INDICATIONS
IBRANCE (PALBOCICLIB) IS INDICATED IN COMBINATION WITH LETROZOLE FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ESTROGEN RECEPTOR (ER)-POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2)-NEGATIVE ADVANCED BREAST CANCER AS INITIAL ENDOCRINE-BASED THERAPY FOR THEIR METASTATIC DISEASE.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON PROGRESSION-FREE SURVIVAL (PFS) [SEE CLINICAL STUDIES]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN A CONFIRMATORY TRIAL.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
125 MG CAPSULES: OPAQUE HARD GELATIN CAPSULES, SIZE 0, WITH CARAMEL CAP AND BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 125” ON THE BODY.
100 MG CAPSULES: OPAQUE HARD GELATIN CAPSULES, SIZE 1, WITH CARAMEL CAP AND LIGHT ORANGE BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 100” ON THE BODY.
75 MG CAPSULES: OPAQUE HARD GELATIN CAPSULES, SIZE 2, WITH LIGHT ORANGE CAP AND BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 75” ON THE BODY.
STORAGE AND HANDLING
IBRANCE IS SUPPLIED IN THE FOLLOWING STRENGTHS AND PACKAGE CONFIGURATIONS:
IBRANCE CAPSULES
PACKAGE CONFIGURATION
CAPSULE STRENGTH (MG)
NDC
CAPSULE DESCRIPTION
BOTTLES OF 21 CAPSULES
125
NDC 0069-0189-21
OPAQUE, HARD GELATIN CAPSULES, SIZE 0, WITH CARAMEL CAP AND BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 125” ON THE BODY
BOTTLES OF 21 CAPSULES
100
NDC 0069-0188-21
OPAQUE, HARD GELATIN CAPSULES, SIZE 1, WITH CARAMEL CAP AND LIGHT ORANGE BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 100” ON THE BODY
BOTTLES OF 21 CAPSULES
75
NDC 0069-0187-21
OPAQUE, HARD GELATIN CAPSULES, SIZE 2, WITH LIGHT ORANGE CAP AND BODY, PRINTED WITH WHITE INK “PFIZER” ON THE CAP, “PBC 75” ON THE BODY
STORE AT 20°C TO 25°C (68°F TO 77°F); EXCURSIONS PERMITTED BETWEEN 15°C TO 30°C (59°F TO 86°F).
DISTRIBUTED BY: PFIZER LABS, DIVISION OF PFIZER INC., NY, NY 10017. ISSUED: FEBRUARY 2015
DOSAGE AND ADMINISTRATION
GENERAL DOSING INFORMATION
THE RECOMMENDED DOSE OF IBRANCE IS A 125 MG CAPSULE TAKEN ORALLY ONCE DAILY FOR 21 CONSECUTIVE DAYS FOLLOWED BY 7 DAYS OFF TREATMENT TO COMPRISE A COMPLETE CYCLE OF 28 DAYS. IBRANCE SHOULD BE TAKEN WITH FOOD [SEE CLINICAL PHARMACOLOGY] IN COMBINATION WITH LETROZOLE 2.5 MG ONCE DAILY GIVEN CONTINUOUSLY THROUGHOUT THE 28-DAY CYCLE. PATIENTS SHOULD BE ENCOURAGED TO TAKE THEIR DOSE AT APPROXIMATELY THE SAME TIME EACH DAY.
IF THE PATIENT VOMITS OR MISSES A DOSE, AN ADDITIONAL DOSE SHOULD NOT BE TAKEN THAT DAY. THE NEXT PRESCRIBED DOSE SHOULD BE TAKEN AT THE USUAL TIME. IBRANCE CAPSULES SHOULD BE SWALLOWED WHOLE (DO NOT CHEW, CRUSH OR OPEN THEM PRIOR TO SWALLOWING). NO CAPSULE SHOULD BE INGESTED IF IT IS BROKEN, CRACKED, OR OTHERWISE NOT INTACT.
DOSE MODIFICATION
DOSE MODIFICATION OF IBRANCE IS RECOMMENDED BASED ON INDIVIDUAL SAFETY AND TOLERABILITY [SEE WARNINGS AND PRECAUTIONS].
