Palbociclib is taken orally and is a highly selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation. Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Testing of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high efficacy against luminal breast cancers, particularly estrogen receptor (ER)-positive breast cancers. Mechanistic analyses revealed that the combination of palbociclib with anti-estrogen agents enhanced the re-activation of retinoblastoma (Rb) through inhibition of Rb phosphorylation resulting in reduced E2F signaling and growth arrest. The enhanced growth arrest of the ER-positive breast cancer cell lines treated with palbociclib and anti-estrogen agents is accompanied by increased cell senescence resulting in a sustained cell cycle arrest following drug removal and increased cell size associated with a senescent phenotype. In vivo
studies using a patient-derived ER-positive breast cancer xenograft model (HBCx-34) demonstrated that the combination of palbociclib and letrozole further enhanced inhibition of Rb phosphorylation, downstream signaling and dose-dependent tumor growth. This supports the contribution of senescence-associated growth arrest as a mechanism associated with the antitumor efficacy of combined palbociclib/ER antagonist in ER-positive breast cancer models.
In the presence or absence of an anti-estrogen, palbociclib-treated bone marrow cells did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The in vitro
breast cancer cells, conversely, became senescent following palbociclib or anti-estrogen treatment with additive effects in combination and remained arrested in the presence of anti-estrogen.
Clinical trial efficacy:
Study 1: Randomized Phase 1/2 study of Ibrance in combination with letrozole (PALOMA-1): The efficacy of palbociclib was evaluated in a randomized, open-label, multicenter study of palbociclib plus letrozole versus letrozole alone conducted in post-menopausal women with ER-positive, HER2-negative advanced breast cancer who did not receive previous systemic treatment for their advanced disease (PALOMA-1).
The study was comprised of a limited Phase 1 portion (N = 12), designed to confirm the safety and tolerability of the combination palbociclib plus letrozole, followed by a randomized Phase 2 portion (N = 165), designed to evaluate the efficacy and safety of palbociclib in combination with letrozole compared with letrozole alone in the first-line treatment of post-menopausal women with ER-positive, HER2-negative advanced breast cancer.
Randomization was stratified by disease site (visceral versus bone only versus other) and by disease-free interval (>12 months from the end of adjuvant treatment to disease recurrence versus ≤12 months from the end of adjuvant treatment to disease recurrence or de novo
The patient demographic and baseline characteristics were generally balanced between the study arms in terms of age, race, disease sites, stage, and prior therapies.
The primary endpoint of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.
The median PFS (mPFS) for patients in the palbociclib plus letrozole arm was 20.2 months (95% confidence interval [CI]: 13.8, 27.5) and 10.2 months (95% CI: 5.7, 12.6) for patients in the letrozole-alone arm. The observed hazard ratio (HR) was 0.488 (95% CI: 0.319, 0.748) in favor of palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of 0.0004.
Study 2 - Randomized Phase 3 Study of Ibrance in combination with letrozole (PALOMA-2): The efficacy of palbociclib in combination with letrozole versus letrozole plus placebo was evaluated in an international, randomized, double-blind, placebo-controlled, parallel-group, multicenter study conducted in women with ER-positive, HER2-negative advanced breast cancer not amenable to resection or radiation therapy with curative intent or metastatic breast cancer who had not received prior systemic treatment for their advanced disease.
A total of 666 post-menopausal women were randomized 2:1 to either the palbociclib plus letrozole arm or to the placebo plus letrozole arm and were stratified by site of disease (visceral, non-visceral), disease-free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo
metastatic, ≤12 months from the end of adjuvant treatment to disease recurrence, >12 months from the end of adjuvant treatment to disease recurrence), and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy, no prior hormonal therapy). Patients with advanced symptomatic visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.
Patients continued to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.
Patients were well matched for baseline demographics and disease characteristics between the palbociclib plus letrozole arm and the placebo plus letrozole arm. The median age of patients enrolled in this study was 62 years (range 28-89); 48.3% of patients had received chemotherapy and 56.3% had received antihormonal therapy in the (neo) adjuvant setting prior to their diagnosis of advanced breast cancer, while 37.2% of patients had received no prior systemic therapy in the (neo) adjuvant setting. Most patients (97.4%) had metastatic disease at baseline; 22.7% of patients had bone only disease and 49.2% of patients had visceral disease.
The primary endpoint of the study was PFS evaluated according to RECIST version 1.1 as assessed by investigator. Secondary efficacy endpoints included objective response (OR), duration of response (DOR), clinical benefit response (CBR), overall survival (OS), safety, EQ-5D scores and health-related quality of life (QoL) assessed using the FACT-B questionnaire.
