Breast Cancer
Conditions
Keywords
hormone-receptor positive advanced breast cancer
Brief summary
The study is aimed to confirm that letrozole + PD 0332991 is safe and tolerable and to assess the effect of the combination on advanced breast cancer
Interventions
DRUGPD 0332991
125 mg/d capsules orally for 3 out of 4 weeks in repeated cycles
DRUGletrozole
2.5 mg/d tablets orally on a continuous regimen
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inoperable estrogen receptor positive and HER2 negative breast cancer. * Postmenopausal status. * Tumor tissue (archived acceptable) available for biomarker studies. For Phase 2 Part 2 - CCND1 amplification and/or loss of p16 as determined by the central laboratory. * Acceptable bone marrow, liver and kidney function.
Exclusion criteria
* Prior or concomitant treatment for advanced breast cancer. * Other major cancer in the past 3 years. * Important cardiovascular events in the past 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 | Maximum treatment duration (approximately 55 months) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Number of Participants With Treatment-Related Adverse Events at Phase 1 | Maximum treatment duration (approximately 55 months) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Number of Participants With Dose Limiting Toxicities at Phase 1 | Cycle 2 (4 weeks) | Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets \<25,000/μL, ANC \<500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count \<50,000/μL; ANC \<1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment. |
| Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | From randomization date to date of first documentation of progression or death (assessed up to 41 months) | PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
| Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1 | Cycle 2 Day 14, Cycle 2 Day 28 | On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing. |
| Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1 | Cycle 2 Day 14, and Cycle 2 Day 28 | On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing. |
| Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1 | Cycle 2 Day 14, and Cycle 2 Day 28 | On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing. |
| Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | Cycle 1 Day 1 prior to dosing, Cycle 1 Day 14 (2, 4 [prior to meal], 8, 24, 48, and 96 hours after dosing of Palbociclib), Cycle 2 Day 1 and Day 14 (prior to and 4 hours after dosing of letrozole) | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Participants with maximum increase from baseline of 30 to less than (\<) 60 msec(borderline) and greater than or equal to (\>=) 60 msec (prolonged) were summarized. |
| Overall Survival (OS) at Phase 2 | From randomization until death (assessed up to 86 months) | Time in weeks or months from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7 or 30.44 if in months. |
| Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | From randomization up to the end of treatment (approximately 41 months) | Percentage of participants with objective response based assessment of confirmed CR or confirmed PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. |
| Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | From randomization up to the end of treatment (approximately 41 months) | Percentage of participants with objective response based assessment of confirmed CR or PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. Measurable disease referred to the lesions that was accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques or as ≥10-16 mm with spiral computer tomography scan (depending on reconstruction interval). Clinical lesions were only be considered measurable when they were superficial (eg, skin nodules, palpable lymph nodes). |
| Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1 | From Baseline up to end of study (assessed up to 55 months) | Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. |
| Number of Participants With CBR at Phase 2 - Investigator Assessment | From randomization up to the end of treatment (approximately 41 months) | CBR is defined as a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) for at least 24 weeks on study according to RECIST. |
| Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | From randomization up to the end of treatment (approximately 41 months) | Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization \[or first dose of study medication for non-randomized studies\] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\] per RECIST). |
| Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Baseline, End of treatment (approximately 41 months) | The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (no pain or does not interfere) to 10 (pain as bad as you can imagine or completely interferes). |
| Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Baseline, End of treatment (approximately 41 months) | The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (no pain or does not interfere) to 10 (pain as bad as you can imagine or completely interferes). |
| Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | Screening visit (≤ 28 Days prior to dosing) | Tissue samples were used for retrospective biomarker analyses. For Phase 2 Part 2, the tissue samples were sent to a central laboratory for the assessment of participant selection biomarkers. For Phase 2 Part 1, the assessment of the biomarkers (CCND1 amplification and/or loss of p16) were performed retrospectively from the available samples. |
| Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | Screening visit (≤ 28 Days prior to dosing) | Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups. |
| Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | Screening visit (≤ 28 Days prior to dosing) | Presence or absence of tumor RB and CyclinD1 were evaluated. The following definitions of expression applied in the below table: Positive: any expression \>0 and Negative: any expression=0. |
| Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 | Screening visit (≤ 28 Days prior to dosing) | Gene copy number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) were evaluated. This analysis was done for Phase 2 combined group. |
| Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | Screening visit (≤ 28 Days prior to dosing) | One 2-mL blood specimen was collected for the analysis of germline polymorphism in CYP19A1 and CCND1 genes. A single nucleotide polymorphism (SNP) rs4646 as defined in the National Center for Biotechnology Information (NCBI) database in the aromatase gene (CYP19A1) was analyzed. A germline polymorphism G/A870 (rs9344) in the CCND1 gene was analyzed. |
| Number of Participants With TEAEs (All Causalities) at Phase 2 | Baseline up to 28 days after last dose of study drug (for a maximum of 86 months) | AE:any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.AEs included both serious and non-serious AEs.SAE:AE resulting in any of following outcomes/deemed significant and jeopardized participants or required treatment to prevent other AE outcomes for any other reason:death;initial or prolonged inpatient hospitalization;life-threatening experience (immediate risk of dying);persistent or significant disability/incapacity;congenital anomaly.Treatment emergent AEs:events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or worsened relative to pre-treatment state.AEs were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and coded using Medical Dictionary for Regulatory Activities (MedDRA). Participants with AE of grade 3 or 4 and grade 5 were reported as Grade 3:Severe, Grade 4:Life threatening, Grade 5:Death related to AE. |
| Number of Participants With Treatment-Related Adverse Events at Phase 2 | Baseline up to 28 days after last dose of study drug (for a maximum of 86 months) | AE: any untoward medical occurrence in a participant who received study drug. AEs included both serious and non-serious adverse events. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs: events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: all AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs were graded according to the CTCAE version 3.0 and coded using the MedDRA. Number of participants with AE of grade 3 or 4 and with AE of grade 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. |
| Duration of Response at Phase 2 - Investigator Assessment | From randomization up to the end of treatment (approximately 41 months) | Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization \[or first dose of study medication for non-randomized studies\] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\] per RECIST). |
| Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1 | From Baseline up to end of study (assessed up to 55 months) | CBR is defined as a confirmed CR, confirmed PR, or stable disease (SD) for at least 24 weeks on study according to RECIST. Confirmed responses are those that persisted on repeat imaging \>= 4 weeks after initial response. |
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
| Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1 | Cycle 1 Day 14, and Cycle 2 Day 14 | On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. |
Countries
Canada, France, Germany, Hungary, Ireland, Italy, Russia, South Africa, South Korea, Spain, Ukraine, United States
Participant flow
Recruitment details
This Phase 1/2, open-label, randomized study enrolled a total of 12 participants at 3 sites in the United States for Phase 1. Phase 1 participants received Palbociclib + Letrozole. In Phase 2, a total of 165 participants were randomized (84 in palbociclib plus letrozole arm and 81 in letrozole alone arm) at 50 sites in 12 countries.
Pre-assignment details
Phase 2 portion has 2 parts. Phase 2, Part 1 - ER positive, HER2 negative postmenopausal women with advanced breast cancer. Phase 2, Part 2- ER positive, HER2 negative postmenopausal women with tumors demonstrating CCND1 gene amplification and/or loss of CDKN2A gene.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 (Palbociclib + Letrozole) In Cycle 1 (3 weeks), participants received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), participants received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment. | 12 |
| Phase 2 (Palbociclib + Letrozole) All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen. | 84 |
| Phase 2 (Letrozole) All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen. | 81 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 13 | 2 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Global deterioration of health status | 2 | 6 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Objective progression or relapse | 8 | 55 | 62 |
| Overall Study | Randomized not Treated | 0 | 1 | 4 |
| Overall Study | Reason not specified | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 6 | 5 |
Baseline characteristics
| Characteristic | Total | Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) |
|---|---|---|---|---|
| Age, Customized 18-44 Years | 7 Participants | 1 Participants | 2 Participants | 4 Participants |
| Age, Customized <18 Years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 45-64 Years | 89 Participants | 6 Participants | 45 Participants | 38 Participants |
| Age, Customized >= 65 Years | 81 Participants | 5 Participants | 37 Participants | 39 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 0 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 159 Participants | 11 Participants | 76 Participants | 72 Participants |
| Sex: Female, Male Female | 177 Participants | 12 Participants | 84 Participants | 81 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 3 / 83 | 1 / 77 | 1 / 33 | 0 / 29 | 2 / 50 | 1 / 48 |
| other Total, other adverse events | 12 / 12 | 83 / 83 | 57 / 77 | 33 / 33 | 22 / 29 | 50 / 50 | 35 / 48 |
| serious Total, serious adverse events | 2 / 12 | 22 / 83 | 6 / 77 | 10 / 33 | 2 / 29 | 12 / 50 | 4 / 48 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities at Phase 1
Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets \<25,000/μL, ANC \<500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count \<50,000/μL; ANC \<1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment.
