Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors
Overview
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Pediatric Brain Tumor Consortium
- Enrollment
- 35
- Locations
- 11
- Primary Endpoint
- Single Dose Area Under the Plasma Concentration Time Curve (AUC)
Overview
Brief Summary
This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD)/phase II recommended dose and describe toxicities related to PD-0332991 (palbociclib isethionate) in children with retinoblastoma protein 1 (Rb1) positive recurrent, progressive or refractory primary central nervous system (CNS) tumors.
II. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive recurrent, progressive or refractory primary CNS tumors.
SECONDARY OBJECTIVES:
I. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS tumors.
II. To evaluate cyclin-dependent kinase (CDK)4/6, cyclin D1-3, Ink4a-ARF copy-number variations in available tumor tissue by array comparative, genomic hybridization (aCGH).
III. To explore the potential relationships between the pharmacokinetics of PD-0332991 and pharmacodynamic response (e.g. percentage change in absolute neutrophil count [ANC], platelet counts).
IV. To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes and transporters and relate these polymorphisms to PD-0332991 pharmacokinetics.
OUTLINE: This is a dose-escalation study.
Patients receive palbociclib isethionate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 4 Years to 21 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients with retinoblastoma protein (Rb1) positive recurrent, progressive or refractory central nervous system (CNS) tumors
- •Histologically confirmed Rb1 positive primary recurrent, progressive, or refractory central nervous system tumors; patients with low grade gliomas are excluded
- •Formalin fixed paraffin embedded tumor tissue (preferably from current recurrence) must be available to assess Rb1 protein status prior to enrollment; only patients with recurrent diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need for available tumor tissue for Rb1 protein status confirmation
- •Patients must have measurable disease (in 2-dimensions) on magnetic resonance imaging (MRI) scan of brain and/or spine to assess preliminary evidence of response
- •Body surface area (BSA):
- •Patients enrolled on dose level 1 (50 mg/m\^2) must have BSA \>= 1.20 m\^2
- •Patients enrolled on dose level 2 (75 mg/m\^2) must have BSA \>= 0.93 m\^2
- •Patients enrolled on dose level 3 (95 mg/m\^2) must have BSA \>= 0.70 m\^2
- •Patients must have received no more than 2 prior chemotherapy regimens and/or focal radiotherapy for their brain tumor and fully recovered from the acute treatment related toxicities of all prior therapies prior to entering this study; for those acute baseline adverse events attributable to prior therapy, patients must meet organ function criteria
- •Chemotherapy: patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study enrollment in the study or at least six (6) weeks for those receiving nitrosourea
Exclusion Criteria
- •Patients with any clinical significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely to interfere with the study procedures or results
- •Patients with low grade gliomas and Rb1 negative tumors
- •Patients who have received any of the following:
- •\> 2 chemotherapy regimens
- •Myeloablative chemotherapy with stem cell rescue
- •Craniospinal irradiation
- •Patients with corrected QT (QTc) interval of \> 450 msec or those on medications known to prolong QTc interval
- •Prior treatment on a CDK inhibitor
- •Patients who are receiving drugs that are strong inducers or inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
- •Patients who are receiving any other investigational therapy
Arms & Interventions
Treatment (palbociclib isethionate)
Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
Intervention: palbociclib isethionate (Drug)
Treatment (palbociclib isethionate)
Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
Intervention: pharmacological study (Other)
Treatment (palbociclib isethionate)
Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
Intervention: laboratory biomarker analysis (Other)
Outcomes
Primary Outcomes
Single Dose Area Under the Plasma Concentration Time Curve (AUC)
Time Frame: Up to day 3
On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.
Steady State Elimination Rate Constant (Ke)
Time Frame: Up to day 22
On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.
Steady State Apparent Volume of Central Compartment (Vc/F)
Time Frame: Up to day 22
On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.
Steady State Half-life (t1/2)
Time Frame: Up to day 22
On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I
Time Frame: 4 weeks
Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II
Time Frame: 4 weeks
Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
Time Frame: 4 weeks
DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of \< 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for \> 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.
Single Dose Elimination Rate Constant (Ke)
Time Frame: Up to day 3
On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.
Single Dose Half-life (t1/2)
Time Frame: Up to day 3
On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.
Single Dose Apparent Oral Clearance (CL/F)
Time Frame: Up to day 3
On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.
Steady State Apparent Oral Clearance (CL/F)
Time Frame: Up to day 22
On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.
Steady State Area Under the Plasma Concentration Time Curve (AUC)
Time Frame: Up to day 22
On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.
Single Dose Apparent Volume of Central Compartment (Vc/F)
Time Frame: Up to day 3
On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.
Secondary Outcomes
- Number of Subjects With Objective Responses(Up to 2 years)
- Association Between Leukopenia and Single Dose Palbociclib AUC(Up to approximately 4 weeks)
- Association Between Neutropenia and Single Dose Palbociclib AUC(Up to approximately 4 weeks)
- Association Between Lymphopenia and Single Dose Palbociclib AUC(Up to approximately 4 weeks)