MANAGEMENT OF SOME ADVERSE REACTIONS [SEE WARNINGS AND PRECAUTIONS] MAY REQUIRE TEMPORARY DOSE INTERRUPTIONS/DELAYS AND/OR DOSE REDUCTIONS, OR PERMANENT DISCONTINUATION AS PER DOSE REDUCTION SCHEDULES PROVIDED IN TABLES 1, 2 AND 3 [SEE WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS AND CLINICAL STUDIES].
TABLE 1: RECOMMENDED DOSE MODIFICATION FOR ADVERSE REACTIONS
DOSE LEVEL
DOSE
RECOMMENDED STARTING DOSE
125 MG/DAY
FIRST DOSE REDUCTION
100 MG/DAY
SECOND DOSE REDUCTION
75 MG/DAY*
*IF FURTHER DOSE REDUCTION BELOW 75 MG/DAY IS REQUIRED, DISCONTINUE THE TREATMENT.
TABLE 2: DOSE MODIFICATION AND MANAGEMENTA – HEMATOLOGIC TOXICITIES
CTCAE GRADE
DOSE MODIFICATIONS
GRADE 1 OR 2
NO DOSE ADJUSTMENT IS REQUIRED.
GRADE 3B
NO DOSE ADJUSTMENT IS REQUIRED. CONSIDER REPEATING COMPLETE BLOOD COUNT MONITORING ONE WEEK LATER. WITHHOLD INITIATION OF NEXT CYCLE UNTIL RECOVERY TO GRADE = 2.
GRADE 3 ANC 3 ( < 1000 TO 500/MM³) + FEVER = 38.5°C AND/OR INFECTION
WITHHOLD IBRANCE AND INITIATION OF NEXT CYCLE UNTIL RECOVERY TO GRADE = 2 ( = 1000/MM³). RESUME AT NEXT LOWER DOSE.
GRADE 4B
WITHHOLD IBRANCE AND INITIATION OF NEXT CYCLE UNTIL RECOVERY TO GRADE = 2. RESUME AT NEXT LOWER DOSE.
GRADING ACCORDING TO CTCAE VERSION 4.0.
ANC=ABSOLUTE NEUTROPHIL COUNT; CTCAE=COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS.
A MONITOR COMPLETE BLOOD COUNT PRIOR TO THE START OF IBRANCE THERAPY AND AT THE BEGINNING OF EACH CYCLE, AS WELL AS ON DAY 14 OF THE FIRST TWO CYCLES, AND AS CLINICALLY INDICATED.
B EXCEPT LYMPHOPENIA (UNLESS ASSOCIATED WITH CLINICAL EVENTS, E.G., OPPORTUNISTIC INFECTIONS).
TABLE 3: DOSE MODIFICATION AND MANAGEMENT – NON-HEMATOLOGIC TOXICITIES
CTCAE GRADE
DOSE MODIFICATIONS
GRADE 1 OR 2
NO DOSE ADJUSTMENT IS REQUIRED.
GRADE = 3 NON-HEMATOLOGIC TOXICITY (IF PERSISTING DESPITE MEDICAL TREATMENT)
WITHHOLD UNTIL SYMPTOMS RESOLVE TO:
GRADE = 1;
GRADE = 2 (IF NOT CONSIDERED A SAFETY RISK FOR THE PATIENT)
RESUME AT THE NEXT LOWER DOSE.
GRADING ACCORDING TO CTCAE VERSION 4.0.
CTCAE=COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS.
SEE MANUFACTURER'S PRESCRIBING INFORMATION FOR THE COADMINISTERED PRODUCT, LETROZOLE, DOSE ADJUSTMENT GUIDELINES IN THE EVENT OF TOXICITY AND OTHER RELEVANT SAFETY INFORMATION OR CONTRAINDICATIONS.
DOSE MODIFICATIONS FOR USE WITH STRONG CYP3A INHIBITORS
AVOID CONCOMITANT USE OF STRONG CYP3A INHIBITORS AND CONSIDER AN ALTERNATIVE CONCOMITANT MEDICATION WITH NO OR MINIMAL CYP3A INHIBITION. IF PATIENTS MUST BE COADMINISTERED A STRONG CYP3A INHIBITOR, REDUCE THE IBRANCE DOSE TO 75 MG ONCE DAILY. IF THE STRONG INHIBITOR IS DISCONTINUED, INCREASE THE IBRANCE DOSE (AFTER 3–5 HALF-LIVES OF THE INHIBITOR) TO THE DOSE USED PRIOR TO THE INITIATION OF THE STRONG CYP3A INHIBITOR [SEE DRUG INTERACTIONS AND CLINICAL PHARMACOLOGY].
