Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Menopause

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Fulvestrant

Palbociclib

Goserelin

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Protein Kinase Inhibitors

Enzyme Inhibitors

Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.

Palbociclib 125 mg/day orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle.

Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle.

Placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle.

Placebo

Pfizer CT.gov Call Center

The study is a randomized, double blind, placebo controlled, Phase 3 clinical trial with the primary objective of demonstrating the superiority of palbociclib in combination with fulvestrant (Faslodex®) over fulvestrant alone in prolonging PFS in women with HR+, HER2 negative metastatic breast cancer whose disease has progressed after prior endocrine therapy. The safety between the two treatment arms will also be compared. During study treatment, pre- and perimenopausal women must be receiving therapy with the LHRH agonist goserelin (Zoladex® or generic).

Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)

MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 TRIAL OF FULVESTRANT (FASLODEX (REGISTERED)). WITH OR WITHOUT PD-0332991 (PALBOCICLIB) +/- GOSERELIN IN WOMEN WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE THERAPY

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

PFS is the time from the date of randomization to the date of the first documentation of objective progression of disease (PD)or death due to any cause in absence of documented PD. Participants lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of a day. Participants with documentation of PD or death after a long interval (2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) =\[progression/death date(censor date) - randomization date + 1\]/30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors(RECIST v1.1) a 20% increase in the sum of diameters of target lesions and the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of existing non-target lesions or the appearance of new lesions.

OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Participants lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = \[death date (censor date) - randomization date + 1\]/30.4.

One-, Two- or Three-year Survival Probability is defined as the probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. Survival time was censored to last date the participant is known to be alive.

OR is defined as the overall complete response (CR) or partial response (PR) according to the RECIST version 1.1 Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per response evaluation criteria in solid tumors criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions (longest for non-nodal and short axis for nodal target lesions); Overall Response (OR) = CR + PR.

DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as \[the date response ended (ie, date of PD or death) - first CR or PR date + 1)\]/30.4. Kaplan-Meier estimate of median of the DR is provided below. No inferential statistical analysis were done for DR. The DR was only calculated for the participants with a CR or PR.

CBR is defined as the overall complete response (CR), partial response (PR) , or stable disease (SD) ≥24 weeks according to the RECIST version 1.1. Clinical Benefit Response Rate (CBRR) is defined as the proportion of participants with CR, PR, or SD ≥24 weeks relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received antitumor treatment other than the study medication prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR and a best response of SD ≥24 weeks was counted as non-responders in the assessment of CBR. Per RECIST v1.1 for target lesions and assessed by MRI: CR, disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For palbociclib, a steady-state trough was to be defined as a predose plasma concentration following at least 8 consecutive days of 125 mg daily dose without dosing interruption and the time window for the PK collection was to be between 22 and 26 hours after the dose (the day prior to PK collection) and no more than 1 hour post-dose on the day of PK collection.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For fulvestrant, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For goserelin, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose.

The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.

The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.

The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represent more severe symptoms.

The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a three level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/ impairment Published weights are available that allow for the creation of a single summary score called the EQ-5D index, which basically ranges from 0 to 1 with low scores representing a higher level of dysfunction and 1 as perfect health. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

A time to event analysis was pre-specified for pain. An analysis of TTD in pain defined as time between baseline and first occurrence of increase of ≥10 points in pain. Deterioration will be defined increase in score of 10 points or greater from baseline. The Kaplan-Meier estimates of quartiles (time to deterioration) with 95% CI is mentioned below.

An AE is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death; is life-threatening; requires hospitalization; results in persistent or significant disability or in congenital anomaly/birth defect. Severity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.

Number of participants with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters Anemia, Hemoglobin increased, Neutrophil count decreased, Platelet count decreased, and White blood cell count decreased) were reported.

Number of participants with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters ALT increased, ALP increased, AST increased, Blood bilirubin increased, Creatinine increased, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hypoalbuminemia, Hypocalcemia, Hypokalemia, Hypomagnesemia, and Hyponatremia) were reported.

AstraZeneca

Pfizer

The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.

All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.

Palbociclib + Fulvestrant

Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.

Placebo + Fulvestrant

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Menopausal Status

The intent-to-treat (ITT) population or full analysis set included all participants who were randomized, with study intervention assignment designated according to initial randomization, regardless of whether participants received study intervention or received a different drug from that to which they were randomized.

Pfizer ClinicalTrials.gov Call Center

The primary hypothesis to be tested was H0: λ≥1 versus. HA: λ\<1, where λ was the palbociclib plus fulvestrant: placebo plus fulvestrant hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Fulvestrant. The study was planned to have 90% power and control the type-I error rate at 0.025.

The intent-to-treat (ITT) population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

Progression-Free Survival (PFS) as Assessed by the Investigator

The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

Overall Survival (OS)-Number of Participants Who Died

Overall Survival (OS)

Survival Probability at Year 1

Survival Probability at Year 2

Survival Probability at Year 3

Survival Probabilities at Year 1, Year 2, and Year 3

The exact test is testing the null hypothesis that the odds ratio of objective response rate is less than or equal to 1 vs. the alternative hypothesis that the odds ratio of objective response rate is greater than 1. An Odds Ratio \>1 means better response in favor of palbociclib plus fulvestrant arm.

