Evaluation of Palbociclib with Irinotecan and Temozolomide or Topotecan and Cyclophosphamide in Pediatric Recurrent/Refractory Solid Tumors
- Trial ID
- 2024-511975-14-00
- Protocol
- A5481092
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of **palbociclib** in combination with **temozolomide** (TMZ) and **irinotecan** (IRN) versus TMZ and IRN chemotherapy alone in the treatment of children, adolescents, and young adults with recurrent or refractory **Ewing sarcoma** (EWS). This comparison is clinically relevant as it aims to determine whether the addition of palbociclib, a CDK4/6 inhibitor, can enhance the therapeutic outcomes in this patient population, potentially offering a more effective treatment option for those with limited alternatives.
Secondary objectives include:
- Further comparing the efficacy of palbociclib in combination with TMZ and IRN versus TMZ and IRN chemotherapy alone.
- Characterizing the toxicity and safety of the combination of TMZ and IRN with or without palbociclib.
- Describing the pharmacokinetics (PK) of palbociclib, TMZ, and IRN in children, adolescents, and young adults with recurrent or refractory EWS when given in combination.
- Assessing 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.
- Evaluating other efficacy parameters of palbociclib combined with topotecan (TOPO) and cyclophosphamide (CTX) in tumor-specific cohorts.
- Describing the PK of palbociclib, TOPO, and CTX in children, adolescents, and young adults with recurrent or refractory solid tumors when given in combination.
Participants
The clinical trial involves a total of **65 participants** who are children, adolescents, and young adults aged between **2 and 21 years**. The study population includes both **male and female subjects** and is characterized by individuals with **recurrent or refractory Ewing sarcoma** and **neuroblastoma**. Participants were selected based on specific inclusion criteria, including a histologically confirmed relapsed or refractory solid tumor, adequate bone marrow, renal, and liver function, and a performance status of at least 50% for patients under 16 years or an ECOG score of 0, 1, or 2 for those over 16 years. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that participants have measurable or evaluable disease, as defined by relevant clinical criteria, and have recovered from any acute toxicities of prior treatments. The sponsor has not provided additional information regarding lifestyle considerations or other demographic details.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy and safety of **palbociclib** in combination with **irinotecan** and **temozolomide** or in combination with **topotecan** and **cyclophosphamide** in pediatric patients with recurrent or refractory solid tumors, including **Ewing sarcoma** and **neuroblastoma**. The trial is structured in two phases, Phase 1 and Phase 2, with the primary objective of comparing the efficacy of the combination therapies against standard chemotherapy alone. The trial commenced on June 28, 2022, and is expected to conclude on November 28, 2025, with recruitment having started on September 27, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Following the screening, participants will be randomized into treatment arms and will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination from the study.
The expected length of participant involvement in the trial is approximately three years, depending on individual response and progression. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on event-free survival, overall survival, and pharmacokinetic parameters, contributing to the understanding of the therapeutic potential of the investigational drug combinations in this patient population.
Treatment
The clinical trial involves the administration of several experimental and comparator medications. **Palbociclib**, an oral solution, is utilized as a primary experimental medication. It is administered orally and is of chemical origin. The formulation is designed for pediatric use, and the dosing schedule is determined based on the study protocol. Compliance with the dosing regimen is monitored throughout the trial to ensure adherence.
**Temozolomide** is another key medication used in the trial, available in both hard capsule and solution for infusion forms. The hard capsule form is administered orally, while the solution for infusion is administered intravenously. Both forms are of chemical origin and are included in the study to evaluate their efficacy in combination with other drugs. The dosing frequency and schedule are specified in the study protocol, with participant compliance being closely monitored.
**Cyclophosphamide monohydrate**, marketed as Endoxan®, is used as a comparator treatment in the trial. It is available as a coated tablet and is administered intravenously. This medication is of chemical origin and is included to compare its effects with those of the experimental treatments. The administration schedule is outlined in the study protocol, and adherence is tracked to ensure accurate data collection.
**Topotecan**, provided as a solution for infusion, is another comparator drug in the study. It is administered intravenously and is of chemical origin. The trial aims to assess its efficacy in combination with other treatments. The dosing regimen is detailed in the protocol, and participant compliance is monitored to maintain the integrity of the trial data.
**Irinotecan hydrochloride trihydrate**, marketed as Irinotecan Hikma, is included in the trial as a solution for infusion. It is administered intravenously and is of chemical origin. The study evaluates its use in combination with other medications, with dosing schedules and participant adherence being carefully monitored as per the study protocol.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **event-free survival** based on investigator assessment. Secondary endpoints include event-free survival assessed by an independent review committee, objective response as assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, progression-free survival, overall survival, and adverse events graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Additionally, pharmacokinetic parameters of palbociclib, temozolomide (TMZ), and irinotecan (IRN) will be evaluated, including maximum concentration (Css,max), time to maximum concentration (Tmax), area under the curve at steady state (AUCss), and clearance (CL/F), as data permit.
Quality of life will be reported by patients at baseline and after 2 and 4 cycles using age-appropriate tools. The trial will also assess days of hospitalization. For tumor-specific cohorts, additional endpoints such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS) will be evaluated. Pharmacokinetic parameters for palbociclib, TMZ, IRN (and its active metabolite SN-38), topotecan (TOPO), and cyclophosphamide (CTX) will also be assessed. The schedule for these assessments will be aligned with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- 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 ≥75,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry); • Hemoglobin ≥8.5 g/dL (transfusion allowed)
- Adequate renal function: Serum creatinine level based on age/gender must be less than or equal to the following maximum upper 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, unless the patient has documented Gilbert's syndrome;Patients with documented Gilbert's syndrome are eligible if direct bilirubin is within normal ranges (≤ULN).
- 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).
- 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.
- Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.
Exclusion Criteria
- 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.
- 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.
- 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.
- 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.
- Systemic anticancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
- Prior irradiation to >50% of the bone marrow
- Participation in other studies involving investigational drug(s) within 2 weeks or 5 halflives, 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.
- 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.
- 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.
- 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. Screening for viral hepatitis and HIV is under discretion of investigator unless required by local regulation.
- 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 or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements as detailed in Section 4.3.
- Pregnant or breastfeeding women.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 17 Jun 2019 | 4 |
 France | Not Recruiting | 17 Jun 2019 | 15 |
 Germany | Not Recruiting | 17 Jun 2019 | 3 |
 Slovakia | Not Recruiting | 17 Jun 2019 | 4 |
 Sweden | Not Recruiting | 17 Jun 2019 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Irinotecan Hikma 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | — | — | PRD6796266 |
PALBOCICLIB | Test | — | ORAL USE | — | — | SUB177204 |
Palbociclib | Test | ORAL SOLUTION | ORAL USE | — | — | PRD11389839 |
TEMOZOLOMIDE | Comparator | — | ORAL USE | — | — | SUB10889MIG |
TEMOZOLOMIDE | Comparator | — | INTRAVENOUS USE | — | — | SUB10889MIG |
PALBOCICLIB | Test | — | ORAL USE | — | — | SUB177204 |
PALBOCICLIB | Test | — | ORAL USE | — | — | SUB177204 |
TEMOZOLOMIDE | Comparator | — | ORAL USE | — | — | SUB10889MIG |
Temozolomide SUN 5 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | — | — | PRD983686 |
Endoxan® | Comparator | COATED TABLET | INTRAVENOUS USE | — | — | PRD351418 |