Study Of Letrozole With Or Without Palbociclib (PD-0332991) For The First-Line Treatment Of Hormone-Receptor Positive Advanced Breast Cancer
Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT00721409
Collaborator
(none)
177
104
2
111.1
1.7
0
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
177 participants
Allocation:
Randomized
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
PHASE 1/2, OPEN-LABEL, RANDOMIZED STUDY OF THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF LETROZOLE PLUS PD 0332991 (ORAL CDK 4/6 INHIBITOR) AND LETROZOLE SINGLE AGENT FOR THE FIRST-LINE TREATMENT OF ER POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER IN POSTMENOPAUSAL WOMEN
Actual Study Start Date
:
Sep 15, 2008
Actual Primary Completion Date
:
Nov 29, 2013
Actual Study Completion Date
:
Dec 20, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A letrozole + PD 0332991 |
Drug: PD 0332991
125 mg/d capsules orally for 3 out of 4 weeks in repeated cycles
Drug: letrozole
2.5 mg/d tablets orally on a continuous regimen
|
| Active Comparator: Arm B letrozole |
Drug: letrozole
2.5 mg/d tablets orally on a continuous regimen
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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.
- 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).
- 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).
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Female
Accepts 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Central Hematology Oncology Medical group Inc. | Alhambra | California | United States | 91801 |
| 2 | UCLA Hematology/Oncology - Alhambra | Alhambra | California | United States | 91801 |
| 3 | CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center | Bakersfield | California | United States | 93309 |
| 4 | St. Joseph Heritage Healthcare | Fullerton | California | United States | 92835 |
| 5 | UCLA West Medical Pharmacy (Drug Management Only) | Los Angeles | California | United States | 90095-1772 |
| 6 | UCLA West Medical Pharmacy | Los Angeles | California | United States | 90095-1772 |
| 7 | Ronald Reagan UCLA Medical Center | Los Angeles | California | United States | 90095-6984 |
| 8 | UCLA West Medical Pharmacy | Los Angeles | California | United States | 90095-7349 |
| 9 | Drug Management Only: UCLA West Medical Pharmacy | Los Angeles | California | United States | 90095 |
| 10 | Drug Management Only | Los Angeles | California | United States | 90095 |
| 11 | Regulatory Managment | Los Angeles | California | United States | 90095 |
| 12 | Ronald Reagan UCLA Medical Center | Los Angeles | California | United States | 90095 |
| 13 | TORI -US Central Administration (Regulatory Management) | Los Angeles | California | United States | 90095 |
| 14 | TORI -US Central Administration | Los Angeles | California | United States | 90095 |
| 15 | TORI Central Administration (Regulatory Management) | Los Angeles | California | United States | 90095 |
| 16 | TORI Central Administration (Regulatory Managment Only) | Los Angeles | California | United States | 90095 |
| 17 | TRIO-US Central Administration | Los Angeles | California | United States | 90095 |
| 18 | UCLA Hematology/Oncology | Los Angeles | California | United States | 90095 |
| 19 | UCLA, Hematology/Oncology | Los Angeles | California | United States | 90095 |
| 20 | Westwood Bowyer Clinic, Peter Morton Medical Building | Los Angeles | California | United States | 90095 |
| 21 | Central Hematology Oncology Medical Group, Inc | Pasadena | California | United States | 91107 |
| 22 | Torrance Health Association, DBA Torrance Memorial Physician Network/Cancer Care Associates | Redondo Beach | California | United States | 90277 |
| 23 | Sansum Santa Barbara Medical Foundation Clinic | Santa Barbara | California | United States | 93105 |
| 24 | Central Coast Medical Oncology Corporation | Santa Maria | California | United States | 93454 |
| 25 | Santa Monica-UCLA Medical Center and Orthopaedic Hospital | Santa Monica | California | United States | 90404 |
| 26 | UCLA Hematology Oncology-Santa Monica | Santa Monica | California | United States | 90404 |
| 27 | UCLA Hematology/Oncology - Santa Clarita | Valencia | California | United States | 91355 |
| 28 | Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care | Duluth | Georgia | United States | 30096 |
| 29 | Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care | Lawrenceville | Georgia | United States | 30046 |
| 30 | Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care | Snellville | Georgia | United States | 30078 |
| 31 | Illinois Cancer Specialists | Chicago | Illinois | United States | 60611 |
| 32 | Resurrection Medical Group | Chicago | Illinois | United States | 60657 |
| 33 | North Shore Oncology-Hematology Associates | Crystal Lake | Illinois | United States | 60014 |
| 34 | North Shore Hematology Oncology | Highland Park | Illinois | United States | 60035 |
| 35 | North Shore Oncology-Hematology Associates | Libertyville | Illinois | United States | 60048 |
| 36 | North Shore Hematology Oncology | Skokie | Illinois | United States | 60077 |
| 37 | Regulatory Office: Comprehensive Cancer Centers of Nevada | Henderson | Nevada | United States | 89014 |
| 38 | Comprehensive Cancer Centers of Nevada | Henderson | Nevada | United States | 89052 |
| 39 | Comprehensive Cancer Centers of Nevada | Henderson | Nevada | United States | 89074 |
| 40 | Comprehensive Cancer Centers of Nevada | Las Vegas | Nevada | United States | 89128 |
| 41 | Comprehensive Cancer Centers of Nevada | Las Vegas | Nevada | United States | 89148 |
| 42 | Comprehensive Cancer Centers of Nevada | Las Vegas | Nevada | United States | 89169 |
| 43 | Texas Oncology-Dallas Presbyterian Hospital | Dallas | Texas | United States | 75231 |
| 44 | Texas Oncology-Baylor Charles A. Sammons Cancer Center | Dallas | Texas | United States | 75246 |
| 45 | Investigational Products Center (IPC) | Fort Worth | Texas | United States | 76177 |
| 46 | US Oncology Research and Clinical Pharmacy | Fort Worth | Texas | United States | 76177 |
| 47 | Virginia Cancer Specialists, PC | Arlington | Virginia | United States | 22205 |
| 48 | Virginia Cancer Specialists, PC | Fairfax | Virginia | United States | 22031 |
| 49 | Virginia Cancer Specialists, PC | Gainesville | Virginia | United States | 20155 |
| 50 | Virginia Cancer Specialists, PC | Leesburg | Virginia | United States | 20176 |
| 51 | Virginia Cancer Specialists, PC | Woodbridge | Virginia | United States | 22191 |
| 52 | BC Cancer Agency - Vancouver Centre | Vancouver | British Columbia | Canada | V5Z 4E6 |
| 53 | CSSS Champlain-Charles-Le Moyne Local HS-0054 | Greenfield Park | Quebec | Canada | J4V 2H1 |
| 54 | Centre Paul Papin, CRLCC | ANGERS Cedex 9 | France | 49933 | |