The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized. Randomized participants with measurable disease at baseline was also included.

Objective Response (OR)

Duration of Response (DR)

Clinical Benefit Response (CBR)

Cycle 1/Day 15

Cycle 2/Day 15

The participants who were treated with Palbociclib + fulvestrant (with or without goserelin) or placebo + fulvestrant (with or without goserelin) and have at least one measured plasma drug concentration. The geometric mean and coefficient of variation was not estimable for Cycle 1/Day 15 and Cycle 2/Day 15 for the reporting arm placebo plus fulvestrant.

Observed Plasma Trough Concentration (Ctrough) for Palbociclib

Cycle 2/Day 1

Cycle 3/Day 1

The 40 participants who participated in the early safety review, who are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and have at least one measured plasma drug concentration.

Ctrough for Fulvestrant

Ctrough for Goserelin

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for Global health status/ QoL

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for physical functioning

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for role functioning

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for emotional functioning

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for cognitive functioning

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for social functioning

Global health status / QoL

Physical functioning

Role functioning

Emotional functioning

Cognitive functioning

Social functioning

The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for fatigue

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for nausea and vomiting

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for pain

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for dyspnoea

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for insomnia

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for appetite loss

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for constipation

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for diarrhoea

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for financial difficulties

Fatigue

Nausea and vomiting

Pain

Dyspnoea

Insomnia

Appetite loss

Constipation

Diarrhoea

Financial difficulties

Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for body image

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for sexual functioning

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for sexual enjoyment

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for future perspective

Body image

Sexual functioning

Sexual enjoyment

Future perspective

Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for systemic therapy side effects

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for breast symptoms

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for arm symptoms

Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for upset by hair loss

Systemic therapy side effects

Breast symptoms

Arm symptoms

Upset by hair loss

Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D)- Health Index Scores

Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale

Treatment with palbociclib plus fulvestrant significantly delayed TTD in pain symptom compared with placebo plus fulvestrant for unstratified analysis.

25% quartile

50% quartile

The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment.

Time to Deterioration (TTD)

With AEs

With SAEs

With Grade 3 or 4 AEs

With Grade 5 AEs

Discontinued palbociclib/placebo due to AEs

The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.

Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities)

Anemia

Hemoglobin increased

Neutrophil count decreased

Platelet count decreased

White blood cell count decreased

Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results

ALT increased

ALP increased

AST increased

Blood bilirubin increased

Creatinine increased

Hypercalcemia

Hyperkalemia

Hypermagnesemia

Hypernatremia

Hypoalbuminemia

Hypocalcemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results

Overall Study

Bone Density Conservation Agents

Tamoxifen

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Palbociclib 125 mg/day, orally once daily on Day 1 to Day 21 followed by 7 days off treatment for each 28 day cycle, plus tamoxifen 20 mg orally once daily (continuously)

Placebo orally once daily on Day 1 to Day 21 followed by 7 days off treatment for each 28 day cycle, plus tamoxifen 20 mg orally once daily (continuously)

Palbociclib, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment

Placebo, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment

Tamoxifen, 20mg, orally once daily (continuously)

For pre/perimenopausal patients only: Goserelin, 3.6 mg, subcutaneously every 4 weeks; or 10.8 mg, subcutaneously every 12 weeks

Kan Yonemori, MD, PhD

This study is conducted to evaluate the benefit of adding palbociclib in hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer patients, regardless of menopausal status, treated with tamoxifen (with or without goserelin) versus tamoxifen alone (with or without goserelin).

PAlbociclib Plus Tamoxifen for the Treatment of Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Women - Asian studY

Asian, International, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tamoxifen With or Without Palbociclib ± Goserelin in Women With Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

The time from the date of randomization to the date of the first documentation of objective progression of disease (PD), clinically diagnosed symptomatic deterioration, or death due to any cause in the absence of documented PD, whichever occurs first.

The time from date of randomization to date of death due to any cause.

The probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate.

Complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) ver.1.1 recorded from randomization until disease progression or death due to any cause.

The time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.

CR or PR or SD \>=24 weeks according to the RECIST version 1.1 recorded in the time period between randomization and disease progression or death of any cause.

Ctrough for tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and endoxifen

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)	NCT01942135	Metastatic Brea...	Palbociclib Fulvestrant Placebo Fulvestrant	18 Years -	Pfizer
PAlbociclib Plus Tamoxifen for the Treatment of Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Women - Asian studY	NCT03423199	Breast Neoplasm...	Palbociclib Placebo Tamoxifen Goserelin	18 Years -	National Cancer Center, Japan
Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)	NCT01942135	Metastatic Brea...	Palbociclib Fulvestrant Placebo Fulvestrant	18 Years -	Pfizer

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