SIDE EFFECTS
THE FOLLOWING TOPICS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
NEUTROPENIA [SEE WARNINGS AND PRECAUTIONS]
INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
PULMONARY EMBOLISM [SEE WARNINGS AND PRECAUTIONS]
CLINICAL STUDIES EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER VARYING CONDITIONS, THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER TRIALS AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
THE SAFETY OF IBRANCE (125 MG/DAY) PLUS LETROZOLE (2.5 MG/DAY) VERSUS LETROZOLE ALONE WAS EVALUATED IN STUDY 1. THE DATA DESCRIBED BELOW REFLECT EXPOSURE TO IBRANCE IN 83 OUT OF 160 PATIENTS WITH ER-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER WHO RECEIVED AT LEAST 1 DOSE OF TREATMENT IN STUDY 1. THE MEDIAN DURATION OF TREATMENT FOR PALBOCICLIB WAS 13.8 MONTHS WHILE THE MEDIAN DURATION OF TREATMENT FOR LETROZOLE ON THE LETROZOLE-ALONE ARM WAS 7.6 MONTHS.
DOSE REDUCTIONS DUE TO AN ADVERSE REACTION OF ANY GRADE OCCURRED IN 36% OF PATIENTS RECEIVING IBRANCE PLUS LETROZOLE. NO DOSE REDUCTION WAS ALLOWED FOR LETROZOLE IN STUDY 1.
PERMANENT DISCONTINUATION DUE TO AN ADVERSE REACTION OCCURRED IN 7 OF 83 (8%) PATIENTS RECEIVING IBRANCE PLUS LETROZOLE AND IN 2 OF 77 (3%) PATIENTS RECEIVING LETROZOLE ALONE. ADVERSE REACTIONS LEADING TO DISCONTINUATION FOR THOSE PATIENTS RECEIVING IBRANCE PLUS LETROZOLE INCLUDED NEUTROPENIA (6%), ASTHENIA (1%), AND FATIGUE (1%).
THE MOST COMMON ADVERSE REACTIONS ( = 10%) OF ANY GRADE REPORTED IN PATIENTS IN THE IBRANCE PLUS LETROZOLE ARM WERE NEUTROPENIA, LEUKOPENIA, FATIGUE, ANEMIA, UPPER RESPIRATORY INFECTION, NAUSEA, STOMATITIS, ALOPECIA, DIARRHEA, THROMBOCYTOPENIA, DECREASED APPETITE, VOMITING, ASTHENIA, PERIPHERAL NEUROPATHY, AND EPISTAXIS.
THE MOST FREQUENTLY REPORTED SERIOUS ADVERSE REACTIONS IN PATIENTS RECEIVING IBRANCE PLUS LETROZOLE WERE PULMONARY EMBOLISM (3 OF 83; 4%) AND DIARRHEA (2 OF 83; 2%).
AN INCREASE INCIDENCE OF INFECTIONS EVENTS WAS OBSERVED IN THE PALBOCICLIB PLUS LETROZOLE ARM (55%) COMPARED TO THE LETROZOLE ALONE ARM (34%). FEBRILE NEUTROPENIA EVENTS HAVE BEEN REPORTED IN THE IBRANCE CLINICAL PROGRAM, ALTHOUGH NO CASES WERE OBSERVED IN STUDY 1. GRADE = 3 NEUTROPENIA WAS MANAGED BY DOSE REDUCTIONS AND/OR DOSE DELAY OR TEMPORARY DISCONTINUATION CONSISTENT WITH A PERMANENT DISCONTINUATION RATE OF 6% DUE TO NEUTROPENIA [SEE DOSAGE AND ADMINISTRATION].
ADVERSE DRUG REACTIONS ( = 10%) REPORTED IN PATIENTS WHO RECEIVED IBRANCE PLUS LETROZOLE OR LETROZOLE ALONE IN STUDY 1 ARE LISTED IN TABLE 4.