| 55 | CHD Vendee | La Roche Sur Yon | France | 85925 | |
| 56 | Gemeinschaftspraxis, Onkologischer Schwerpunkt am Oskar-Helene-Heim | Berlin | Germany | 14195 | |
| 57 | Gemeinschaftspraxis Haematologie-Onkologie | Dresden | Germany | 01307 | |
| 58 | Martin-Luther-Universitaet Halle-Wittenberg | Halle/Saale | Germany | 06097 | |
| 59 | Universitaetsklinik und Poliklinik fuer Gynaekologie, Martin-Luther-Universitaet Halle-Wittenberg | Halle/Saale | Germany | 06120 | |
| 60 | Nationales Centrum fuer Tumorerkrankungen | Heidelberg | Germany | 69120 | |
| 61 | Frauenaerzte Pruener Gang Abts & Partner | Kiel | Germany | 24103 | |
| 62 | Klinik und Poliklinik fuer Frauenheilkunde und Geburtshilfe Universitaetsklinik Mainz | Mainz | Germany | 55101 | |
| 63 | Onkolog. Gemeinschaftspraxis | Muenchen | Germany | 80335 | |
| 64 | Frauenklinik vom Roten Kreuz | Muenchen | Germany | 80637 | |
| 65 | Frauenklinik und Poliklinik Klinikum rechts der Isar, Technische Universitaet Muenchen | Muenchen | Germany | 81675 | |
| 66 | Mutterhaus der Borromaeerinnen, Innere Medizin I | Trier | Germany | 54290 | |
| 67 | Szent Margit Korhaz, Onkologia | Budapest | Hungary | 1032 | |
| 68 | Orszagos Onkologiai Intezet, Kemoterapia B | Budapest | Hungary | 1122 | |
| 69 | Fovarosi Onkormanyzat Uzsoki Utcai Korhaz | Budapest | Hungary | 1145 | |
| 70 | Petz Aladar Megyei Oktato Korhaz, Onkoradiologia | Gyor | Hungary | 9023 | |
| 71 | Borsod-Abauj-Zemplen Megyei Korhaz és Egyetemi Oktato Korhaz, Onkologia | Miskolc | Hungary | 3526 | |
| 72 | Szabolcs-Szatmar-Bereg Megyei Korhazak es | Nyiregyhaza | Hungary | 4400 | |
| 73 | Markusovszky Egyetemi Oktatokorhaz, Onkoradiologiai Osztaly | Szombathely | Hungary | 9700 | |
| 74 | Bon Secours Hospital | Cork | Ireland | ||
| 75 | St. James's Hospital | Dublin 8 | Ireland | ||
| 76 | St. Vincent's University Hospital | Dublin | Ireland | 4 | |
| 77 | Mater Misericordiae University Hospital | Dublin | Ireland | 7 | |
| 78 | Mater Private Hospital | Dublin | Ireland | 7 | |
| 79 | Divisione Oncologia Medica Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST | Meldola | FC | Italy | 47014 |
| 80 | M.O. di Oncologia - Azienda USL di Rimini - Ospedale "Cervesi" | Cattolica | Italy | 47841 | |
| 81 | Ospedale Civile di Faenza Centro Oncologico | Faenza, RA | Italy | 48018 | |
| 82 | Unita' Operativa di Oncologia, Ospedale Civile di Lugo | Lugo, RA | Italy | 48022 | |
| 83 | Ospedale Civile di Ravenna | Ravenna | Italy | 48100 | |
| 84 | Azienda Unita Sanitaria Locale di Rimini, U.O. di Oncologia ed Oncoematologia Ospedale degli Infermi | Rimini | Italy | 47900 | |
| 85 | Ospedale Villa San Pietro | Roma | Italy | 00189 | |
| 86 | National Cancer Center, Center for Breast Cancer | Goyang-si | Gyeonggi-do | Korea, Republic of | 10408 |
| 87 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 | |
| 88 | Samsung Medical Center | Seoul | Korea, Republic of | 135-710 | |
| 89 | Federal State Budgetary Scientific Institution | Moscow | Russian Federation | 115478 | |
| 90 | Pyatigorsk Oncology Center | Pyatigorsk | Russian Federation | 357502 | |
| 91 | State Budgetary Healthcare Institution "Samara Regional Clinical Oncology Dispensary" | Samara | Russian Federation | 443031 | |
| 92 | Republican Clinical Oncology Dispensary of the Ministry of Health of Bashkortostan Republic | Ufa | Russian Federation | 450054 | |
| 93 | Department of Oncotherapy, National Hospital | Bloemfontein | South Africa | 9301 | |
| 94 | Eastleigh Breast Care Centre | Pretoria | South Africa | 0041 | |
| 95 | Ico-Hospitalet | Hospitalet de Llobregat | Barcelona | Spain | 08907 |
| 96 | Hospital General Universitario Vall D'Hebron | Barcelona | Spain | 08035 | |
| 97 | Centro Oncologico de Galicia | La Coruña | Spain | 15009 | |
| 98 | Hospital Universitario 12 de Octubre | Madrid | Spain | 28041 | |
| 99 | Hospital Universitario Virgen Del Rocio | Sevilla | Spain | 41013 | |
| 100 | Department of Oncology and Medical Radiology, SI "DMA of MOH, Ukraine, "MI "Dnipropetrovsk City | Dnipropetrovsk | Ukraine | 49102 | |
| 101 | Municipal Treatment-and-Prophylactic Institution 'Donetsk City Oncological Dispensary' Radiology dep | Donetsk | Ukraine | 83087 | |
| 102 | Municipal clinical treatment-and-propyilactic institution "Donetsk regional oncology center', | Donetsk | Ukraine | 83092 | |
| 103 | Kyiv City Clinical Oncologic Center | Kyiv | Ukraine | 03115 | |
| 104 | Lviv State Oncologic Regional Treatment and Diagnostic Centre | Lviv | Ukraine | 79031 |
Sponsors and Collaborators
- Pfizer
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT00721409
Other Study ID Numbers:
- A5481003
- 2008-002392-27
First Posted:
Jul 24, 2008
Last Update Posted:
Nov 4, 2019
Last Verified:
Oct 1, 2019
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Pfizer
Additional relevant MeSH terms:
Study Results
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 Detail | 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. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. |
| Period Title: Overall Study | |||
| STARTED | 12 | 84 | 81 |
| Treated | 12 | 83 | 77 |
| COMPLETED | 0 | 2 | 2 |
| NOT COMPLETED | 12 | 82 | 79 |
Baseline Characteristics
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Total |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 12 | 84 | 81 | 177 |
| Age, Customized (Count of Participants) | ||||
| <18 Years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| 18-44 Years |
1
8.3%
|
2
2.4%
|
4
4.9%
|
7
4%
|
| 45-64 Years |
6
50%
|
45
53.6%
|
38
46.9%
|
89
50.3%
|
| >= 65 Years |
5
41.7%
|
37
44%
|
39
48.1%
|
81
45.8%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
12
100%
|
84
100%
|
81
100%
|
177
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
6
7.1%
|
4
4.9%
|
10
5.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
1
1.2%
|
1
1.2%
|
2
1.1%
|
| White |
11
91.7%
|
76
90.5%
|
72
88.9%
|
159
89.8%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
8.3%
|
1
1.2%
|
4
4.9%
|
6
3.4%
|
Outcome Measures
| Title | Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any agent of the combination. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| Participants with AEs |
12
100%
|
| Participants with SAEs |
2
16.7%
|
| Participants with Grade 3 or 4 AEs |
11
91.7%
|
| Participants with Grade 5 AEs |
0
0%
|
| Title | Number of Participants With Treatment-Related Adverse Events at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any agent of the combination. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| Participants with AEs |
12
100%
|
| Participants with SAEs |
0
0%
|
| Participants with Grade 3 or 4 AEs |
11
91.7%
|
| Participants with Grade 5 AEs |
0
0%
|