At the data cutoff date of 26 February 2016, the study met its primary objective of improving PFS. The observed HR was 0.576 (95% CI: 0.463, 0.718) in favor of palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of <0.000001. An updated analysis of the primary and secondary endpoints was performed after additional 15 months of follow up (data cutoff date: 31 May 2017). A total of 405 PFS events were observed; 245 events (55.2%) in the palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm respectively.
Table 1 shows the efficacy results based on the primary and the updated analyses from the PALOMA-2 study, as assessed by the investigator and by the independent review. (See Table 1.)
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The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in Figure 1 as follows. (See Figure 1.)
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A series of prespecified subgroup PFS analyses was performed based on baseline demographic and disease characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in the palbociclib plus letrozole arm was observed in all individual patient subgroups defined by stratification factors and baseline characteristics in the primary and in the updated analyses.
At the time of the updated analyses, the times to initiation of the first and the second subsequent anticancer therapies were also assessed. Similarly, the time to initiation of subsequent chemotherapy was also evaluated. The results from these analyses are shown in Table 2. (See Table 2.)
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The results of the times to initiation of the first and the second subsequent systemic anticancer therapy analyses suggest that the improvement in PFS observed with the addition of palbociclib to letrozole in the first-line treatment setting delayed the initiation of first and second subsequent anticancer therapy. Similarly, first-line palbociclib plus letrozole therapy delayed the initiation of first subsequent chemotherapy compared with placebo plus letrozole.
An analysis of time-to-deterioration composite endpoint (TTD) in Functional Assessment of Cancer Therapy-Breast (FACT-B), defined as the time between baseline and first occurrence of decrease of ≥7 points in FACT-B scores, was carried out based on survival analysis methods using a Cox proportional hazards model and log-rank test. No statistically significant difference was observed in TTD in FACT-B total scores between the palbociclib plus letrozole arm and the placebo plus letrozole arm (HR of 1.042 [95% CI: 0.838, 1.295]; 1-sided p-value=0.663).
Study 3: Randomized, Phase 3 study of Ibrance in combination with fulvestrant (PALOMA-3): The efficacy of palbociclib in combination with fulvestrant versus placebo plus fulvestrant was evaluated in an international, randomized, double-blind, parallel-group, multicenter study conducted in women with HR-positive, HER2-negative advanced breast cancer, not amenable to resection or radiation therapy with curative intent or metastatic breast cancer, regardless of their menopausal status, whose disease progressed after prior endocrine therapy in the (neo) adjuvant or metastatic setting.
A total of 521 pre/post-menopausal women whose disease had progressed during or within 12 months after completion of adjuvant endocrine therapy or during or within 1 month after prior endocrine therapy for advanced disease were randomized 2:1 to the palbociclib plus fulvestrant arm or the placebo plus fulvestrant arm and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus post-menopausal), and presence of visceral metastases. Pre/perimenopausal women received the LHRH agonist goserelin. Patients with advanced/metastatic, symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.
Crossover between treatment arms was not allowed.
Patients were well balanced for baseline demographics and prognostic characteristics between the palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The majority of patients in each treatment arm were White, <65 years of age, had documented sensitivity to prior hormonal therapy and were post-menopausal. Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemic therapy and most patients in each treatment arm had received a previous chemotherapy regimen. More than a half (62%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 60% had visceral metastases, and 60% had received more than 1 prior hormonal regimen for the primary diagnosis.
The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST version 1.1. Supportive PFS analyses were based on an Independent Central Radiology Review. Secondary endpoints included OR, DOR, CBR, OS, safety, change in QoL, and TTD. Patient-reported outcomes including Global QoL and pain were measured using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) and the Breast Cancer Module (BR23) questionnaire.
The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis conducted on 82% of the planned PFS events at final analysis; the results crossed the prespecified Haybittle-Peto efficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and a clinically meaningful treatment effect.
The estimated HR from the stratified analysis was 0.422 (95% CI: 0.318, 0.560; 1-sided p<0.000001) in favor of palbociclib plus fulvestrant.
The mPFS was 9.2 months (95% CI: 7.5, NE) in the palbociclib plus fulvestrant arm and 3.8 months (95% CI: 3.5, 5.5) in the placebo plus fulvestrant arm. (See Figure 2 and Table 3.)
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Prolongation of PFS in the palbociclib plus fulvestrant arm was also demonstrated in individual patient subgroups supporting internal consistency of PFS benefit findings within the study, and was supported by a random sample Blinded Independent Central Review (BICR) audit analysis conducted on 40.5% (N=211) of 521 randomized patients.
Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior and for duration of Study 2.
The palbociclib plus fulvestrant arm demonstrated similar clinical benefit in the pre/perimenopausal patient population (HR = 0.435 [95% CI: 0.228, 0.831]) and post-menopausal population (HR = 0.409 [95% CI: 0.298, 0.560]). Similarly, the mPFS for the palbociclib plus fulvestrant arm was 9.5 months (95% CI: 7.2, NE) in the pre/perimenopausal setting versus 9.2 months (95% CI: 7.5, NE) in the post-menopausal setting; while the mPFS in the placebo plus fulvestrant arm was 5.6 months (95% CI: 1.8, NE) in the pre/perimenopausal setting versus 3.7 months (95% CI: 3.5, 5.5) in the post-menopausal setting.
Patient-reported symptoms were assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23. A total of 335 patients in the palbociclib plus fulvestrant arm and 166 patients in the placebo plus fulvestrant arm completed the questionnaire at baseline and at least 1 post-baseline visit.
Time to Deterioration (TTD) was prespecified as time between baseline and first occurrence of ≥10-point increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a symptom benefit by significantly delaying TTD in pain symptom scores compared with placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; p<0.001).
After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events (59.5% of randomized patients). A 6.9-month improvement in median OS in the palbociclib plus fulvestrant arm compared with the placebo plus fulvestrant arm was observed, although this result was not statistically significant at the prespecified significance level of 0.0235. A higher proportion of patients in the placebo plus fulvestrant arm received post-progression systemic treatments overall in comparison with the patients in the palbociclib plus fulvestrant arm (80.5% versus 71.8%) respectively. Also, in placebo plus fulvestrant arm, 15.5% of randomized patients received palbociclib and other CDK inhibitors as post-progression subsequent treatments. The results from the final OS data from PALOMA-3 Study are presented in Table 4. The relevant Kaplan-Meier plots are shown in Figures 2 and 3. (See Table 4 and Figure 3.)
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Click on icon to see table/diagram/image
A positive treatment effect of palbociclib plus fulvestrant versus placebo plus fulvestrant on OS was observed in the majority of the prespecified subgroups. Due to the low event number and smaller sample size in some of the prespecified subgroups, the magnitude of estimated effect of palbociclib added to fulvestrant could not always be determined. The OS results from patients subgroups defined by stratification factors at randomization are reported in Table 5 as follows. (See Table 5.)
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The estimated survival probabilities for palbociclib plus fulvestrant versus placebo plus fulvestrant were respectively: 65.3% (95% CI: 59.9, 70.2) vs. 57.3% (95% CI: 49.2, 64.6) at 2 years and 49.6% (95% CI: 44.0, 54.9) vs. 40.8% (95% CI: 32.9, 48.5) at 3 years.
The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.
The time to Cmax
) of palbociclib is generally between 6 to 12 hours following oral administration. The mean absolute bioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax
increase proportionally with dose in general. Steady-state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulates with a median accumulation ratio of 2.4 (range 1.5-4.2).
Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of Ibrance with food.
Compared to palbociclib given under overnight fasted conditions, the AUCinf
of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after palbociclib dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability of palbociclib exposure. Based on these results, palbociclib should be taken with food.
Gastric pH elevating medication effect: In a healthy subject study, co-administration of a single 125 mg dose of Ibrance with multiple doses of the PPI rabeprazole under fed conditions decreased palbociclib Cmax
by 41%, but had limited impact on AUCinf
(13% decrease), when compared to a single 125 mg dose of Ibrance administered alone. Given the reduced effect on gastric pH of H2 receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure. In another healthy subject study, co-administration of a single 125 mg dose of Ibrance with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf
by 62% and 80%, respectively, when compared with a single dose of Ibrance administered alone.
: Binding of palbociclib to human plasma proteins in vitro
was ~85%, with no concentration dependence over the concentration range of 500 ng/mL to 5,000 ng/mL. The mean fraction unbound (fu
) of palbociclib in human plasma in vivo
increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib fu
in human plasma in vivo
with worsening renal function. The geometric mean apparent volume of distribution (Vz
/F) was 2,583 (26%) L.
Metabolism: In vitro
and in vivo
studies indicate that palbociclib undergoes extensive hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14
C] palbociclib to humans, the major 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. The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. The majority of the material was excreted as metabolites. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. In vitro
studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.08 L/h, and the mean plasma elimination half-life was 28.8 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. Excretion of unchanged palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively.
Age, gender, and body weight:
Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age ranging from 22 to 89 years, and body weight ranging 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.