Time frame: Cycle 2 (4 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Dose Limiting Toxicities at Phase 1 | Grade 4 Neutropenia | 2 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Dose Limiting Toxicities at Phase 1 | <80% of doses due to elevated creatinine | 1 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Maximum treatment duration (approximately 55 months)
Population: Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 | Participants with AEs | 12 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 | Participants with SAEs | 2 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 | Participants with Grade 3 or 4 AEs | 11 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 | Participants with Grade 5 AEs | 0 Participants |
Primary
Number of Participants With Treatment-Related Adverse Events at Phase 1
An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Maximum treatment duration (approximately 55 months)
Population: Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 1 | Participants with AEs | 12 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 1 | Participants with SAEs | 0 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 1 | Participants with Grade 3 or 4 AEs | 11 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 1 | Participants with Grade 5 AEs | 0 Participants |
Primary
Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment
PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs).
Time frame: From randomization date to date of first documentation of progression or death (assessed up to 41 months)
Population: Intent-to-Treat (ITT) was used. This represented all randomized participants from Ph2P1 or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 20.2 Months |
| Phase 2 (Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 10.2 Months |
| Ph2P1 (Palbociclib + Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 26.1 Months |
| Ph2P1 (Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 5.7 Months |
| Ph2P2 (Palbociclib + Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 18.1 Months |
| Ph2P2 (Letrozole) | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment | 11.1 Months |
Comparison: The primary hypothesis to be tested was H0: λ=1 versus. HA: λ\<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Stratified analysis was presented above.p-value: 0.000495% CI: [0.319, 0.748]Log Rank
Comparison: The primary hypothesis to be tested was H0: λ=1 versus. HA: λ\<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.p-value: <0.000195% CI: [0.156, 0.572]Log Rank
Comparison: The primary hypothesis to be tested was H0: λ=1 versus. HA: λ\<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.p-value: 0.004695% CI: [0.303, 0.853]Log Rank
Secondary
Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2
The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (no pain or does not interfere) to 10 (pain as bad as you can imagine or completely interferes).
Time frame: Baseline, End of treatment (approximately 41 months)
Population: Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.8 Units on a scale | Standard Error 0.32 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.6 Units on a scale | Standard Error 0.43 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 0.7 Units on a scale | Standard Error 0.48 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 1.1 Units on a scale | Standard Error 0.4 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | 0.8 Units on a scale | Standard Error 0.5 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.8 Units on a scale | Standard Error 0.34 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 0.8 Units on a scale | Standard Error 0.46 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 0.8 Units on a scale | Standard Error 0.46 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 0.3 Units on a scale | Standard Error 0.39 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 0.1 Units on a scale | Standard Error 0.35 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | 0.2 Units on a scale | Standard Error 0.36 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.4 Units on a scale | Standard Error 0.3 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 0.2 Units on a scale | Standard Error 0.31 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.8 Units on a scale | Standard Error 0.32 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 0.6 Units on a scale | Standard Error 0.41 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.3 Units on a scale | Standard Error 0.35 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.1 Units on a scale | Standard Error 0.53 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | 0.6 Units on a scale | Standard Error 0.72 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 1.0 Units on a scale | Standard Error 0.66 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.6 Units on a scale | Standard Error 0.34 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 1.0 Units on a scale | Standard Error 0.55 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 1.0 Units on a scale | Standard Error 0.53 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.7 Units on a scale | Standard Error 0.42 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 0.4 Units on a scale | Standard Error 0.34 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.3 Units on a scale | Standard Error 0.56 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 0.2 Units on a scale | Standard Error 0.69 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 0.2 Units on a scale | Standard Error 0.58 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | -0.2 Units on a scale | Standard Error 0.62 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 0.3 Units on a scale | Standard Error 0.63 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.5 Units on a scale | Standard Error 0.63 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 0.2 Units on a scale | Standard Error 0.74 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.6 Units on a scale | Standard Error 0.6 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.9 Units on a scale | Standard Error 0.61 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 0.5 Units on a scale | Standard Error 0.71 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | 1.0 Units on a scale | Standard Error 0.69 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 1.2 Units on a scale | Standard Error 0.51 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 