstrates increased FDG uptake on PET scan AND viable neuroblastoma confirmed by current or prior biopsy; •bone marrow involvement with more than 5% neuroblastoma cells in atleast one sample from bilateral bone marrow biopsies; •In non MIBG-avid refractory soft tissue disease that does not demonstrate increased FDG uptake; lesion biopsy is required to document the presence of viable neuroblastoma, unless patient has a new soft tissue lesion (radiographicevidence of disease progression). Patients with EWS enrolled to Phase 2 portion of the study are eligible with at least evaluable disease (eg, boneonly disease with no soft tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any nonhematological 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 ≥8 years of age) negative at screening and at the baseline visit.

Exclusion criteria 19

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 these medications 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. 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.
3. 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.
4. 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.
5. Systemic anticancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
6. Prior irradiation to >50% of the bone marrow
7. Participation in other studies involving investigational drug(s) within 2 weeks or 5 halflives, whichever is longer, prior to study entry.
8. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
9. 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.
10. 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.
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 discretion of investigator unless required by local regulation.
16. 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.
17. 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.
18. Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements as detailed in Section 4.3.
19. Pregnant or breastfeeding women.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-free survival based on investigator assessment. Tumor Specific Cohorts: - AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 4.03), timing, seriousness, and relationship to study therapy; laboratory test data including HbA1c as characterized by type, frequency, severity (as graded by NCI CTCAE version 4.03), and timing; ECG parameters, and vital signs.

Secondary endpoints 10

1. Event-free survival (EFS) assessed by an independent review committee.
2. Objective response (OR), as assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
3. PET-CT response after cycle 4 compared to objective response onMRI/CT.
4. Progression free survival (PFS) based on investigator assessment.
5. Overall survival (OS).
6. Adverse Events (AEs) as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version 4.03.
7. Pharmacokinetic parameters of palbociclib, TMZ, IRN: -Palbociclib PK: MD (assuming steady state is achieved) - Css,max, Tmax, AUCss, τ, Css,trough, and CL/F, as data permit. -TMZ PK: MD - Css,max, Tmax, AUCss, τ, Css,trough, and CL/F, as data permit. -IRN (and active metabolite, SN-38) PK: MD - Css,max, Tmax, AUCss, τ, Css,trough, and CL/F, as data permit.
8. QoL reported by patient at baseline and after 2 and 4 cycles using ageappropriate tools.
9. Days of hospitalization
10. Tumor-Specific Cohorts: -DOR, PFS, and OS. -Pharmacokinetic parameters of palbociclib,TMZ, IRN (and active metabolite, SN-38), TOPO and CTX - PK: MD - Css,max, Tmax, AUCss, τ, Css,trough, and CL/F, as data permit.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 5

Locations

5 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 69 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications