Ibrance palbociclib 100 mg Tablet, Film Coated — NDC 0069-0486-03 (Billing 00069-0486-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle.

Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following palbociclib removal and was greater if antiestrogen treatment was continued.

In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.

12.2Pharmacodynamics Cardiac Electrophysiology The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc (i.e., >20 ms) at 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.

12.3Pharmacokinetics The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Absorption The maximum observed concentration (C max ) of palbociclib is generally observed between 4 to 12 hours (time to reach maximum concentration, T max ) following oral administration of IBRANCE tablets. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%.

In the dosing range of 25 mg to 225 mg, the AUC and C max increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2).

Food Effect : The area under the concentration-time curve from zero to infinity (AUC INF ) and C max of palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), and by 9% and 10%, respectively, when IBRANCE tablets were given with a moderate-fat, standard-calorie meal (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate, and fat, respectively), compared to IBRANCE tablets given under overnight fasted conditions.

Distribution Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction unbound (f u ) of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib f u in human plasma in vivo with worsening renal function.

The geometric mean apparent volume of distribution (V z /F) was 2583 L with a coefficient of variation (CV) of 26%. Metabolism In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following o… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle.

Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following palbociclib removal and was greater if antiestrogen treatment was continued.

In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.

12.3Pharmacokinetics The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Absorption The maximum observed concentration (C max ) of palbociclib is generally observed between 4 to 12 hours (time to reach maximum concentration, T max ) following oral administration of IBRANCE tablets. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%.

In the dosing range of 25 mg to 225 mg, the AUC and C max increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2).

Food Effect : The area under the concentration-time curve from zero to infinity (AUC INF ) and C max of palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), and by 9% and 10%, respectively, when IBRANCE tablets were given with a moderate-fat, standard-calorie meal (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate, and fat, respectively), compared to IBRANCE tablets given under overnight fasted conditions.

Distribution Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction unbound (f u ) of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib f u in human plasma in vivo with worsening renal function.

The geometric mean apparent volume of distribution (V z /F) was 2583 L with a coefficient of variation (CV) of 26%. Metabolism In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [ 14 C]palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways.

Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively.

In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib. Elimination The geometric mean apparent oral clearance (CL/F) of palbociclib was

63.1L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [ 14 C] palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites.

Specific Populations Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib. Hepatic Impairment Data from a pharmacokinetic trial in subjects with… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc (i.e., >20 ms) at 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.

14 CLINICAL STUDIES

14.1HER2-Negative Metastatic Breast Cancer PALOMA-2: IBRANCE plus Letrozole Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy PALOMA-2 was an international, randomized, double-blind, parallel-group, multicenter study of IBRANCE plus letrozole versus placebo plus letrozole conducted in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. A total of 666 patients were randomized 2:1 to IBRANCE plus letrozole or placebo plus letrozole.

Randomization was stratified by disease site (visceral versus non-visceral), disease-free interval (de novo metastatic versus ≤12 months from the end of adjuvant treatment to disease recurrence versus >12 months from the end of adjuvant treatment to disease recurrence), and nature of prior (neo)adjuvant anticancer therapies (prior hormonal therapies versus no prior hormonal therapy). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

The major efficacy outcome of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST). Additional efficacy outcome measures were confirmed overall response rate (ORR) as assessed by the investigator according to RECIST Version 1.1 and overall survival (OS). Patients enrolled in this study had a median age of 62 years (range 28 to 89).

The majority of patients were White (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (98%). Forty-eight percent of patients had received chemotherapy and 56% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Thirty-seven percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting.

The majority of patients (97%) had metastatic disease. Twenty-three percent of patients had bone only disease, and 49% of patients had visceral disease. Major efficacy results from PALOMA-2 are summarized in Table 12 and Figure 1.

Consistent results were observed across patient subgroups of disease-free interval (DFI), disease site, and prior therapy. The treatment effect of the combination on PFS was also supported by an independent review of radiographs. Based on the prespecified final OS analysis conducted after 435 events, OS was not statistically significant.

Table 12. Efficacy Results – PALOMA-2 IBRANCE plus Letrozole Placebo plus Letrozole CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; NE=not estimable; OS=overall survival; PFS=progression‑free survival. Progression-free survival for ITT (investigator assessment) N=444 N=222 Number of PFS events (%) 194 (43.7) 137 (61.7) Median progression-free survival (months, 95% CI) 24.8 (22.1, NE) 14.5 (12.9, 17.1) Hazard ratio (95% CI) and p-value 0.576 (0.463, 0.718) Cox proportional hazards model stratified by disease site (visceral vs. non-visceral) per randomization. , p<0.0001 Stratified log-rank test one-sided p-value.

Objective Response for patients with measurable disease (investigator assessment) N=338 N=171 Objective response rate Response is based on confirmed responses. (%, 95% CI) 55.3 (49.9, 60.7) 44.4 (36.9, 52.2) Overall survival for ITT N=444 N=222 Number of OS events (%) 287 (64.6) 148 (66.7) Median OS (months, 95% CI) 53.8 (49.8, 59.2) 49.8 (42.3, 56.4) Hazard ratio (95% CI) and p‑value 0.921 (0.755, 1.124) , p=0.2087 Figure 1. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-2 (Investigator Assessment, Intent-to-Treat Population) LET=letrozole; PAL=palbociclib; PBO=placebo.

PALOMA-3: IBRANCE plus… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat study. Oral administration of palbociclib for 2 years resulted in an increased incidence of microglial cell tumors in the central nervous system of male rats at a dose of 30 mg/kg/day (approximately 8 times the human clinical exposure based on AUC). There were no neoplastic findings in female rats at doses up to 200 mg/kg/day (approximately 5 times the human clinical exposure based on AUC).

Oral administration of palbociclib to male and female rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 60 mg/kg/day. Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the bone marrow of male rats at doses ≥100 mg/kg/day for 3 weeks. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay.

In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure [AUC], at the recommended dose, respectively). The adverse effects of palbociclib on male reproductive function and fertility were observed in the repeat-dose toxicology studies in rats and dogs and a male fertility study in rats.

In repeat-dose toxicology studies, palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle at ≥30 mg/kg/day in rats and ≥0.2 mg/kg/day in dogs included decreased organ weight, atrophy or degeneration, hypospermia, intratubular cellular debris, and decreased secretion. Partial reversibility of male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-dosing period, respectively. These doses in rats and dogs resulted in approximately ≥10 and 0.1 times, respectively, the exposure [AUC] in humans at the recommended dose.

In the fertility and early embryonic development study in male rats, palbociclib caused no effects on mating but resulted in a slight decrease in fertility in association with lower sperm motility and density at 100 mg/kg/day with projected exposure levels [AUC] of 20 times the exposure in humans at the recommended dose.