1.1 Units on a scale | Standard Error 0.71 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.9 Units on a scale | Standard Error 0.47 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 0.7 Units on a scale | Standard Error 0.67 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.9 Units on a scale | Standard Error 0.48 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Interference Scale | 0.4 Units on a scale | Standard Error 0.36 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Enjoyment of life | 0.8 Units on a scale | Standard Error 0.52 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Sleep | 0.1 Units on a scale | Standard Error 0.42 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Normal work | 0.4 Units on a scale | Standard Error 0.45 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Mood | 0.4 Units on a scale | Standard Error 0.44 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Relations | 0.8 Units on a scale | Standard Error 0.37 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | General Activity | 0.3 Units on a scale | Standard Error 0.37 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 | Walking ability | 0.0 Units on a scale | Standard Error 0.43 |
Comparison: Statistical analysis presented above is for Pain Interference Scale.p-value: 0.334695% CI: [-0.5, 1.3]t-test, 2 sided
Comparison: Statistical analysis presented above is for Pain Interference Scale.p-value: 0.56395% CI: [-1, 1.9]t-test, 2 sided
Comparison: Statistical analysis presented above is for Pain Severity Scale.p-value: 0.442795% CI: [-0.7, 1.6]t-test, 2 sided
Secondary
Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2
The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (no pain or does not interfere) to 10 (pain as bad as you can imagine or completely interferes).
Time frame: Baseline, End of treatment (approximately 41 months)
Population: Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | 0.2 Units on a scale | Standard Error 0.33 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 0.6 Units on a scale | Standard Error 0.42 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.4 Units on a scale | Standard Error 0.27 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.4 Units on a scale | Standard Error 0.29 |
| Phase 1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.3 Units on a scale | Standard Error 0.35 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | 0.2 Units on a scale | Standard Error 0.34 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.4 Units on a scale | Standard Error 0.27 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 0.1 Units on a scale | Standard Error 0.42 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.1 Units on a scale | Standard Error 0.36 |
| Phase 2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.2 Units on a scale | Standard Error 0.32 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.1 Units on a scale | Standard Error 0.31 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.3 Units on a scale | Standard Error 0.31 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 0.2 Units on a scale | Standard Error 0.6 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | -0.1 Units on a scale | Standard Error 0.48 |
| Ph2P1 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.0 Units on a scale | Standard Error 0.36 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | 0.2 Units on a scale | Standard Error 0.64 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.3 Units on a scale | Standard Error 0.66 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.7 Units on a scale | Standard Error 0.5 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 0.0 Units on a scale | Standard Error 0.89 |
| Ph2P1 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.3 Units on a scale | Standard Error 0.62 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.6 Units on a scale | Standard Error 0.41 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.5 Units on a scale | Standard Error 0.4 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.3 Units on a scale | Standard Error 0.55 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | 0.4 Units on a scale | Standard Error 0.45 |
| Ph2P2 (Palbociclib + Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 1.2 Units on a scale | Standard Error 0.55 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain Severity Scale | 0.1 Units on a scale | Standard Error 0.36 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain on the average | 0.3 Units on a scale | Standard Error 0.4 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its least in the last 24 hours | 0.2 Units on a scale | Standard Error 0.31 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain right now | 0.0 Units on a scale | Standard Error 0.43 |
| Ph2P2 (Letrozole) | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 | Pain at its worst in the last 24 hours | 0.1 Units on a scale | Standard Error 0.43 |
Comparison: Statistical analysis presented above is for Pain Severity Scale.p-value: 0.6995% CI: [-0.7, 1]t-test, 2 sided
Comparison: Statistical analysis presented above is for Pain Severity Scale.p-value: 0.712595% CI: [-1.8, 1.2]t-test, 2 sided
Comparison: Statistical analysis presented above is for Pain Severity Scale.p-value: 0.401295% CI: [-0.6, 1.5]t-test, 2 sided
Secondary
Duration of Response at Phase 2 - Investigator Assessment
Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization \[or first dose of study medication for non-randomized studies\] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\] per RECIST).
Time frame: From randomization up to the end of treatment (approximately 41 months)
Population: A subset of ITT population i.e., participants who had response was used for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 20.3 Months |
| Phase 2 (Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 11.1 Months |
| Ph2P1 (Palbociclib + Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 20.9 Months |
| Ph2P1 (Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 10.8 Months |
| Ph2P2 (Palbociclib + Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 20.2 Months |
| Ph2P2 (Letrozole) | Duration of Response at Phase 2 - Investigator Assessment | 14.8 Months |
Secondary
Number of Participants With CBR at Phase 2 - Investigator Assessment
CBR is defined as a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) for at least 24 weeks on study according to RECIST.