TABLE 4: ADVERSE REACTIONS* ( = 10%) IN STUDY 1
SYSTEM ORGAN CLASS
ADVERSE REACTION
IBRANCE + LETROZOLE
(N=83)
LETROZOLE ALONE
(N=77)
ALL GRADES %
GRADE 3 %
GRADE 4%
ALL GRADES %
GRADE 3 %
GRADE 4 %
INFECTIONS AND INFESTATIONS
URIA
31
1
0
18
0
0
BLOOD AND LYMPHATIC SYSTEM DISORDERS
NEUTROPENIA
75
48
6
5
1
0
LEUKOPENIA
43
19
0
3
0
0
ANEMIA
35
5
1
7
1
0
THROMBOCYTOPENIA
17
2
0
1
0
0
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE
16
1
0
7
0
0
NERVOUS SYSTEM DISORDERS
PERIPHERAL NEUROPATHYB
13
0
0
5
0
0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
EPISTAXIS
11
0
0
1
0
0
GASTROINTESTINAL DISORDERS
STOMATITISC
25
0
0
7
1
0
NAUSEA
25
2
0
13
1
0
DIARRHEA
21
4
0
10
0
0
VOMITING
15
0
0
4
1
0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
ALOPECIA
22D
N/A
N/A
3E
N/A
N/A
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
FATIGUE
41
2
2
23
1
0
ASTHENIA
13
2
0
4
0
0
*ADVERSE REACTION RATES REPORTED IN THE TABLE INCLUDE ALL REPORTED EVENTS REGARDLESS OF CAUSALITY.
GRADING ACCORDING TO CTCAE VERSION 3.0.
CTCAE=COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS; N=NUMBER OF SUBJECTS; N/A=NOT APPLICABLE; URI=UPPER RESPIRATORY INFECTION.
A URI INCLUDES: INFLUENZA, INFLUENZA LIKE ILLNESS, LARYNGITIS, NASOPHARYNGITIS, PHARYNGITIS, RHINITIS, SINUSITIS, UPPER RESPIRATORY TRACT INFECTION.
B PERIPHERAL NEUROPATHY INCLUDES: NEUROPATHY PERIPHERAL, PERIPHERAL SENSORY NEUROPATHY.
C STOMATITIS INCLUDES: APHTHOUS STOMATITIS, CHEILITIS, GLOSSITIS, GLOSSODYNIA, MOUTH ULCERATION, MUCOSAL INFLAMMATION, ORAL PAIN, OROPHARYNGEAL DISCOMFORT, OROPHARYNGEAL PAIN, STOMATITIS.
D GRADE 1 EVENTS - 21%; GRADE 2 EVENTS - 1%.
E GRADE 1 EVENTS - 3%.
TABLE 5: LABORATORY ABNORMALITIES FOR PATIENTS IN STUDY 1
LABORATORY ABNORMALITY
IBRANCE + LETROZOLE
(N=83)
LETROZOLE ALONE
(N=77)
ALL GRADES %
GRADE 3 %
GRADE 4 %
ALL GRADES %
GRADE 3 %
GRADE 4 %
WHITE BLOOD CELLS
95
44
0
26
0
0
DECREASED NEUTROPHILS DECREASED
94
57
5
17
3
0
LYMPHOCYTES DECREASED
81
17
1
35
3
0
HEMOGLOBIN DECREASED
83
5
1
40
3
0
PLATELETS DECREASED
61
3
0
16
3
0
N=NUMBER OF PATIENTS.
READ THE IBRANCE (PALBOCICLIB CAPSULES FOR ORAL ADMINISTRATION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THERE IS NO KNOWN ANTIDOTE FOR IBRANCE. THE TREATMENT OF OVERDOSE OF IBRANCE SHOULD CONSIST OF GENERAL SUPPORTIVE MEASURES.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
PALBOCICLIB IS AN INHIBITOR OF CYCLIN-DEPENDENT KINASE (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 PROTEIN (RB) 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 LEADS TO INCREASED CELL SENESCENCE, WHICH WAS SUSTAINED FOR UP TO 6 DAYS FOLLOWING DRUG REMOVAL. 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.
PHARMACODYNAMICS
CARDIAC ELECTROPHYSIOLOGY
THE EFFECT OF PALBOCICLIB ON THE QTC INTERVAL WAS EVALUATED IN 184 PATIENTS WITH ADVANCED CANCER. NO LARGE CHANGE (I.E., > 20 MS) IN THE QTC INTERVAL WAS DETECTED AT THE MEAN OBSERVED MAXIMAL STEADY-STATE PALBOCICLIB CONCENTRATION FOLLOWING A THERAPEUTIC SCHEDULE (E.G., 125 MG DAILY FOR 21 CONSECUTIVE DAYS FOLLOWED BY 7 DAYS OFF TO COMPRISE A COMPLETE CYCLE OF 28 DAYS).