| Title | Number of Participants With Dose Limiting Toxicities at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any agent of the combination. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| Grade 4 Neutropenia |
2
16.7%
|
| <80% of doses due to elevated creatinine |
1
8.3%
|
| Title | Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 84 | 81 | 34 | 32 | 50 | 49 |
| Median (95% Confidence Interval) [Months] |
20.2
|
10.2
|
26.1
|
5.7
|
18.1
|
11.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0004 |
| Comments | 1-sided p-value from the log-rank test stratified by stratification factors per randomization and Part. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.488 | |
| Confidence Interval |
(2-Sided) 95% 0.319 to 0.748 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | 1-sided p-value from the log-rank test. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.299 | |
| Confidence Interval |
(2-Sided) 95% 0.156 to 0.572 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0046 |
| Comments | 1-sided p-value from the log-rank test. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.508 | |
| Confidence Interval |
(2-Sided) 95% 0.303 to 0.853 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| Number (95% Confidence Interval) [Percentage of participants] |
33.3
277.5%
|
| Title | Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| Number (95% Confidence Interval) [Percentage of participants] |
83.3
694.2%
|
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng·hr/mL] |
1982
(29)
|
1933
(31)
|
| Title | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
115.8
(28)
|
108.4
(29)
|
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Median (Full Range) [Hour] |
7.92
(28)
|
7.92
(29)
|
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Mean (Standard Deviation) [Hour] |
28.81
(5.0462)
|
NA
(NA)
|
| Title | Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [L/hr] |
63.08
(29)
|
NA
(NA)
|
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib Alone (Cycle 1 Day 14) | Palbociclib + Letrozole (Cycle 2 Day 14) |
|---|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [L] |
2583
(26)
|
NA
(NA)
|
| Title | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib + Letrozole (Cycle 2 Day 14) | Letrozole Alone (Cycle 2 Day 28) |
|---|---|---|
| Arm/Group Description | Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole. | Participants received daily 2.5 mg doses of letrozole alone. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng·hr/mL] |
1739
(30)
|
1936
(35)
|
| Title | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib + Letrozole (Cycle 2 Day 14) | Letrozole Alone (Cycle 2 Day 28) |
|---|---|---|
| Arm/Group Description | Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole. | Participants received daily 2.5 mg doses of letrozole alone. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
94.95
(27)
|
104.0
(31)
|
| Title | Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Palbociclib + Letrozole (Cycle 2 Day 14) | Letrozole Alone (Cycle 2 Day 28) |
|---|---|---|
| Arm/Group Description | Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole. | Participants received daily 2.5 mg doses of letrozole alone. |
| Measure Participants | 12 | 12 |
| Median (Full Range) [Hour] |
2.00
(27)
|
1.04
(31)
|
| Title | Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any agent of the combination. |
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 12 |
| QTcB - Change <30 |
9
75%
|
| QTcB - 30 ≤ change <60 |
3
25%
|
| QTcB - Change ≥60 |
0
0%
|
| QTcF - Change <30 |
11
91.7%
|
| QTcF - 30 ≤ change <60 |
1
8.3%
|
| QTcF - Change ≥60 |
0
0%
|
| QTcS - Change <30 |
8
66.7%
|
| QTcS - 30 ≤ change <60 |
4
33.3%
|
| QTcS - Change ≥60 |
0
0%
|
| Title | Overall Survival (OS) at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 84 | 81 | 34 | 32 | 50 | 49 |
| Median (95% Confidence Interval) [Months] |
37.5
|
34.5
|
37.5
|
33.3
|
35.1
|
35.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2812 |
| Comments | 1-sided p-value from the log-rank test stratified by Part (α = 0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.897 | |
| Confidence Interval |
(2-Sided) 95% 0.623 to 1.294 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2803 |
| Comments | 1-sided p-value from the unstratified log-rank test (α=0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.837 | |
| Confidence Interval |
(2-Sided) 95% 0.458 to 1.527 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3875 |
| Comments | 1-sided p-value from the unstratified log-rank test (α=0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.935 | |
| Confidence Interval |
(2-Sided) 95% 0.590 to 1.480 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 84 | 81 | 34 | 32 | 50 | 49 |
| Number (95% Confidence Interval) [Percentage of participants] |
42.9
357.5%
|
33.3
39.6%
|
44.1
54.4%
|
25.0
14.1%
|
42.0
NaN
|
38.8
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1347 |
| Comments | 1-sided p-value is from the stratified exact test (1-sided, α =0.10) | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.50 | |
| Confidence Interval |
(2-Sided) 95% 0.76 to 2.97 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0849 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.37 | |
| Confidence Interval |
(2-Sided) 95% 0.74 to 7.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4515 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.14 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 2.76 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in ITT population with measurable disease were used. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 65 | 66 | 27 | 23 | 21 | 43 |
| Number (95% Confidence Interval) [Percentage of participants] |
55.4
461.7%
|
39.4
46.9%
|
55.6
68.6%
|
34.8
19.7%
|
55.3
NaN
|
41.9
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0471 |
| Comments | 1-sided p-value is from the stratified exact test (1-sided, α =0.10) | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.93 | |
| Confidence Interval |
(2-Sided) 95% 0.91 to 4.08 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1180 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.34 | |
| Confidence Interval |
(2-Sided) 95% 0.65 to 8.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1631 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.72 | |
| Confidence Interval |
(2-Sided) 95% 0.65 to 4.54 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Duration of Response at Phase 2 - Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| A subset of ITT population i.e., participants who had response was used for this analysis. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 36 | 27 | 15 | 8 | 21 | 19 |
| Median (95% Confidence Interval) [Months] |
20.3
|
11.1
|
20.9
|
10.8
|
20.2
|
14.8
|
| Title | Number of Participants With CBR at Phase 2 - Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 84 | 81 | 34 | 32 | 50 | 49 |