Time frame: From randomization up to the end of treatment (approximately 41 months)
Population: ITT was used. This represented all randomized patients from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 81.0 Percentage of participants |
| Phase 2 (Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 58.0 Percentage of participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 76.5 Percentage of participants |
| Ph2P1 (Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 43.8 Percentage of participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 84.0 Percentage of participants |
| Ph2P2 (Letrozole) | Number of Participants With CBR at Phase 2 - Investigator Assessment | 67.3 Percentage of participants |
Comparison: CBR CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio \>1 means better response in favor of palbociclib + letrozole arm.p-value: 0.000995% CI: [1.48, 6.98]Cochran-Mantel-Haenszel
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.006595% CI: [1.3, 13.9]Chi-squared
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.044295% CI: [0.89, 7.7]Chi-squared
Secondary
Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Participants with maximum increase from baseline of 30 to less than (\<) 60 msec(borderline) and greater than or equal to (\>=) 60 msec (prolonged) were summarized.
Time frame: Cycle 1 Day 1 prior to dosing, Cycle 1 Day 14 (2, 4 [prior to meal], 8, 24, 48, and 96 hours after dosing of Palbociclib), Cycle 2 Day 1 and Day 14 (prior to and 4 hours after dosing of letrozole)
Population: Safety analysis set included all participants who received at least 1 dose of any agent of the combination.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcB - Change <30 | 9 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcB - 30 ≤ change <60 | 3 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcB - Change ≥60 | 0 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcF - Change <30 | 11 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcF - 30 ≤ change <60 | 1 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcF - Change ≥60 | 0 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcS - Change <30 | 8 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcS - 30 ≤ change <60 | 4 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 | QTcS - Change ≥60 | 0 Participants |
Secondary
Number of Participants With TEAEs (All Causalities) at Phase 2
AE:any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.AEs included both serious and non-serious AEs.SAE:AE resulting in any of following outcomes/deemed significant and jeopardized participants or required treatment to prevent other AE outcomes for any other reason:death;initial or prolonged inpatient hospitalization;life-threatening experience (immediate risk of dying);persistent or significant disability/incapacity;congenital anomaly.Treatment emergent AEs:events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or worsened relative to pre-treatment state.AEs were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and coded using Medical Dictionary for Regulatory Activities (MedDRA). Participants with AE of grade 3 or 4 and grade 5 were reported as Grade 3:Severe, Grade 4:Life threatening, Grade 5:Death related to AE.
Time frame: Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
Population: All treated as treated set included all treated participants classified by the treatment actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 22 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 83 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 1 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 70 Participants |
| Phase 2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 19 Participants |
| Phase 2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 6 Participants |
| Phase 2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 66 Participants |
| Phase 2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 10 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 29 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 33 Participants |
| Ph2P1 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 2 Participants |
| Ph2P1 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 5 Participants |
| Ph2P1 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 25 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 41 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 12 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 50 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 1 Participants |
| Ph2P2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 3 or 4 AEs | 14 Participants |
| Ph2P2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with AEs | 41 Participants |
| Ph2P2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P2 (Letrozole) | Number of Participants With TEAEs (All Causalities) at Phase 2 | Participants with SAEs | 4 Participants |
Secondary
Number of Participants With Treatment-Related Adverse Events at Phase 2
AE: any untoward medical occurrence in a participant who received study drug. AEs included both serious and non-serious adverse events. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs: events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: all AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs were graded according to the CTCAE version 3.0 and coded using the MedDRA. Number of participants with AE of grade 3 or 4 and with AE of grade 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE.
Time frame: Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
Population: All treated as treated set included all treated participants classified by the treatment actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 78 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 1 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 57 Participants |
| Phase 1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Phase 2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 2 Participants |
| Phase 2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 0 Participants |
| Phase 2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 33 Participants |
| Phase 2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 25 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 0 Participants |
| Ph2P1 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 32 Participants |
| Ph2P1 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 13 Participants |
| Ph2P1 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P1 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 0 Participants |
| Ph2P1 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 0 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 32 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 1 Participants |
| Ph2P2 (Palbociclib + Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 46 Participants |
| Ph2P2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with SAEs | 0 Participants |
| Ph2P2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 3 or 4 AEs | 2 Participants |
| Ph2P2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with Grade 5 AEs | 0 Participants |
| Ph2P2 (Letrozole) | Number of Participants With Treatment-Related Adverse Events at Phase 2 | Participants with AEs | 20 Participants |
Secondary
Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment
Percentage of participants with objective response based assessment of confirmed CR or confirmed PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions.
