Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

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.

• palbociclib isethionate (Drug), also known as 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, 827022-33-3, palbociclib, PD 0332991-0054, PD-0332991, PD-332991, PF-00080665-73: Given PO
• pharmacological study (Other), also known as pharmacological studies: Correlative studies
• laboratory biomarker analysis (Other): Correlative studies

Primary outcomes

• Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I [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 [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) [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 Apparent Volume of Central Compartment (Vc/F) [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.
• Single Dose Elimination Rate Constant (Ke) [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) [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) [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.
• Single Dose Area Under the Plasma Concentration Time Curve (AUC) [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 Apparent Volume of Central Compartment (Vc/F) [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 Elimination Rate Constant (Ke) [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 Half-life (t1/2) [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.
• Steady State Apparent Oral Clearance (CL/F) [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) [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.

Secondary outcomes

• Number of Subjects With Objective Responses [Up to 2 years]: Objective responses included complete response (CR) and partial response (PR).
• Association Between Neutropenia and Single Dose Palbociclib AUC [Up to approximately 4 weeks]: Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.
• Association Between Lymphopenia and Single Dose Palbociclib AUC [Up to approximately 4 weeks]: Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.
• Association Between Leukopenia and Single Dose Palbociclib AUC [Up to approximately 4 weeks]: White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.

Other outcomes

• Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations [At enrollment]: CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations [At enrollment]: CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Number of Subjects With Cyclin D1 Copy Number Variations [At enrollment]: Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Number of Subjects With Cyclin D2 Copy Number Variations [At enrollment]: Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Number of Subjects With Cyclin D3 Copy Number Variations [At enrollment]: Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Number of Subjects With Ink4a-ARF Loss Copy Number Variations [At enrollment]: Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
• Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1) [At enrollment]: Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.
• Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2) [At enrollment]: Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.

Sex: All, ages: 4 Years to 21 Years

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
* Biologic therapy: patients should have received their last dose of biologic agent >= 7 days prior to enrollment; in the event the patient has received another biologic agent and has experienced >= grade 2 myelosuppression, then at least three (3) weeks must have elapsed prior to enrollment; if the investigational or biologic agent has a prolonged half-life then at least three (3) weeks interval is required
* Radiotherapy: patients must have had their last fraction of:

  * Focal irradiation > 2 weeks prior to enrollment
* Corticosteroids: patients who are receiving dexamethasone or other corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment; it is recommended that patients be off all steroid therapy or receive the least dose that will control their neurologic symptoms
* Growth factors: all colony forming growth factor(s) have been discontinued for at least one week prior to enrollment (filgrastim, sargramostim, and erythropoietin); for patients on long acting growth factors, the interval should be two weeks
* Patients with neurological deficits that are stable for a minimum of one week prior to registration
* Patients must be able to swallow capsules
* Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 60
* Absolute neutrophil count >= 1,000/mm\^3
* Platelets >= 100,000/mm\^3 transfusion independent (no platelet transfusion one week prior to enrollment)
* Hemoglobin >= 8 g/dl
* Total bilirubin =< 1.5 times upper limit of institutional normal (ULN) for age
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =< 3 x institutional upper limit of normal for age
* Serum albumin >= 3 g/dL
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

  * 1 to < 2 years: 0.6 (male), 0.6 (female)
  * 2 to < 6 years: 0.8 (male), 0.8 (female)
  * 6 to < 10 years: 1 (male), 1 (female)
  * 10 to < 13 years: 1.2 (male), 1.2 (female)
  * 13 to < 16 years: 1.5 (male), 1.4 (female)
  * >= 16 years: 1.7 (male), 1.4 (female)
* Female patients of childbearing potential must have a negative serum pregnancy test at the time of enrollment
* Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control while being treated on this study
* Patient and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

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
* Patients who require enzyme inducing anti-convulsants to control seizures
* Patients with cataracts on ophthalmologic examination