| Number (95% Confidence Interval) [Percentage of participants] |
81.0
675%
|
58.0
69%
|
76.5
94.4%
|
43.8
24.7%
|
84.0
NaN
|
67.3
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0009 |
| Comments | 1-sided p-value is from the stratified exact test (1-sided, α =0.10). | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 3.18 | |
| Confidence Interval |
(2-Sided) 95% 1.48 to 6.98 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0065 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.18 | |
| Confidence Interval |
(2-Sided) 95% 1.30 to 13.90 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0442 |
| Comments | Chi-square test was used (1-sided, α=0.10) | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.55 | |
| Confidence Interval |
(2-Sided) 95% 0.89 to 7.70 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 84 | 81 | 34 | 32 | 50 | 49 |
| Median (95% Confidence Interval) [Months] |
20.2
|
10.2
|
26.1
|
5.7
|
18.8
|
11.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | 1-sided p-value is from the stratified log-rank test (α =0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.399 | |
| Confidence Interval |
(2-Sided) 95% 0.265 to 0.601 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | 1-sided p-value is from unstratified log-rank test (α=0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.299 | |
| Confidence Interval |
(2-Sided) 95% 0.156 to 0.572 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0030 |
| Comments | 1-sided p-value is from unstratified log-rank test (α=0.10). | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.486 | |
| Confidence Interval |
(2-Sided) 95% 0.288 to 0.822 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 76 | 74 | 29 | 27 | 47 | 47 |
| Pain at its worst in the last 24 hours |
0.6
(0.42)
|
0.1
(0.42)
|
0.2
(0.60)
|
0.0
(0.89)
|
1.2
(0.55)
|
0.1
(0.43)
|
| Pain at its least in the last 24 hours |
0.4
(0.27)
|
0.4
(0.27)
|
0.3
(0.31)
|
0.7
(0.50)
|
0.5
(0.40)
|
0.2
(0.31)
|
| Pain on the average |
0.2
(0.33)
|
0.2
(0.34)
|
-0.1
(0.48)
|
0.2
(0.64)
|
0.4
(0.45)
|
0.3
(0.40)
|
| Pain right now |
0.3
(0.35)
|
0.1
(0.36)
|
0.1
(0.31)
|
0.3
(0.66)
|
0.3
(0.55)
|
0.0
(0.43)
|
| Pain Severity Scale |
0.4
(0.29)
|
0.2
(0.32)
|
0.0
(0.36)
|
0.3
(0.62)
|
0.6
(0.41)
|
0.1
(0.36)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Severity Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6900 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.2 | |
| Confidence Interval |
(2-Sided) 95% -0.7 to 1.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Severity Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7125 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -1.8 to 1.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Severity Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4012 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.5 | |
| Confidence Interval |
(2-Sided) 95% -0.6 to 1.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 76 | 74 | 29 | 27 | 47 | 47 |
| General Activity |
1.1
(0.40)
|
0.2
(0.31)
|
1.0
(0.66)
|
0.2
(0.58)
|
1.2
(0.51)
|
0.3
(0.37)
|
| Mood |
0.8
(0.50)
|
0.2
(0.36)
|
0.6
(0.72)
|
-0.2
(0.62)
|
1.0
(0.69)
|
0.4
(0.44)
|
| Walking ability |
0.8
(0.46)
|
0.1
(0.35)
|
1.0
(0.55)
|
0.3
(0.63)
|
0.7
(0.67)
|
0.0
(0.43)
|
| Normal work |
0.7
(0.48)
|
0.3
(0.39)
|
1.0
(0.53)
|
0.2
(0.74)
|
0.5
(0.71)
|
0.4
(0.45)
|
| Relations |
0.8
(0.32)
|
0.8
(0.32)
|
0.6
(0.34)
|
0.6
(0.60)
|
0.9
(0.47)
|
0.8
(0.37)
|
| Sleep |
0.6
(0.43)
|
0.3
(0.35)
|
0.1
(0.53)
|
0.5
(0.63)
|
0.9
(0.61)
|
0.1
(0.42)
|
| Enjoyment of life |
0.8
(0.46)
|
0.6
(0.41)
|
0.4
(0.34)
|
0.2
(0.69)
|
1.1
(0.71)
|
0.8
(0.52)
|
| Pain Interference Scale |
0.8
(0.34)
|
0.4
(0.30)
|
0.7
(0.42)
|
0.3
(0.56)
|
0.9
(0.48)
|
0.4
(0.36)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 (Palbociclib + Letrozole), Phase 2 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Interference Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3346 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.4 | |
| Confidence Interval |
(2-Sided) 95% -0.5 to 1.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Interference Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5630 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.4 | |
| Confidence Interval |
(2-Sided) 95% -1.0 to 1.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole) |
|---|---|---|
| Comments | Statistical analysis presented above is for Pain Severity Scale. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4427 |
| Comments | P-values are based on 2-sample t-test. | |
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.5 | |
| Confidence Interval |
(2-Sided) 95% -0.7 to 1.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments. |
| Arm/Group Title | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|
| Arm/Group Description | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 22 | 24 | 50 | 48 |
| CCND1>=1.5 |
12
(0.66)
100%
|
9
(0.58)
10.7%
|
39
(0.51)
48.1%
|
44
(0.37)
24.9%
|
| p16/INK4A<0.8 |
0
(0.72)
0%
|
2
(0.62)
2.4%
|
19
(0.69)
23.5%
|
12
(0.44)
6.8%
|
| CCND1>=1.5 and p16/INK4A<0.8 |
0
(0.55)
0%
|
2
(0.63)
2.4%
|
8
(0.67)
9.9%
|
8
(0.43)
4.5%
|
| Title | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 |
|---|---|
| Description | Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups. |
| Time Frame | Screening visit (≤ 28 Days prior to dosing) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants in the Safety Analysis set who had a Ki67 protein biomarker assessment. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 74 | 71 | 24 | 26 | 50 | 45 |
| <=20% |
26
(0.40)
216.7%
|
31
(0.31)
36.9%
|
7
(0.66)
8.6%
|
16
(0.58)
9%
|
19
(0.51)
NaN
|
15
(0.37)
NaN
|
| >20% |
48
(0.50)
400%
|
40
(0.36)
47.6%
|
17
(0.72)
21%
|
10
(0.62)
5.6%
|
31
(0.69)
NaN
|
30
(0.44)
NaN
|
| Title | Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Protein biomarkers analysis set included all participants in the safety analysis set who had at least protein biomarker assessment. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 45 | 35 | 12 | 16 | 33 | 19 |
| CyclinD1 - Positive |
41
(0.40)
341.7%
|
32
(0.31)
38.1%
|
10
(0.66)
12.3%
|
16
(0.58)
9%
|
31
(0.51)
NaN
|
16
(0.37)
NaN
|
| CyclinD1 - Negative |
3
(0.50)
25%
|
3
(0.36)
3.6%
|
2
(0.72)
2.5%
|
0
(0.62)
0%
|
1
(0.69)
NaN
|
3
(0.44)
NaN
|
| RB - Positive |
41
341.7%
|
32
38.1%
|
10
12.3%
|
16
9%
|
31
NaN
|
16
NaN
|
| RB - Negative |
2
16.7%
|
2
2.4%
|
2
2.5%
|
0
0%
|
0
NaN
|
2
NaN
|
| Title | Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 72 | 72 |
| CCND1 |
2.76
(1.875)
|
2.73
(1.559)
|
| p16/INK4A |
0.83
(0.224)
|
0.87
(0.173)
|