Time frame: From randomization up to the end of treatment (approximately 41 months)
Population: ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 42.9 Percentage of participants |
| Phase 2 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 33.3 Percentage of participants |
| Ph2P1 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 44.1 Percentage of participants |
| Ph2P1 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 25.0 Percentage of participants |
| Ph2P2 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 42.0 Percentage of participants |
| Ph2P2 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment | 38.8 Percentage of participants |
Comparison: Objective Response CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio \>1 means better response in favor of palbociclib + letrozole arm.p-value: 0.134795% CI: [0.76, 2.97]Cochran-Mantel-Haenszel
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.084995% CI: [0.74, 7.84]Chi-squared
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.451595% CI: [0.48, 2.76]Chi-squared
Secondary
Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment
Percentage of participants with objective response based assessment of confirmed CR or PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. Measurable disease referred to the lesions that was accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques or as ≥10-16 mm with spiral computer tomography scan (depending on reconstruction interval). Clinical lesions were only be considered measurable when they were superficial (eg, skin nodules, palpable lymph nodes).
Time frame: From randomization up to the end of treatment (approximately 41 months)
Population: Participants in ITT population with measurable disease were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 55.4 Percentage of participants |
| Phase 2 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 39.4 Percentage of participants |
| Ph2P1 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 55.6 Percentage of participants |
| Ph2P1 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 34.8 Percentage of participants |
| Ph2P2 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 55.3 Percentage of participants |
| Ph2P2 (Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment | 41.9 Percentage of participants |
Comparison: Objective Response CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio \>1 means better response in favor of palbociclib + letrozole arm.p-value: 0.047195% CI: [0.91, 4.08]Cochran-Mantel-Haenszel
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.11895% CI: [0.65, 8.66]Chi-squared
Comparison: Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.p-value: 0.163195% CI: [0.65, 4.54]Chi-squared
Secondary
Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1
Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions.
Time frame: From Baseline up to end of study (assessed up to 55 months)
Population: Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1 | 33.3 Percentage of participants |
Secondary
Overall Survival (OS) at Phase 2
Time in weeks or months from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7 or 30.44 if in months.
Time frame: From randomization until death (assessed up to 86 months)
Population: ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Overall Survival (OS) at Phase 2 | 37.5 Months |
| Phase 2 (Letrozole) | Overall Survival (OS) at Phase 2 | 34.5 Months |
| Ph2P1 (Palbociclib + Letrozole) | Overall Survival (OS) at Phase 2 | 37.5 Months |
| Ph2P1 (Letrozole) | Overall Survival (OS) at Phase 2 | 33.3 Months |
| Ph2P2 (Palbociclib + Letrozole) | Overall Survival (OS) at Phase 2 | 35.1 Months |
| Ph2P2 (Letrozole) | Overall Survival (OS) at Phase 2 | 35.7 Months |
Comparison: Stratified analysis was presented above. Hazard ratio was assuming proportional hazards, a hazard ratio less than 1 indicated a reduction in hazard rate in favor of palbociclib + letrozole.p-value: 0.281295% CI: [0.623, 1.294]Log Rank
Comparison: Unstratified analysis was presented above.p-value: 0.280395% CI: [0.458, 1.527]Log Rank
Comparison: Unstratified analysis was presented above.p-value: 0.387595% CI: [0.59, 1.48]Log Rank
Secondary
Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1
CBR is defined as a confirmed CR, confirmed PR, or stable disease (SD) for at least 24 weeks on study according to RECIST. Confirmed responses are those that persisted on repeat imaging \>= 4 weeks after initial response.
Time frame: From Baseline up to end of study (assessed up to 55 months)
Population: Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1 | 83.3 Percentage of participants |
Secondary
Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2
One 2-mL blood specimen was collected for the analysis of germline polymorphism in CYP19A1 and CCND1 genes. A single nucleotide polymorphism (SNP) rs4646 as defined in the National Center for Biotechnology Information (NCBI) database in the aromatase gene (CYP19A1) was analyzed. A germline polymorphism G/A870 (rs9344) in the CCND1 gene was analyzed.