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I (Primary), Number, mg/m2/day: Stratum I 75
• Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II (Primary), Number, mg/m2/day: Stratum II 75
• Number of Patients Who Experienced Dose Limiting Toxicities (DLTs) (Primary), Count of participants, Participants: Stratum I, Dose Level 1 (50 mg/m2) 0; Stratum I, Dose Level 2 (75 mg/m2) 2; Stratum I, Dose Level 3 (95 mg/m2) 2; Stratum II, Dose Level 1 (50 mg/m2) 0; Stratum II, Dose Level 2 (75mg/m2) 1
• Single Dose Apparent Volume of Central Compartment (Vc/F) (Primary), Median, L/m^2: Stratum I, Dose Level 1 (50 mg/m2) 672 (622 to 1189); Stratum I, Dose Level 2 (75 mg/m2) 741 (562 to 1856); Stratum I, Dose Level 3 (95 mg/m2) 708 (601 to 819); Stratum II, Dose Level 1 (50 mg/m2) 847 (373 to 1153); Stratum II, Dose Level 2 (75mg/m2) 850 (398 to 3653)
• Single Dose Elimination Rate Constant (Ke) (Primary), Median, per hour: Stratum I, Dose Level 1 (50 mg/m2) 0.053 (0.045 to 0.055); Stratum I, Dose Level 2 (75 mg/m2) 0.053 (0.030 to 0.070); Stratum I, Dose Level 3 (95 mg/m2) 0.048 (0.023 to 0.083); Stratum II, Dose Level 1 (50 mg/m2) 0.051 (0.031 to 0.070); Stratum II, Dose Level 2 (75mg/m2) 0.051 (0.014 to 0.097)
• Single Dose Half-life (t1/2) (Primary), Median, hour: Stratum I, Dose Level 1 (50 mg/m2) 13.0 (12.5 to 15.5); Stratum I, Dose Level 2 (75 mg/m2) 13.0 (9.9 to 22.8); Stratum I, Dose Level 3 (95 mg/m2) 14.6 (8.4 to 29.8); Stratum II, Dose Level 1 (50 mg/m2) 13.8 (10.0 to 22.0); Stratum II, Dose Level 2 (75mg/m2) 13.5 (7.1 to 48.7)
• Single Dose Apparent Oral Clearance (CL/F) (Primary), Median, L/h/m^2: Stratum I, Dose Level 1 (50 mg/m2) 35.8 (34.4 to 53.1); Stratum I, Dose Level 2 (75 mg/m2) 38.4 (29.3 to 72.0); Stratum I, Dose Level 3 (95 mg/m2) 33.7 (17.3 to 63.3); Stratum II, Dose Level 1 (50 mg/m2) 37.2 (16.9 to 64.3); Stratum II, Dose Level 2 (75mg/m2) 24.4 (11.7 to 355.0)
• Single Dose Area Under the Plasma Concentration Time Curve (AUC) (Primary), Median, h*ng/mL: Stratum I, Dose Level 1 (50 mg/m2) 1156 (810 to 1164); Stratum I, Dose Level 2 (75 mg/m2) 1743 (892 to 2537); Stratum I, Dose Level 3 (95 mg/m2) 2407 (1485 to 3252); Stratum II, Dose Level 1 (50 mg/m2) 1289 (747 to 2834); Stratum II, Dose Level 2 (75mg/m2) 2538 (189 to 2951)
• Steady State Apparent Volume of Central Compartment (Vc/F) (Primary), Median, L/m^2: Stratum I, Dose Level 1 (50 mg/m2) 491 (465 to 517); Stratum I, Dose Level 2 (75 mg/m2) 449 (282 to 1560); Stratum I, Dose Level 3 (95 mg/m2) 442 (383 to 501); Stratum II, Dose Level 1 (50 mg/m2) 705 (250 to 1308); Stratum II, Dose Level 2 (75mg/m2) 458 (247 to 919)
• Steady State Elimination Rate Constant (Ke) (Primary), Median, per hour: Stratum I, Dose Level 1 (50 mg/m2) 0.052 (0.041 to 0.066); Stratum I, Dose Level 2 (75 mg/m2) 0.050 (0.017 to 0.110); Stratum I, Dose Level 3 (95 mg/m2) 0.062 (0.054 to 0.071); Stratum II, Dose Level 1 (50 mg/m2) 0.032 (0.024 to 0.049); Stratum II, Dose Level 2 (75mg/m2) 0.039 (0.032 to 0.074)