| Title | Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Polymorphism analysis set included participants in the safety analysis set who had at least 1 polymorphism assessment. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 76 | 74 | 30 | 28 | 46 | 46 |
| CYP19A1 - A/A Genotype |
7.9
(0.42)
65.8%
|
5.4
(0.42)
6.4%
|
10.0
(0.60)
12.3%
|
10.7
(0.89)
6%
|
6.5
(0.55)
NaN
|
2.2
(0.43)
NaN
|
| CYP19A1 - C/A Genotype |
34.2
(0.27)
285%
|
36.5
(0.27)
43.5%
|
33.3
(0.31)
41.1%
|
42.9
(0.50)
24.2%
|
34.8
(0.40)
NaN
|
32.6
(0.31)
NaN
|
| CYP19A1 - C/C Genotype |
57.9
(0.33)
482.5%
|
58.1
(0.34)
69.2%
|
56.7
(0.48)
70%
|
46.4
(0.64)
26.2%
|
58.7
(0.45)
NaN
|
65.2
(0.40)
NaN
|
| CCND1 - A/A Genotype |
26.3
(0.35)
219.2%
|
28.4
(0.36)
33.8%
|
33.3
(0.31)
41.1%
|
39.3
(0.66)
22.2%
|
21.7
(0.55)
NaN
|
21.7
(0.43)
NaN
|
| CCND1 - G/A Genotype |
47.4
(0.29)
395%
|
47.3
(0.32)
56.3%
|
43.3
(0.36)
53.5%
|
42.9
(0.62)
24.2%
|
50.0
(0.41)
NaN
|
50.0
(0.36)
NaN
|
| CCND1 - G/G Genotype |
26.3
219.2%
|
24.3
28.9%
|
23.3
28.8%
|
17.9
10.1%
|
28.3
NaN
|
28.3
NaN
|
| Title | Number of Participants With TEAEs (All Causalities) at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All treated as treated set included all treated participants classified by the treatment actually received. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 83 | 77 | 33 | 29 | 50 | 48 |
| Participants with AEs |
83
691.7%
|
66
78.6%
|
33
40.7%
|
25
14.1%
|
50
NaN
|
41
NaN
|
| Participants with SAEs |
22
183.3%
|
6
7.1%
|
10
12.3%
|
2
1.1%
|
12
NaN
|
4
NaN
|
| Participants with Grade 3 or 4 AEs |
70
583.3%
|
19
22.6%
|
29
35.8%
|
5
2.8%
|
41
NaN
|
14
NaN
|
| Participants with Grade 5 AEs |
1
8.3%
|
0
0%
|
0
0%
|
0
0%
|
1
NaN
|
0
NaN
|
| Title | Number of Participants With Treatment-Related Adverse Events at Phase 2 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All treated as treated set included all treated participants classified by the treatment actually received. |
| Arm/Group Title | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. |
| Measure Participants | 83 | 77 | 33 | 29 | 50 | 48 |
| Participants with AEs |
78
650%
|
33
39.3%
|
32
39.5%
|
13
7.3%
|
46
NaN
|
20
NaN
|
| Participants with SAEs |
1
8.3%
|
0
0%
|
0
0%
|
0
0%
|
1
NaN
|
0
NaN
|
| Participants with Grade 3 or 4 AEs |
57
475%
|
2
2.4%
|
25
30.9%
|
0
0%
|
32
NaN
|
2
NaN
|
| Participants with Grade 5 AEs |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
Adverse Events
| Time Frame | Baseline up to 28 days after last dose of study drug (for a maximum of 86 months) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | An event may be categorized as serious in one participant and non serious in another participant, or one participant may experience both serious and non serious event. All treatment emergent AEs and SAEs were collected and reported. The same event may appear as both AE and SAE. All-cause mortality data included all anticipated and unanticipated deaths due to any cause. Analysis was done on participants who received at least one dose of study drug. | |||||||||||||
| Arm/Group Title | Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) | |||||||
| Arm/Group Description | 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. | 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. | 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. | All participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | Participants were randomized to receive Letrozole plus Palbociclib. 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. | Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm. | |||||||
All Cause Mortality |
||||||||||||||
| Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 3/83 (3.6%) | 1/77 (1.3%) | 1/33 (3%) | 0/29 (0%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
Serious Adverse Events |
||||||||||||||
| Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/12 (16.7%) | 22/83 (26.5%) | 6/77 (7.8%) | 10/33 (30.3%) | 2/29 (6.9%) | 12/50 (24%) | 4/48 (8.3%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Anaemia | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Cardiac disorders | ||||||||||||||
| Cardiac failure | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| Abdominal pain | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Colitis ischaemic | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Diarrhoea | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Gastrointestinal disorder | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Ileus | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Oesophageal achalasia | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Nausea | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Vomiting | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gastritis | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Inguinal hernia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| General disorders | ||||||||||||||
| Asthenia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Chest pain | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Disease progression | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Pain | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Infections and infestations | ||||||||||||||
| Erysipelas | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Gangrene | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Influenza | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Pneumonia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Staphylococcal bacteraemia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Upper respiratory tract infection | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Campylobacter infection | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Infective exacerbation of chronic obstructive airways disease | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Mastoiditis | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Injury, poisoning and procedural complications | ||||||||||||||
| Fractured sacrum | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Hip fracture | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Humerus fracture | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Upper limb fracture | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Investigations | ||||||||||||||
| Alanine aminotransferase increased | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Aspartate aminotransferase increased | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Blood alkaline phosphatase increased | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gamma-glutamyltransferase increased | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Back pain | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Bone pain | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Intervertebral disc protrusion | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 2/50 (4%) | 0/48 (0%) | |||||||