PHARMACOKINETICS
THE PHARMACOKINETICS OF PALBOCICLIB WERE CHARACTERIZED IN PATIENTS WITH SOLID TUMORS INCLUDING ADVANCED BREAST CANCER AND IN HEALTHY SUBJECTS.
ABSORPTION
THE MEAN CMAX OF PALBOCICLIB IS GENERALLY OBSERVED BETWEEN 6 TO 12 HOURS (TIME TO REACH MAXIMUM CONCENTRATION, TMAX) FOLLOWING ORAL ADMINISTRATION. 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 CMAX 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 1.5-4.2).
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 IBRANCE GIVEN UNDER OVERNIGHT FASTED CONDITIONS, THE POPULATION AVERAGE AUCINF AND CMAX OF PALBOCICLIB INCREASED BY 21% AND 38%, RESPECTIVELY, WHEN GIVEN WITH HIGH-FAT, HIGH-CALORIE FOOD (APPROXIMATELY 800 TO 1000 CALORIES WITH 150, 250, AND 500 TO 600 CALORIES FROM PROTEIN, CARBOHYDRATE AND FAT, RESPECTIVELY), BY 12% AND 27%, RESPECTIVELY, WHEN GIVEN WITH LOW-FAT, LOW-CALORIE FOOD (APPROXIMATELY 400 TO 500 CALORIES WITH 120, 250, AND 28 TO 35 CALORIES FROM PROTEIN, CARBOHYDRATE AND FAT, RESPECTIVELY), AND BY 13% AND 24%, RESPECTIVELY, WHEN MODERATE-FAT, STANDARD CALORIE FOOD (APPROXIMATELY 500 TO 700 CALORIES WITH 75 TO 105, 250 TO 350 AND 175 TO 245 CALORIES FROM PROTEIN, CARBOHYDRATE AND FAT, RESPECTIVELY) WAS GIVEN ONE HOUR BEFORE AND TWO HOURS AFTER IBRANCE DOSING.
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 GEOMETRIC MEAN APPARENT VOLUME OF DISTRIBUTION (VZ/F) WAS 2583 L (26% CV).
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 [14C]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 63.1 L/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 [14C]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.
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.
PEDIATRIC POPULATION
PHARMACOKINETICS OF IBRANCE HAVE NOT BEEN EVALUATED IN PATIENTS < 18 YEARS OF AGE.
DRUG INTERACTIONS
IN VITRO DATA INDICATE THAT CYP3A AND SULT ENZYME SULT2A1 ARE MAINLY INVOLVED IN THE METABOLISM OF PALBOCICLIB. PALBOCICLIB IS A WEAK TIME-DEPENDENT INHIBITOR OF CYP3A FOLLOWING DAILY 125 MG DOSING TO STEADY STATE IN HUMANS. IN VITRO, PALBOCICLIB IS NOT AN INHIBITOR OF CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, AND 2D6, AND IS NOT AN INDUCER OF CYP1A2, 2B6, 2C8, AND 3A4 AT CLINICALLY RELEVANT CONCENTRATIONS.
CYP3A INHIBITORS: DATA FROM A DRUG INTERACTION TRIAL IN HEALTHY SUBJECTS (N=12) INDICATE THAT COADMINISTRATION OF MULTIPLE 200 MG DAILY DOSES OF ITRACONAZOLE WITH A SINGLE 125 MG IBRANCE DOSE INCREASED PALBOCICLIB AUCINF AND THE CMAX BY APPROXIMATELY 87% AND 34%, RESPECTIVELY, RELATIVE TO A SINGLE 125 MG IBRANCE DOSE GIVEN ALONE.
CYP3A INDUCERS: DATA FROM A DRUG INTERACTION TRIAL IN HEALTHY SUBJECTS (N=14) INDICATE THAT COADMINISTRATION OF MULTIPLE 600 MG DAILY DOSES OF RIFAMPIN WITH A SINGLE 125 MG IBRANCE DOSE DECREASED PALBOCICLIB AUCINF AND THE CMAX BY 85% AND 70%, RESPECTIVELY, RELATIVE TO A SINGLE 125 MG IBRANCE DOSE GIVEN ALONE.