Time frame: Screening visit (≤ 28 Days prior to dosing)
Population: Polymorphism analysis set included participants in the safety analysis set who had at least 1 polymorphism assessment.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 57.9 Percentage of participants | 0.33 |
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 47.4 Percentage of participants | 0.29 |
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 26.3 Percentage of participants | — |
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 26.3 Percentage of participants | 0.35 |
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 7.9 Percentage of participants | 0.42 |
| Phase 1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 34.2 Percentage of participants | 0.27 |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 58.1 Percentage of participants | 0.34 |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 5.4 Percentage of participants | 0.42 |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 47.3 Percentage of participants | 0.32 |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 24.3 Percentage of participants | — |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 36.5 Percentage of participants | 0.27 |
| Phase 2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 28.4 Percentage of participants | 0.36 |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 33.3 Percentage of participants | 0.31 |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 56.7 Percentage of participants | 0.48 |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 43.3 Percentage of participants | 0.36 |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 33.3 Percentage of participants | 0.31 |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 23.3 Percentage of participants | — |
| Ph2P1 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 10.0 Percentage of participants | 0.6 |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 17.9 Percentage of participants | — |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 39.3 Percentage of participants | 0.66 |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 42.9 Percentage of participants | 0.62 |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 42.9 Percentage of participants | 0.5 |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 10.7 Percentage of participants | 0.89 |
| Ph2P1 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 46.4 Percentage of participants | 0.64 |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 28.3 Percentage of participants | — |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 34.8 Percentage of participants | 0.4 |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 21.7 Percentage of participants | 0.55 |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 58.7 Percentage of participants | 0.45 |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 6.5 Percentage of participants | 0.55 |
| Ph2P2 (Palbociclib + Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 50.0 Percentage of participants | 0.41 |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/A Genotype | 50.0 Percentage of participants | 0.36 |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - G/G Genotype | 28.3 Percentage of participants | — |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CCND1 - A/A Genotype | 21.7 Percentage of participants | 0.43 |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/C Genotype | 65.2 Percentage of participants | 0.4 |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - A/A Genotype | 2.2 Percentage of participants | 0.43 |
| Ph2P2 (Letrozole) | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 | CYP19A1 - C/A Genotype | 32.6 Percentage of participants | 0.31 |
Secondary
Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67
Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups.
Time frame: Screening visit (≤ 28 Days prior to dosing)
Population: All participants in the Safety Analysis set who had a Ki67 protein biomarker assessment.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 26 Participants | 0.4 |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 48 Participants | 0.5 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 31 Participants | 0.31 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 40 Participants | 0.36 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 7 Participants | 0.66 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 17 Participants | 0.72 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 16 Participants | 0.58 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 10 Participants | 0.62 |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 19 Participants | 0.51 |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 31 Participants | 0.69 |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | <=20% | 15 Participants | 0.37 |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 | >20% | 30 Participants | 0.44 |
Secondary
Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1
Tissue samples were used for retrospective biomarker analyses. For Phase 2 Part 2, the tissue samples were sent to a central laboratory for the assessment of participant selection biomarkers. For Phase 2 Part 1, the assessment of the biomarkers (CCND1 amplification and/or loss of p16) were performed retrospectively from the available samples.
Time frame: Screening visit (≤ 28 Days prior to dosing)
Population: Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 | 12 Participants | 0.66 |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 and p16/INK4A<0.8 | 0 Participants | 0.55 |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | p16/INK4A<0.8 | 0 Participants | 0.72 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 | 9 Participants | 0.58 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 and p16/INK4A<0.8 | 2 Participants | 0.63 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | p16/INK4A<0.8 | 2 Participants | 0.62 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | p16/INK4A<0.8 | 19 Participants | 0.69 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 | 39 Participants | 0.51 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 and p16/INK4A<0.8 | 8 Participants | 0.67 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 | 44 Participants | 0.37 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | CCND1>=1.5 and p16/INK4A<0.8 | 8 Participants | 0.43 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 | p16/INK4A<0.8 | 12 Participants | 0.44 |
Secondary
Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1
Presence or absence of tumor RB and CyclinD1 were evaluated. The following definitions of expression applied in the below table: Positive: any expression \>0 and Negative: any expression=0.