| Arthralgia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Osteonecrosis of jaw | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Fallopian tube cancer | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Plasma cell myeloma | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Nervous system disorders | ||||||||||||||
| Neuralgia | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Brain stem infarction | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Renal and urinary disorders | ||||||||||||||
| Nephrolithiasis | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Renal disorder | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Urethral obstruction | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Acute kidney injury | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Pulmonary embolism | 1/12 (8.3%) | 4/83 (4.8%) | 0/77 (0%) | 4/33 (12.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Dyspnoea | 0/12 (0%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Subcutaneous emphysema | 0/12 (0%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||
| Phase 1 (Palbociclib + Letrozole) | Phase 2 (Palbociclib + Letrozole) | Phase 2 (Letrozole) | Ph2P1 (Palbociclib + Letrozole) | Ph2P1 (Letrozole) | Ph2P2 (Palbociclib + Letrozole) | Ph2P2 (Letrozole) | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 12/12 (100%) | 83/83 (100%) | 57/77 (74%) | 33/33 (100%) | 22/29 (75.9%) | 50/50 (100%) | 35/48 (72.9%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Anaemia | 4/12 (33.3%) | 29/83 (34.9%) | 3/77 (3.9%) | 13/33 (39.4%) | 0/29 (0%) | 16/50 (32%) | 3/48 (6.3%) | |||||||
| Leukopenia | 8/12 (66.7%) | 36/83 (43.4%) | 3/77 (3.9%) | 16/33 (48.5%) | 1/29 (3.4%) | 20/50 (40%) | 2/48 (4.2%) | |||||||
| Lymphopenia | 0/12 (0%) | 3/83 (3.6%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Neutropenia | 11/12 (91.7%) | 62/83 (74.7%) | 4/77 (5.2%) | 26/33 (78.8%) | 1/29 (3.4%) | 36/50 (72%) | 3/48 (6.3%) | |||||||
| Thrombocytopenia | 3/12 (25%) | 16/83 (19.3%) | 2/77 (2.6%) | 8/33 (24.2%) | 1/29 (3.4%) | 8/50 (16%) | 1/48 (2.1%) | |||||||
| Ear and labyrinth disorders | ||||||||||||||
| Vertigo | 1/12 (8.3%) | 1/83 (1.2%) | 2/77 (2.6%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 2/48 (4.2%) | |||||||
| Ear pain | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Endocrine disorders | ||||||||||||||
| Hyperthyroidism | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Thyroid mass | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Eye disorders | ||||||||||||||
| Dry eye | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Lacrimation increased | 2/12 (16.7%) | 3/83 (3.6%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 2/50 (4%) | 0/48 (0%) | |||||||
| Visual impairment | 1/12 (8.3%) | 4/83 (4.8%) | 1/77 (1.3%) | 1/33 (3%) | 1/29 (3.4%) | 3/50 (6%) | 0/48 (0%) | |||||||
| Cataract | 1/12 (8.3%) | 2/83 (2.4%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Presbyopia | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| Abdominal discomfort | 1/12 (8.3%) | 0/83 (0%) | 2/77 (2.6%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 2/48 (4.2%) | |||||||
| Abdominal distension | 1/12 (8.3%) | 0/83 (0%) | 2/77 (2.6%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Abdominal pain | 0/12 (0%) | 7/83 (8.4%) | 4/77 (5.2%) | 7/33 (21.2%) | 0/29 (0%) | 0/50 (0%) | 4/48 (8.3%) | |||||||
| Abdominal pain upper | 0/12 (0%) | 2/83 (2.4%) | 4/77 (5.2%) | 1/33 (3%) | 1/29 (3.4%) | 1/50 (2%) | 3/48 (6.3%) | |||||||
| Constipation | 3/12 (25%) | 13/83 (15.7%) | 7/77 (9.1%) | 8/33 (24.2%) | 4/29 (13.8%) | 5/50 (10%) | 3/48 (6.3%) | |||||||
| Diarrhoea | 6/12 (50%) | 18/83 (21.7%) | 9/77 (11.7%) | 9/33 (27.3%) | 2/29 (6.9%) | 9/50 (18%) | 7/48 (14.6%) | |||||||
| Dry mouth | 1/12 (8.3%) | 3/83 (3.6%) | 4/77 (5.2%) | 2/33 (6.1%) | 2/29 (6.9%) | 1/50 (2%) | 2/48 (4.2%) | |||||||
| Dyspepsia | 3/12 (25%) | 4/83 (4.8%) | 2/77 (2.6%) | 1/33 (3%) | 0/29 (0%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Flatulence | 0/12 (0%) | 2/83 (2.4%) | 1/77 (1.3%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Food poisoning | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 1/48 (2.1%) | |||||||
| Chronic gastritis | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gastrooesophageal reflux disease | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 1/33 (3%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gingival pain | 1/12 (8.3%) | 4/83 (4.8%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 4/50 (8%) | 0/48 (0%) | |||||||
| Mouth ulceration | 1/12 (8.3%) | 2/83 (2.4%) | 1/77 (1.3%) | 2/33 (6.1%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Nausea | 6/12 (50%) | 25/83 (30.1%) | 11/77 (14.3%) | 12/33 (36.4%) | 7/29 (24.1%) | 13/50 (26%) | 4/48 (8.3%) | |||||||
| Stomatitis | 2/12 (16.7%) | 10/83 (12%) | 2/77 (2.6%) | 5/33 (15.2%) | 1/29 (3.4%) | 5/50 (10%) | 1/48 (2.1%) | |||||||
| Rectal haemorrhage | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Toothache | 1/12 (8.3%) | 6/83 (7.2%) | 2/77 (2.6%) | 1/33 (3%) | 1/29 (3.4%) | 5/50 (10%) | 1/48 (2.1%) | |||||||
| Vomiting | 3/12 (25%) | 15/83 (18.1%) | 3/77 (3.9%) | 9/33 (27.3%) | 2/29 (6.9%) | 6/50 (12%) | 1/48 (2.1%) | |||||||
| Oral disorder | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gastritis | 0/12 (0%) | 1/83 (1.2%) | 4/77 (5.2%) | 0/33 (0%) | 2/29 (6.9%) | 1/50 (2%) | 2/48 (4.2%) | |||||||
| General disorders | ||||||||||||||
| Asthenia | 1/12 (8.3%) | 11/83 (13.3%) | 4/77 (5.2%) | 2/33 (6.1%) | 0/29 (0%) | 9/50 (18%) | 4/48 (8.3%) | |||||||
| Chest pain | 0/12 (0%) | 3/83 (3.6%) | 4/77 (5.2%) | 0/33 (0%) | 2/29 (6.9%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Facial pain | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Fatigue | 10/12 (83.3%) | 34/83 (41%) | 18/77 (23.4%) | 14/33 (42.4%) | 7/29 (24.1%) | 20/50 (40%) | 11/48 (22.9%) | |||||||
| Influenza like illness | 1/12 (8.3%) | 5/83 (6%) | 2/77 (2.6%) | 3/33 (9.1%) | 1/29 (3.4%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Mucosal inflammation | 0/12 (0%) | 7/83 (8.4%) | 2/77 (2.6%) | 2/33 (6.1%) | 0/29 (0%) | 5/50 (10%) | 2/48 (4.2%) | |||||||
| Non-cardiac chest pain | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Oedema peripheral | 2/12 (16.7%) | 6/83 (7.2%) | 8/77 (10.4%) | 3/33 (9.1%) | 5/29 (17.2%) | 3/50 (6%) | 3/48 (6.3%) | |||||||
| Pain | 2/12 (16.7%) | 3/83 (3.6%) | 3/77 (3.9%) | 1/33 (3%) | 2/29 (6.9%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Pyrexia | 0/12 (0%) | 9/83 (10.8%) | 2/77 (2.6%) | 8/33 (24.2%) | 0/29 (0%) | 1/50 (2%) | 2/48 (4.2%) | |||||||