Pharmacokinetics of palbociclib have not been evaluated in patients <18 years of age.
Of 444 patients who received Ibrance in Study 2, 181 patients (41%) were ≥65 years of age.
Of 347 patients who received Ibrance in Study 3, 86 patients (24.8%) were ≥65 years of age.
No overall differences in safety or effectiveness of Ibrance were observed between these patients and younger patients.
Data from a pharmacokinetic trial in subjects with varying degrees of hepatic function indicate that palbociclib unbound exposure (unbound AUCinf
) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C), respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax
) was increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 40 patients had mild hepatic impairment based on National Cancer institute (NCI) classification (total bilirubin ≤Upper Limit of Normal (ULN) and Aspartate Aminotransferase (AST) >ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the pharmacokinetics (PK) of palbociclib.
Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total palbociclib exposure (AUCinf
) was increased by 39%, 42%, and 31% with mild (60 mL/min≤CrCl<90 mL/min), moderate (30 mL/min≤CrCl<60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to subjects with normal (CrCl ≥90 mL/min) renal function. Peak palbociclib exposure (Cmax
) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the PK of palbociclib. The pharmacokinetics of palbociclib has not been studied in patients requiring hemodialysis.
In a pharmacokinetic study in healthy volunteers, palbociclib AUCinf
values were 30% and 35% higher, respectively, in Japanese subjects when compared with non-Asian subjects after a single oral dose. However, this finding was not reproduced consistently in subsequent studies in Japanese or Asian breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety and efficacy data across Asian and non-Asian populations, no dose adjustment based on Asian race is considered necessary.
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 did not prolong QTc to any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).
Toxicology: Preclinical safety data:
The primary target organ findings following single and/or repeat dosing included hematolymphopoietic and male reproductive organ effects in rats and dogs, and effects on bone and actively growing incisors in rats only. These systemic toxicities were generally observed at clinically relevant exposures based on AUC. Partial to full reversal of effects on the hematolymphopoietic, male reproductive systems, and incisor teeth were established, whereas the bone effect was not reversed following a 12-week nondosing period. In addition, cardiovascular effects (QTc prolongation, decreased heart rate, and increased RR interval and systolic blood pressure) were identified in telemetered dogs at ≥4 times human clinical exposure based on Cmax
Carcinogenicity: Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat study. Palbociclib was negative for carcinogenicity in transgenic mice at doses up to 60 mg/kg/day (No Observed Effect Level [NOEL] approximately 11 times human clinical exposure based on AUC). Palbociclib-related neoplastic finding in rats included an increased incidence of microglial cell tumors in the central nervous system of males at 30 mg/kg/day; there were no neoplastic findings in female rats at any dose up to 200 mg/kg/day. The NOEL for palbociclib-related carcinogenicity effects was 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and 200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males and females, respectively. The relevance of the male rat neoplastic finding to humans is unknown.
Genotoxicity: Palbociclib was not mutagenic in a bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro
human lymphocyte chromosome aberration assay.
Palbociclib induced micronuclei via an aneugenic mechanism in Chinese Hamster Ovary cells in vitro
and in the bone marrow of male rats at doses ≥100 mg/kg/day. The no-observed effect level for aneugenicity was approximately 7 times human clinical exposure based on AUC.
Impairment of fertility: Palbociclib did not affect mating or fertility in female rats at any dose tested up to 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC) and no adverse effects were observed in 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 5 and 3 times human clinical exposure based on AUC, respectively).
Palbociclib is considered to have the potential to impair reproductive function and fertility in male humans based on nonclinical findings in rats and dogs. Palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle included decreased organ weight, atrophy or degeneration, hypospermia, intratubular cellular debris, lower sperm motility and density, and decreased secretion. These findings were observed in rats and/or dogs at exposures ≥9 times or subtherapeutic compared to human clinical exposure based on AUC. Partial reversibility of male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-dosing period, respectively. Despite these male reproductive organ findings, there were no effects on mating or fertility in male rats at projected exposure levels 13 times human clinical exposure based on AUC.
Developmental toxicity: Palbociclib was fetotoxic in pregnant animals. An increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra) at ≥100 mg/kg/day was observed in rats. Reduced fetal body weights were observed at a maternally toxic dose of 300 mg/kg/day in rats (3 times human clinical exposure based on AUC), and an increased incidence of skeletal variations, including small phalanges in the forelimb was observed at a maternally toxic dose of 20 mg/kg/day in rabbits (4 times human clinical exposure based on AUC). Actual fetal exposure and cross-placenta transfer have not been examined.