Time frame: Screening visit (≤ 28 Days prior to dosing)
Population: Protein biomarkers analysis set included all participants in the safety analysis set who had at least protein biomarker assessment.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 41 Participants | — |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 2 Participants | — |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 41 Participants | 0.4 |
| Phase 1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 3 Participants | 0.5 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 32 Participants | 0.31 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 2 Participants | — |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 3 Participants | 0.36 |
| Phase 2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 32 Participants | — |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 2 Participants | — |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 10 Participants | 0.66 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 2 Participants | 0.72 |
| Ph2P1 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 10 Participants | — |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 0 Participants | — |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 16 Participants | 0.58 |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 16 Participants | — |
| Ph2P1 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 0 Participants | 0.62 |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 1 Participants | 0.69 |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 31 Participants | 0.51 |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 31 Participants | — |
| Ph2P2 (Palbociclib + Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 0 Participants | — |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Negative | 2 Participants | — |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Positive | 16 Participants | 0.37 |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | RB - Positive | 16 Participants | — |
| Ph2P2 (Letrozole) | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 | CyclinD1 - Negative | 3 Participants | 0.44 |
Secondary
Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2
Gene copy number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) were evaluated. This analysis was done for Phase 2 combined group.
Time frame: Screening visit (≤ 28 Days prior to dosing)
Population: Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 | CCND1 | 2.76 Copy number | Standard Deviation 1.875 |
| Phase 1 (Palbociclib + Letrozole) | Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 | p16/INK4A | 0.83 Copy number | Standard Deviation 0.224 |
| Phase 2 (Letrozole) | Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 | p16/INK4A | 0.87 Copy number | Standard Deviation 0.173 |
| Phase 2 (Letrozole) | Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 | CCND1 | 2.73 Copy number | Standard Deviation 1.559 |
Secondary
Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1
On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time frame: Cycle 2 Day 14, Cycle 2 Day 28
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1 | 1739 ng·hr/mL | Geometric Coefficient of Variation 30 |
| Phase 2 (Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1 | 1936 ng·hr/mL | Geometric Coefficient of Variation 35 |
Secondary
Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1
On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time frame: Cycle 2 Day 14, and Cycle 2 Day 28
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1 | 94.95 ng/mL | Geometric Coefficient of Variation 27 |
| Phase 2 (Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1 | 104.0 ng/mL | Geometric Coefficient of Variation 31 |
Secondary
Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1
On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing.
Time frame: Cycle 2 Day 14, and Cycle 2 Day 28
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1 | 2.00 Hour | Full Range 27 |
| Phase 2 (Letrozole) | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1 | 1.04 Hour | Full Range 31 |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1 | 63.08 L/hr | Geometric Coefficient of Variation 29 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1 | NA L/hr | — |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1 | 2583 L | Geometric Coefficient of Variation 26 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1 | NA L | — |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1 | 1982 ng·hr/mL | Geometric Coefficient of Variation 29 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1 | 1933 ng·hr/mL | Geometric Coefficient of Variation 31 |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1 | 115.8 ng/mL | Geometric Coefficient of Variation 28 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1 | 108.4 ng/mL | Geometric Coefficient of Variation 29 |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1 | 28.81 Hour | Standard Deviation 5.0462 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1 | NA Hour | — |
Secondary
Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1
On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.
Time frame: Cycle 1 Day 14, and Cycle 2 Day 14
Population: The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1 | 7.92 Hour | Full Range 28 |
| Phase 2 (Letrozole) | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1 | 7.92 Hour | Full Range 29 |
Secondary
Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment
Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of randomization \[or first dose of study medication for non-randomized studies\] plus 1) divided by 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\] per RECIST).
Time frame: From randomization up to the end of treatment (approximately 41 months)
Population: ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Palbociclib + Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 20.2 Months |
| Phase 2 (Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 10.2 Months |
| Ph2P1 (Palbociclib + Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 26.1 Months |
| Ph2P1 (Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 5.7 Months |
| Ph2P2 (Palbociclib + Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 18.8 Months |
| Ph2P2 (Letrozole) | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment | 11.1 Months |
Comparison: Kaplan-Meier method was applied for median and 95% CI. Hazard ratio was based on assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of palbociclib + letrozole.p-value: <0.000195% CI: [0.265, 0.601]Log Rank
Comparison: Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.p-value: <0.000195% CI: [0.156, 0.572]Log Rank
Comparison: Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.p-value: 0.00395% CI: [0.288, 0.822]Log Rank