| Temperature intolerance | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Chills | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Face oedema | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Peripheral swelling | 1/12 (8.3%) | 4/83 (4.8%) | 2/77 (2.6%) | 2/33 (6.1%) | 0/29 (0%) | 2/50 (4%) | 2/48 (4.2%) | |||||||
| Immune system disorders | ||||||||||||||
| Seasonal allergy | 2/12 (16.7%) | 1/83 (1.2%) | 1/77 (1.3%) | 1/33 (3%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Infections and infestations | ||||||||||||||
| Conjunctivitis | 0/12 (0%) | 5/83 (6%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 3/50 (6%) | 0/48 (0%) | |||||||
| Bronchitis | 1/12 (8.3%) | 3/83 (3.6%) | 2/77 (2.6%) | 3/33 (9.1%) | 1/29 (3.4%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Cystitis | 0/12 (0%) | 3/83 (3.6%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 3/50 (6%) | 1/48 (2.1%) | |||||||
| Diverticulitis | 0/12 (0%) | 0/83 (0%) | 2/77 (2.6%) | 0/33 (0%) | 2/29 (6.9%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Ear infection | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gastroenteritis viral | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 1/48 (2.1%) | |||||||
| Herpes zoster | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Influenza | 1/12 (8.3%) | 8/83 (9.6%) | 1/77 (1.3%) | 4/33 (12.1%) | 1/29 (3.4%) | 4/50 (8%) | 0/48 (0%) | |||||||
| Localised infection | 2/12 (16.7%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Nasopharyngitis | 1/12 (8.3%) | 12/83 (14.5%) | 7/77 (9.1%) | 7/33 (21.2%) | 3/29 (10.3%) | 5/50 (10%) | 4/48 (8.3%) | |||||||
| Oral herpes | 1/12 (8.3%) | 3/83 (3.6%) | 0/77 (0%) | 3/33 (9.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Pneumonia | 1/12 (8.3%) | 1/83 (1.2%) | 2/77 (2.6%) | 0/33 (0%) | 2/29 (6.9%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Sinusitis | 2/12 (16.7%) | 2/83 (2.4%) | 2/77 (2.6%) | 1/33 (3%) | 2/29 (6.9%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Skin infection | 2/12 (16.7%) | 2/83 (2.4%) | 1/77 (1.3%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Tooth infection | 2/12 (16.7%) | 2/83 (2.4%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Upper respiratory tract infection | 3/12 (25%) | 12/83 (14.5%) | 2/77 (2.6%) | 8/33 (24.2%) | 2/29 (6.9%) | 4/50 (8%) | 0/48 (0%) | |||||||
| Urinary tract infection | 2/12 (16.7%) | 9/83 (10.8%) | 5/77 (6.5%) | 6/33 (18.2%) | 3/29 (10.3%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Herpes simplex | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Gingivitis | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Rhinitis | 2/12 (16.7%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Cellulitis | 0/12 (0%) | 2/83 (2.4%) | 2/77 (2.6%) | 2/33 (6.1%) | 1/29 (3.4%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Injury, poisoning and procedural complications | ||||||||||||||
| Contusion | 2/12 (16.7%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Thermal burn | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Fall | 0/12 (0%) | 7/83 (8.4%) | 3/77 (3.9%) | 4/33 (12.1%) | 0/29 (0%) | 3/50 (6%) | 3/48 (6.3%) | |||||||
| Periorbital haemorrhage | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Skin abrasion | 1/12 (8.3%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Skin injury | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Investigations | ||||||||||||||
| Alanine aminotransferase increased | 0/12 (0%) | 6/83 (7.2%) | 1/77 (1.3%) | 3/33 (9.1%) | 1/29 (3.4%) | 3/50 (6%) | 0/48 (0%) | |||||||
| Aspartate aminotransferase increased | 0/12 (0%) | 6/83 (7.2%) | 1/77 (1.3%) | 2/33 (6.1%) | 1/29 (3.4%) | 4/50 (8%) | 0/48 (0%) | |||||||
| Blood alkaline phosphatase increased | 0/12 (0%) | 8/83 (9.6%) | 3/77 (3.9%) | 2/33 (6.1%) | 2/29 (6.9%) | 6/50 (12%) | 1/48 (2.1%) | |||||||
| Blood creatinine increased | 2/12 (16.7%) | 4/83 (4.8%) | 5/77 (6.5%) | 1/33 (3%) | 3/29 (10.3%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Blood phosphorus decreased | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Gamma-glutamyltransferase increased | 0/12 (0%) | 4/83 (4.8%) | 1/77 (1.3%) | 2/33 (6.1%) | 0/29 (0%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Red blood cell count decreased | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Weight decreased | 2/12 (16.7%) | 4/83 (4.8%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 4/50 (8%) | 0/48 (0%) | |||||||
| White blood cell count decreased | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Weight increased | 0/12 (0%) | 3/83 (3.6%) | 6/77 (7.8%) | 1/33 (3%) | 2/29 (6.9%) | 2/50 (4%) | 4/48 (8.3%) | |||||||
| Metabolism and nutrition disorders | ||||||||||||||
| Decreased appetite | 3/12 (25%) | 17/83 (20.5%) | 5/77 (6.5%) | 9/33 (27.3%) | 2/29 (6.9%) | 8/50 (16%) | 3/48 (6.3%) | |||||||
| Diabetes mellitus | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Hyperkalaemia | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Hypocalcaemia | 0/12 (0%) | 4/83 (4.8%) | 2/77 (2.6%) | 2/33 (6.1%) | 1/29 (3.4%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Hypokalaemia | 1/12 (8.3%) | 2/83 (2.4%) | 1/77 (1.3%) | 1/33 (3%) | 1/29 (3.4%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Hyponatraemia | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Hyperuricaemia | 0/12 (0%) | 3/83 (3.6%) | 2/77 (2.6%) | 0/33 (0%) | 1/29 (3.4%) | 3/50 (6%) | 1/48 (2.1%) | |||||||
| Dehydration | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Arthralgia | 5/12 (41.7%) | 22/83 (26.5%) | 14/77 (18.2%) | 9/33 (27.3%) | 5/29 (17.2%) | 13/50 (26%) | 9/48 (18.8%) | |||||||
| Back pain | 3/12 (25%) | 17/83 (20.5%) | 13/77 (16.9%) | 6/33 (18.2%) | 5/29 (17.2%) | 11/50 (22%) | 8/48 (16.7%) | |||||||
| Bone pain | 0/12 (0%) | 10/83 (12%) | 3/77 (3.9%) | 6/33 (18.2%) | 2/29 (6.9%) | 4/50 (8%) | 1/48 (2.1%) | |||||||
| Joint swelling | 2/12 (16.7%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Muscle spasms | 0/12 (0%) | 5/83 (6%) | 3/77 (3.9%) | 1/33 (3%) | 2/29 (6.9%) | 4/50 (8%) | 1/48 (2.1%) | |||||||
| Musculoskeletal chest pain | 2/12 (16.7%) | 3/83 (3.6%) | 3/77 (3.9%) | 1/33 (3%) | 2/29 (6.9%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Musculoskeletal pain | 1/12 (8.3%) | 9/83 (10.8%) | 5/77 (6.5%) | 3/33 (9.1%) | 3/29 (10.3%) | 6/50 (12%) | 2/48 (4.2%) | |||||||
| Myalgia | 1/12 (8.3%) | 6/83 (7.2%) | 3/77 (3.9%) | 2/33 (6.1%) | 0/29 (0%) | 4/50 (8%) | 3/48 (6.3%) | |||||||
| Osteonecrosis of jaw | 1/12 (8.3%) | 3/83 (3.6%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 3/50 (6%) | 0/48 (0%) | |||||||
| Pain in extremity | 3/12 (25%) | 9/83 (10.8%) | 7/77 (9.1%) | 3/33 (9.1%) | 1/29 (3.4%) | 6/50 (12%) | 6/48 (12.5%) | |||||||
| Spinal pain | 0/12 (0%) | 5/83 (6%) | 3/77 (3.9%) | 1/33 (3%) | 0/29 (0%) | 4/50 (8%) | 3/48 (6.3%) | |||||||