• Steady State Half-life (t1/2) (Primary), Median, hour: Stratum I, Dose Level 1 (50 mg/m2) 13.7 (10.5 to 16.9); Stratum I, Dose Level 2 (75 mg/m2) 13.7 (6.5 to 41.6); Stratum I, Dose Level 3 (95 mg/m2) 11.3 (9.8 to 12.8); Stratum II, Dose Level 1 (50 mg/m2) 23.1 (14.2 to 29.4); Stratum II, Dose Level 2 (75mg/m2) 17.9 (9.4 to 21.4)
• Steady State Apparent Oral Clearance (CL/F) (Primary), Median, L/h/m^2: Stratum I, Dose Level 1 (50 mg/m2) 26.6 (19.0 to 34.2); Stratum I, Dose Level 2 (75 mg/m2) 25.8 (12.3 to 101.0); Stratum I, Dose Level 3 (95 mg/m2) 28.1 (20.8 to 35.3); Stratum II, Dose Level 1 (50 mg/m2) 17.0 (9.7 to 64.0); Stratum II, Dose Level 2 (75mg/m2) 16.1 (12.1 to 62.4)
• Steady State Area Under the Plasma Concentration Time Curve (AUC) (Primary), Median, h*ng/mL: Stratum I, Dose Level 1 (50 mg/m2) 1211 (972 to 1450); Stratum I, Dose Level 2 (75 mg/m2) 2143 (521 to 4070); Stratum I, Dose Level 3 (95 mg/m2) 2193 (1520 to 3168); Stratum II, Dose Level 1 (50 mg/m2) 1410 (559 to 3301); Stratum II, Dose Level 2 (75mg/m2) 2359 (952 to 4253)
• Number of Subjects With Objective Responses (Secondary), Count of participants, Participants: Stratum I, Dose Level 1 (50 mg/m2) 0; Stratum I, Dose Level 2 (75 mg/m2) 0; Stratum I, Dose Level 3 (95 mg/m2) 0; Stratum II, Dose Level 1 (50 mg/m2) 0; Stratum II, Dose Level 2 (75mg/m2) 0
• Association Between Neutropenia and Single Dose Palbociclib AUC (Secondary), Mean, h*ng/mL: All Patients 1424.4 +/- 966.3
• Association Between Lymphopenia and Single Dose Palbociclib AUC (Secondary), Mean, h*ng/mL: All Patients 1727.5 +/- 882.6
• Association Between Leukopenia and Single Dose Palbociclib AUC (Secondary), Mean, h*ng/mL: All Patients 1420.3 +/- 955.1
• Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations (Other pre specified)
• Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations (Other pre specified)
• Number of Subjects With Cyclin D1 Copy Number Variations (Other pre specified)
• 5 more outcome measures not shown.

Adverse events

Time frame: Up to 2 years after starting treatment

Serious adverse events by term

Other adverse events by term

• Results publication: Raetz EA, Teachey DT, Minard C, Liu X, Norris RE, Denic KZ, Reid J, Evensen NA, Gore L, Fox E, Loh ML, Weigel BJ, Carroll WL. Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1). Pediatr Blood Cancer. 2023 Nov;70(11):e30609. doi: 10.1002/pbc.30609. Epub 2023 Aug 8. PMID 37553297

• Informed Consent Form (PDF, 2018-06-28)
• Study Protocol and Statistical Analysis Plan (PDF, 2018-06-28)

• David Van Mater, MD, Principal investigator, Pediatric Brain Tumor Consortium

NIH grants: U01CA081457