CYP3A SUBSTRATES: PALBOCICLIB IS A WEAK TIME-DEPENDENT INHIBITOR OF CYP3A FOLLOWING DAILY 125 MG DOSING TO STEADY STATE IN HUMANS. IN A DRUG INTERACTION TRIAL IN HEALTHY SUBJECTS (N=26), COADMINISTRATION OF MIDAZOLAM WITH MULTIPLE DOSES OF IBRANCE INCREASED THE MIDAZOLAM AUCINF AND THE CMAX VALUES BY 61% AND 37%, RESPECTIVELY, AS COMPARED WITH ADMINISTRATION OF MIDAZOLAM ALONE.
GASTRIC PH ELEVATING MEDICATIONS: IN A DRUG INTERACTION TRIAL IN HEALTHY SUBJECTS, COADMINISTRATION OF A SINGLE 125 MG DOSE OF IBRANCE WITH MULTIPLE DOSES OF THE PROTON PUMP INHIBITORS (PPI) RABEPRAZOLE UNDER FED CONDITIONS DECREASED PALBOCICLIB CMAX BY 41%, BUT HAD LIMITED IMPACT ON AUCINF (13% DECREASE), WHEN COMPARED TO A SINGLE 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, COADMINISTRATION OF A SINGLE DOSE OF IBRANCE WITH MULTIPLE DOSES OF THE PPI RABEPRAZOLE UNDER FASTED CONDITIONS DECREASED PALBOCICLIB AUCINF AND CMAX BY 62% AND 80%, RESPECTIVELY, WHEN COMPARED TO A SINGLE DOSE OF IBRANCE ADMINISTERED ALONE.
LETROZOLE: DATA FROM A DRUG INTERACTION TRIAL IN PATIENTS WITH BREAST CANCER SHOWED THAT THERE WAS NO DRUG INTERACTION BETWEEN PALBOCICLIB AND LETROZOLE WHEN THE TWO DRUGS WERE COADMINISTERED.
EFFECT OF PALBOCICLIB ON TRANSPORTERS: IN VITRO EVALUATIONS INDICATED THAT PALBOCICLIB HAS A LOW POTENTIAL TO INHIBIT THE ACTIVITIES OF DRUG TRANSPORTERS P-GLYCOPROTEIN (P-GP), BREAST CANCER RESISTANCE PROTEIN (BCRP), ORGANIC ANION TRANSPORTER (OAT)1, OAT3, ORGANIC CATION TRANSPORTER (OCT)2 AND ORGANIC ANION TRANSPORTING POLYPEPTIDE (OATP)1B1, OATP1B3 AT CLINICALLY RELEVANT CONCENTRATIONS.
EFFECT OF TRANSPORTERS ON PALBOCICLIB: BASED ON IN VITRO DATA, P-GP AND BCRP MEDIATED TRANSPORT ARE UNLIKELY TO AFFECT THE EXTENT OF ORAL ABSORPTION OF PALBOCICLIB AT THERAPEUTIC DOSES.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
ALTERED GLUCOSE METABOLISM (GLYCOSURIA, HYPERGLYCEMIA, DECREASED INSULIN) ASSOCIATED WITH CHANGES IN THE PANCREAS (ISLET CELL VACUOLATION), EYE (CATARACTS, LENS DEGENERATION), TEETH (DEGENERATION/NECROSIS OF AMELOBLASTS IN ACTIVELY GROWING TEETH), KIDNEY (TUBULE VACUOLATION, CHRONIC PROGRESSIVE NEPHROPATHY), AND ADIPOSE TISSUE (ATROPHY) WERE IDENTIFIED IN THE 27-WEEK REPEAT-DOSE TOXICOLOGY STUDY IN RATS AND WERE MOST PREVALENT IN MALES AT DOSES = 30 MG/KG/DAY (APPROXIMATELY 11 TIMES THE HUMAN EXPOSURE (AUC) AT THE RECOMMENDED DOSE). SOME OF THESE FINDINGS (GLYCOSURIA/HYPERGLYCEMIA, PANCREATIC ISLET CELL VACUOLATION, AND KIDNEY TUBULE VACUOLATION) WERE PRESENT IN THE 15-WEEK REPEAT-DOSE TOXICOLOGY STUDY IN RATS, BUT WITH LOWER INCIDENCE AND SEVERITY. THE RATS USED IN THESE STUDIES WERE APPROXIMATELY 7 WEEKS OLD AT THE BEGINNING OF THE STUDIES. ALTERED GLUCOSE METABOLISM OR ASSOCIATED CHANGES IN PANCREAS, EYE, TEETH, KIDNEY, AND ADIPOSE TISSUE WERE NOT IDENTIFIED IN DOGS IN REPEAT-DOSE TOXICOLOGY STUDIES UP TO 39 WEEKS DURATION.