| Temporomandibular joint syndrome | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Arthropathy | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Muscular weakness | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Limb discomfort | 0/12 (0%) | 0/83 (0%) | 2/77 (2.6%) | 0/33 (0%) | 2/29 (6.9%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Osteoporosis | 0/12 (0%) | 2/83 (2.4%) | 1/77 (1.3%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Tumour pain | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Nervous system disorders | ||||||||||||||
| Dizziness | 3/12 (25%) | 10/83 (12%) | 3/77 (3.9%) | 3/33 (9.1%) | 3/29 (10.3%) | 7/50 (14%) | 0/48 (0%) | |||||||
| Dysgeusia | 1/12 (8.3%) | 6/83 (7.2%) | 0/77 (0%) | 4/33 (12.1%) | 0/29 (0%) | 2/50 (4%) | 0/48 (0%) | |||||||
| Headache | 4/12 (33.3%) | 12/83 (14.5%) | 8/77 (10.4%) | 6/33 (18.2%) | 3/29 (10.3%) | 6/50 (12%) | 5/48 (10.4%) | |||||||
| Memory impairment | 1/12 (8.3%) | 2/83 (2.4%) | 1/77 (1.3%) | 1/33 (3%) | 1/29 (3.4%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Neuropathy peripheral | 2/12 (16.7%) | 9/83 (10.8%) | 4/77 (5.2%) | 6/33 (18.2%) | 2/29 (6.9%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Paraesthesia | 1/12 (8.3%) | 1/83 (1.2%) | 2/77 (2.6%) | 0/33 (0%) | 2/29 (6.9%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Sciatica | 1/12 (8.3%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Sinus headache | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Syncope | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Radicular pain | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Peripheral sensory neuropathy | 0/12 (0%) | 3/83 (3.6%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 3/50 (6%) | 0/48 (0%) | |||||||
| Psychiatric disorders | ||||||||||||||
| Anxiety | 1/12 (8.3%) | 2/83 (2.4%) | 4/77 (5.2%) | 2/33 (6.1%) | 4/29 (13.8%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Depression | 3/12 (25%) | 4/83 (4.8%) | 5/77 (6.5%) | 2/33 (6.1%) | 4/29 (13.8%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Insomnia | 3/12 (25%) | 8/83 (9.6%) | 6/77 (7.8%) | 4/33 (12.1%) | 3/29 (10.3%) | 4/50 (8%) | 3/48 (6.3%) | |||||||
| Mood altered | 1/12 (8.3%) | 4/83 (4.8%) | 1/77 (1.3%) | 2/33 (6.1%) | 0/29 (0%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Sleep disorder | 0/12 (0%) | 3/83 (3.6%) | 1/77 (1.3%) | 0/33 (0%) | 0/29 (0%) | 3/50 (6%) | 1/48 (2.1%) | |||||||
| Renal and urinary disorders | ||||||||||||||
| Dysuria | 3/12 (25%) | 4/83 (4.8%) | 2/77 (2.6%) | 2/33 (6.1%) | 2/29 (6.9%) | 2/50 (4%) | 0/48 (0%) | |||||||
| Pollakiuria | 1/12 (8.3%) | 4/83 (4.8%) | 1/77 (1.3%) | 4/33 (12.1%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Incontinence | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Reproductive system and breast disorders | ||||||||||||||
| Breast discomfort | 0/12 (0%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Breast pain | 0/12 (0%) | 2/83 (2.4%) | 4/77 (5.2%) | 2/33 (6.1%) | 3/29 (10.3%) | 0/50 (0%) | 1/48 (2.1%) | |||||||
| Pelvic pain | 1/12 (8.3%) | 2/83 (2.4%) | 2/77 (2.6%) | 1/33 (3%) | 0/29 (0%) | 1/50 (2%) | 2/48 (4.2%) | |||||||
| Vaginal discharge | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Vulvovaginal pruritus | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Cough | 3/12 (25%) | 12/83 (14.5%) | 8/77 (10.4%) | 9/33 (27.3%) | 4/29 (13.8%) | 3/50 (6%) | 4/48 (8.3%) | |||||||
| Dyspnoea | 5/12 (41.7%) | 14/83 (16.9%) | 7/77 (9.1%) | 4/33 (12.1%) | 3/29 (10.3%) | 10/50 (20%) | 4/48 (8.3%) | |||||||
| Epistaxis | 0/12 (0%) | 9/83 (10.8%) | 1/77 (1.3%) | 4/33 (12.1%) | 0/29 (0%) | 5/50 (10%) | 1/48 (2.1%) | |||||||
| Nasal congestion | 2/12 (16.7%) | 2/83 (2.4%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Oropharyngeal pain | 1/12 (8.3%) | 9/83 (10.8%) | 1/77 (1.3%) | 5/33 (15.2%) | 0/29 (0%) | 4/50 (8%) | 1/48 (2.1%) | |||||||
| Rhinitis allergic | 1/12 (8.3%) | 1/83 (1.2%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Rhinorrhoea | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Sinus congestion | 3/12 (25%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Snoring | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Lower respiratory tract congestion | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Alopecia | 1/12 (8.3%) | 18/83 (21.7%) | 2/77 (2.6%) | 8/33 (24.2%) | 1/29 (3.4%) | 10/50 (20%) | 1/48 (2.1%) | |||||||
| Dermatitis contact | 1/12 (8.3%) | 0/83 (0%) | 1/77 (1.3%) | 0/33 (0%) | 1/29 (3.4%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Dry skin | 2/12 (16.7%) | 6/83 (7.2%) | 4/77 (5.2%) | 2/33 (6.1%) | 1/29 (3.4%) | 4/50 (8%) | 3/48 (6.3%) | |||||||
| Hyperhidrosis | 0/12 (0%) | 4/83 (4.8%) | 1/77 (1.3%) | 1/33 (3%) | 0/29 (0%) | 3/50 (6%) | 1/48 (2.1%) | |||||||
| Ingrown hair | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Nail disorder | 1/12 (8.3%) | 5/83 (6%) | 1/77 (1.3%) | 3/33 (9.1%) | 0/29 (0%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Pain of skin | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 1/33 (3%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Pruritus | 0/12 (0%) | 5/83 (6%) | 2/77 (2.6%) | 1/33 (3%) | 0/29 (0%) | 4/50 (8%) | 2/48 (4.2%) | |||||||
| Rash | 3/12 (25%) | 7/83 (8.4%) | 4/77 (5.2%) | 3/33 (9.1%) | 1/29 (3.4%) | 4/50 (8%) | 3/48 (6.3%) | |||||||
| Skin disorder | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Skin swelling | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Swelling face | 1/12 (8.3%) | 1/83 (1.2%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 1/50 (2%) | 0/48 (0%) | |||||||
| Night sweats | 1/12 (8.3%) | 3/83 (3.6%) | 1/77 (1.3%) | 1/33 (3%) | 0/29 (0%) | 2/50 (4%) | 1/48 (2.1%) | |||||||
| Erythema | 0/12 (0%) | 3/83 (3.6%) | 3/77 (3.9%) | 0/33 (0%) | 1/29 (3.4%) | 3/50 (6%) | 2/48 (4.2%) | |||||||
| Vascular disorders | ||||||||||||||
| Haematoma | 0/12 (0%) | 0 | 2/83 (2.4%) | 0 | 0/77 (0%) | 0 | 2/33 (6.1%) | 0 | 0/29 (0%) | 0 | 0/50 (0%) | 0 | 0/48 (0%) | 0 |
| Hot flush | 3/12 (25%) | 19/83 (22.9%) | 11/77 (14.3%) | 9/33 (27.3%) | 5/29 (17.2%) | 10/50 (20%) | 6/48 (12.5%) | |||||||
| Hypertension | 0/12 (0%) | 6/83 (7.2%) | 5/77 (6.5%) | 1/33 (3%) | 2/29 (6.9%) | 5/50 (10%) | 3/48 (6.3%) | |||||||
| Lymphoedema | 0/12 (0%) | 4/83 (4.8%) | 0/77 (0%) | 2/33 (6.1%) | 0/29 (0%) | 2/50 (4%) | 0/48 (0%) | |||||||
| Peripheral vascular disorder | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
| Phlebitis | 1/12 (8.3%) | 0/83 (0%) | 0/77 (0%) | 0/33 (0%) | 0/29 (0%) | 0/50 (0%) | 0/48 (0%) | |||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
| Name/Title | Pfizer ClinicalTrials.gov Call Center |
|---|---|
| Organization | Pfizer, Inc. |
| Phone | 1-800-718-1021 |
| ClinicalTrials.gov_Inquiries@pfizer.com |
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT00721409
Other Study ID Numbers:
- A5481003
- 2008-002392-27
First Posted:
Jul 24, 2008
Last Update Posted:
Nov 4, 2019
Last Verified:
Oct 1, 2019