Clinical Trials /

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

NCT03709680

Description:

This study will evaluate palbociclib in combination with chemotherapy (temozolomide and irinotecan) in children, adolescents and young adults with recurrent or refractory solid tumors. The main purpose of this study is to evaluate the safety of palbociclib in combination with chemotherapy in order to estimate the maximum tolerated dose. Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
  • Official Title: PHASE 1 STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF PALBOCICLIB (IBRANCE (REGISTERED)) IN COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS

Clinical Trial IDs

  • ORG STUDY ID: A5481092
  • NCT ID: NCT03709680

Conditions

  • Solid Tumors
  • Ewing Sarcoma
  • Rhabdoid Tumor
  • Rhabdomyosarcoma
  • Neuroblastoma
  • Medulloblastoma

Interventions

DrugSynonymsArms
PalbociclibIbranceSingle Arm
TemozolomideSingle Arm
IrinotecanSingle Arm

Purpose

This study will evaluate palbociclib in combination with chemotherapy (temozolomide and irinotecan) in children, adolescents and young adults with recurrent or refractory solid tumors. The main purpose of this study is to evaluate the safety of palbociclib in combination with chemotherapy in order to estimate the maximum tolerated dose. Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalPalbociclib in combination with temozolomide and irinotecan
  • Palbociclib
  • Temozolomide
  • Irinotecan

Eligibility Criteria

        Inclusion:

          1. For dose escalation part: Histologically confirmed solid tumor (including CNS tumors
             but not lymphomas).

          2. For dose expansion cohort: Histologically confirmed solid tumor including but not
             limited to Ewing sarcoma, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and
             medulloblastoma.

          3. For tumor-specific cohorts: Histologically confirmed solid tumor including but not
             limited to rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Ewing
             sarcoma is not eligible for tumor-specific cohorts.

          4. Age ≥2 and <21 years at the time of study entry.

          5. Lansky performance status ≥50% for patients ≤12 years of age, or Eastern Cooperative
             Oncology Group (ECOG) 0, 1 or 2 for patients >12 years of age.

          6. Adequate bone marrow function: Absolute neutrophil count ≥1000/mm3; Platelet count
             ≥100,000/mm3 (transfusion independent); Hemoglobin ≥8.5 g/dL (transfusion allowed);

          7. Adequate renal function (serum creatinine level based on age/gender must be less than
             or equal to the maximum upper limits specified in protocol)

          8. 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.

          9. Measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS
             disease.

         10. Recovered to CTCAE Grade ≤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.

         11. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and
             at the baseline visit.

         12. Evidence of a personally signed and dated informed consent document indicating that
             the patient or a legally acceptable representative/parent(s)/legal guardian, for
             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.

         13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
             and other procedures.

        Exclusion:

          1. 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.

          2. Prior intolerability to IRN and/or TMZ.

          3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers or strong uridine
             diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1
             Day 1 (C1D1).

          4. Prior growth factors within 7 days before study entry or peg-filgrastim within 14 days
             before study entry.

          5. Radiation therapy within 14 days before study entry.

          6. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for
             nitrosoureas.

          7. Previous high dose chemotherapy requiring stem cell rescue within 90 days or
             persistent AE >Grade 1.

          8. Prior irradiation to >50% of the bone marrow.

          9. Participation in other studies involving investigational drug(s) within 2 weeks or 5
             half lives, whichever is longer, prior to study entry.

         10. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line
             placement are not considered major surgeries.

         11. Known or suspected hypersensitivity to palbociclib, IRN and/or TMZ.

         12. 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.

         13. 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.

         14. Hereditary bone marrow failure disorder.

         15. QTc >470 msec.

         16. 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%.

         17. Recent or ongoing clinically significant gastrointestinal disorder that may interfere
             with absorption of orally administered drugs (eg, gastrectomy).

         18. 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.

         19. Other 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.

         20. 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.

         21. Fertile male patients and female patients of childbearing potential who are unwilling
             or unable to use a highly effective method of contraception as outlined in this
             protocol for the duration of the study and for at least 90 after the last dose of
             investigational product.
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation Part: Frequency of dose-limiting toxicities (DLT)
Time Frame:First cycle (cycle length is approximately 21 days)
Safety Issue:
Description:For Dose Escalation Part: DLT defined as any of the following events occurring during the first cycle (cycle length approximately 21 days) and considered at least possibly-related to study medication:Grade 4 neutropenia lasting greater than 7 days;Grade 4 thrombocytopenia lasting greater than 7 days or need for platelet transfusion for a platelet count of less than 20,000 per cubic millimeters twice within a 7-day period;greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia;Grade 3 or greater non-hematologic toxicities despite optimal treatment;any Grade 2 or greater non-hematologic toxicity requiring discontinuation or interruption of palbociclib for 7 or more consecutive days during the first cycle or any grade non-hematologic toxicity that delays the start of Cycle 2 by more than 14 days;clinically significant non-hematologic laboratory test abnormality Grade 3 or greater not resolving to Grade 1 or baseline within 7 days.

Secondary Outcome Measures

Measure:Frequency of adverse events
Time Frame:At least 28 days after last dose
Safety Issue:
Description:Adverse events to be reported during treatment and for at least 28 days after last dose.
Measure:Percentage of participants with laboratory abnormalities
Time Frame:At least 28 days after last dose
Safety Issue:
Description:Magnesium, Calcium, Creatinine, Albumin, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Phosphorus, Total Bilirubin, Blood urea nitrogen, Alkaline phosphatase, Sodium, Potassium, Chloride, Platelet Count, White Blood Cell Count (differential), hemoglobin, INR or prothrombin Time, HbA1c
Measure:Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings
Time Frame:At least 28 days after last dose
Safety Issue:
Description:Clinically significant ECG findings included: corrected QT (QTc) > 450 ms, QTc >500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.
Measure:Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Time Frame:At least 28 days after last dose
Safety Issue:
Description:systolic and diastolic blood pressure, pulse
Measure:Percentage of Participants With Complete Response or Partial Response
Time Frame:Through the end of treatment (up to at least 28 days after last dose)
Safety Issue:
Description:Patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies during study treatment, assessed approximately every 4 cycles (each cycle is approximately 21 days).
Measure:Duration of response (DoR) for Participants Who Achieved Complete Response or Partial Response
Time Frame:Up to 2 years
Safety Issue:
Description:DoR defined as time from date of first response (Complete Response or Partial Response) in responders to date of progression or death
Measure:Progression Free Survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:PFS defined as time from date of enrollment to earliest date of the death or progressive disease
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:OS defined as the time from enrollment to date of death due to any cause.
Measure:Palbociclib Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Palbociclib Pharmacokinetics, Maximum plasma concentration time (Tmax)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Palbociclib Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2,5, 6,14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Palbociclib Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Palbociclib Pharmacokinetics, Oral plasma clearance (CL/F)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Temozolomide (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Temozolomide (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Temozolomide (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Temozolomide (and active metabolites) Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Temozolomide (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Irinotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Irinotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Irinotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Irinotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit
Measure:Irinotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F)
Time Frame:Pharmacokinetics sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days.
Safety Issue:
Description:Multiple Dose (assuming steady state is achieved), as data permit

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • Solid tumor, Ewing and Rhabdomyosarcoma, Neuroblastoma, brain
  • tumor

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