CLINICAL STUDIES
STUDY 1 WAS A RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY OF IBRANCE PLUS LETROZOLE VERSUS LETROZOLE ALONE 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 165 PATIENTS WERE RANDOMIZED IN STUDY 1. 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 ADVANCED DISEASE). 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 PROGRESSIVE DISEASE, UNMANAGEABLE TOXICITY, OR CONSENT WITHDRAWAL.
PATIENTS ENROLLED IN THIS STUDY HAD A MEDIAN AGE OF 63 YEARS (RANGE 38 TO 89). THE MAJORITY OF PATIENTS WERE CAUCASIAN (90%) AND ALL PATIENTS HAD AN EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS (PS) OF 0 OR 1. FORTY-THREE PERCENT OF PATIENTS HAD RECEIVED CHEMOTHERAPY AND 33% HAD RECEIVED ANTIHORMONAL THERAPY IN THE NEOADJUVANT OR ADJUVANT SETTING PRIOR TO THEIR DIAGNOSIS OF ADVANCED BREAST CANCER. FORTY-NINE PERCENT OF PATIENTS HAD NO PRIOR SYSTEMIC THERAPY IN THE NEOADJUVANT OR ADJUVANT SETTING. THE MAJORITY OF PATIENTS (98%) HAD METASTATIC DISEASE. NINETEEN PERCENT OF PATIENTS HAD BONE ONLY DISEASE AND 48% OF PATIENTS HAD VISCERAL DISEASE.
THE MAJOR EFFICACY OUTCOME MEASURE OF THE STUDY WAS INVESTIGATOR-ASSESSED PFS EVALUATED ACCORDING TO RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.0 (RECIST). MAJOR EFFICACY RESULTS FROM STUDY 1 ARE SUMMARIZED IN TABLE 6 AND FIGURE 1. CONSISTENT RESULTS WERE OBSERVED ACROSS PATIENT SUBGROUPS OF, DISEASE-FREE INTERVAL, DISEASE SITE AND PRIOR THERAPY. THE TREATMENT EFFECT OF THE COMBINATION ON PFS WAS ALSO SUPPORTED BY A RETROSPECTIVE INDEPENDENT REVIEW OF RADIOGRAPHS WITH AN OBSERVED HAZARD RATIO (HR) OF 0.621 (95% CI: 0.378, 1.019). OVERALL RESPONSE RATE IN PATIENTS WITH MEASURABLE DISEASE AS ASSESSED BY THE INVESTIGATOR WAS HIGHER IN THE IBRANCE PLUS LETROZOLE COMPARED TO THE LETROZOLE ALONE ARM (55.4% VERSUS 39.4%). AT THE TIME OF THE FINAL ANALYSIS OF PFS, OVERALL SURVIVAL (OS) DATA WAS NOT MATURE WITH 37% OF EVENTS.
TABLE 6: EFFICACY RESULTS – STUDY 1 (INVESTIGATOR ASSESSMENT, INTENT-TO-TREAT POPULATION)
IBRANCE + LETROZOLE
(N=84)
LETROZOLE
(N=81)
PROGRESSION-FREE SURVIVAL (PFS)
NUMBER OF PFS EVENTS (%)
41 (48.8%)
59 (72.8%)
HAZARD RATIO (95% CI)
0.488 (0.319, 0.748)
MEDIAN PFS [MONTHS] (95% CI)
20.2 (13.8, 27.5)
10.2 (5.7, 12.6)
CI=CONFIDENCE INTERVAL; N=NUMBER OF PATIENTS.
FIGURE 1: KAPLAN-MEIER CURVES OF PROGRESSION-FREE SURVIVAL – STUDY 1 (INVESTIGATOR ASSESSMENT, INTENT-TO-TREAT POPULATION)