A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2)

Study Overview
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Brief Summary
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The study is designed to compare the clinical benefit following treatment with letrozole in combination with PD-0332991 versus letrozole in combination with placebo in postmenopausal women with ER(+)/HER2(-) advanced breast cancer who have not received prior systemic anti cancer therapies for their advanced/metastatic disease.

Official Title
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A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 3 STUDY OF PD-0332991 (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) BREAST CANCER WHO HAVE NOT RECEIVED ANY PRIOR SYSTEMIC ANTI CANCER TREATMENT FOR ADVANCED DISEASE

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: PD-0332991
* Drug: Letrozole
* Drug: Placebo
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women with locoregionally recurrent or metastatic disease not amenable to curative therapy. Confirmed diagnosis of ER positive breast cancer No prior systemic anti-cancer therapy for advanced ER+ disease. Postmenopausal women Measurable disease as per Response Evaluation Criterion in Solid Tumors [RECIST] or bone-only disease Eastern Cooperative Oncology Group [ECOG] 0-2 Adequate organ and marrow function Patient must agree to provide tumor tissue Exclusion Criteria: Confirmed diagnosis of HER2 positive disease Patients with advanced, symptomatic, visceral spread that are at risk of life threatening complication in the short term Known uncontrolled or symptomatic CNS metastases Prior (neo)adjuvant treatment with letrozole or anastrozole with DFI ≤ 12-months from completion of treatment. Prior treatment with any CDK 4/6 inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-0332991 + Letrozole<br>PD-0332991, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously). | Drug: PD-0332991<br>* PD-0332991, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole<br>* Letrozole, 2.5mg, orally once daily (continuously)<br>|
| Active Comparator: Placebo + Letrozole<br>Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously). | Drug: Placebo<br>* Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole<br>* Letrozole, 2.5mg, orally once daily (continuously)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) as Assessed by the Investigator. | PFS is defined as the time from the date of randomization to the date of the first documentation of objective tumor progression as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or death due to any cause in the absence of documented PD, whichever occurs first. If tumor progression data include more than 1 date, the first date will be used. PFS (in months) will be calculated as (first event date - randomization date +1)/30.4. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target lesions, or the appearance of new lesions. | From randomization date to date of first documentation of progression OR death (up to approximately 2.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response as Assessed by the Investigator | Objective Response (OR) defined as the overall complete response (CR) or partial response (PR) according to the RECIST v1.1. Objective Response Rate (ORR) is defined as proportion of patients with CR or PR relative to all randomized patients with measurable disease at baseline. Patients who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: ≥30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression. | From randomization until end of treatment (up to approximately 2.5 years) | 
| Objective Response: Patients With Measurable Disease at Baseline as Assessed by the Investigator | The OR is defined as the overall CR or PR according to the RECIST v1.1. ORR is defined as proportion of patients with CR or PR relative to all randomized patients with measurable disease at baseline. Patients who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: ≥30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression. | From randomization until end of treatment (up to approximately 2.5 years) | 
| Duration of Response (DR) | 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 will be used. DR was calculated as [the date response ended (i.e. date of PD or death) - first CR or PR date + 1)]/30.4. DR would only be calculated for the subgroup of patients with an objective tumor response. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: ≥30% decrease under baseline of the sum of diameters of all target measurable lesions.The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression. | From randomization until end of treatment (up to approximately 2.5 years) | 
| Disease Control (DC)/Clinical Benefit Response (CBR) | DC is defined as the overall CR, PR, or stable disease (SD) ≥24 weeks according to the RECIST version 1.1. Disease Control Rate (DCR) is defined as the patients with CR, PR, or SD ≥24 weeks relative to all randomized participants. Participants who do not have on-study radiographic tumor reevaluation, who received anti-tumor treatment, a best response of SD≥24 weeks, or who died, progressed,or dropped out for any reason prior to achieving reaching a CR or PR and a best response of SD≥24 weeks was counted as non-responders in DCR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: ≥30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. SD: neither sufficient shrinkage nor increase to qualify for disease progression | From randomization until end of treatment (up to approximately 2.5 years) | 
| PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) | PFS by biomarker status by Investigator assessment. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Positive is defined as H-Score ≥1 and negative as H-Score <1. H-Score is calculated as the sum of the % of cells at each level of staining intensity (0, 1+, 2+, and 3+) multiplied by the staining intensity value: H-Score = (% at 0)*0 + (% at 1+)*1 + (% at 2+)*2 + (% at 3+)*3. H-Score values range from 0 to 300. ER stands for estrogen receptor and Rb stands for retinoblastoma susceptibility gene product. | From randomization until end of treatment (up to approximately 24 Months) | 
| Corrected QT Interval (QTc) Time-matched Change From Baseline on Cycle 1 Day 14 | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The 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). Time-matched change from baseline values were reported for QTc analysis population. | Time-matched triplicate ECGs were collected at 0 (predose), 2, 4, 6 and 8 hours on Day 0 and on Cycle1 Day14 | 
| Percentage of Participants With Corrected QT Interval (QTc) | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The 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). Percentage of participants with post-baseline maximum absolute values and maximum increase from baseline were summarized for the safety analysis population. | For safety monitoring triplicate ECGs were obtained at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycles 1 and Cycle 2, then on Day 1 of Cycles 4, 7, and 10. ECGs beyond Cycle 10 were performed as clinically indicated | 
| Observed Plasma Trough Concentration (Ctrough) at Steady-State | Summary of Plasma Palbociclib Within-Patient Mean Steady-State Trough Concentrations. | 0 hour (predose) on Day 14 of cycles 1 and 2 | 
| Change From Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index | The EuroQol EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarized to create a single summary score. An overall utility score is calculated based on these domains, with a range score from 0 (worse health scenario) to a maximum of 1.0 (best health scenario). | From Baseline up to 2.5 years | 
| Change From Baseline Between Treatment Comparison in Functional Assessment of Cancer Therapy -Breast (FACT-B) | FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consisted of the FACT-G (27-item) and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much. FACT-B total score = Physical Well-Being + Social/Family Well-Being + Emotional Well-Being + Functional Well-Being + Breast Cancer Subscale. As each of the items ranges from 0-4, the range of possible scores is 0-144, with 0 being the worst possible score and 144 the best. | From Baseline up to 2.5 years | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) | An AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. SAE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization; resulted in persistent or significant disability or in congenital anomaly/birth defect. TEAE were events that 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 pretreatment state. Severity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0 as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening and Grade 5 = death related to AE. | From date of randomization up to 28 days after last dose of study drug, (assessed up to data cut-off date of 15-Nov-2021, approximately 8.7 years) | 
| Overall Survival (OS) | OS was defined as the time from date of randomization to date of death due to any cause. Participants without survival data beyond the date of their last follow-up were censored on the last date they were known to be alive. | From date of randomization until death due to any cause or censored, (assessed up to data cut-off date of 15-Nov-2021, approximately 8.7 years) | 
| Survival Probability at 1 Year, 2 Year and 3 Year | One, two or three-year survival probability was defined as the probability of survival 1 year, 2 or 3 years after the date of randomization. The survival probability was estimated using the Kaplan-Meier method and 2-sided 95% confidence interval (CI) was calculated using the product limit method. | 1, 2 and 3 years after randomization | 
| Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade | Laboratory abnormalities included anemia, hemoglobin increased, neutrophils (absolute), platelets, white blood cells, alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormalities were graded by CTCAE version (v) 4.0 as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe and Grade 4 = life-threatening. Categories with at least 1 non-zero data values are reported. | From randomization up to 28 days after last dose of study drug (assessed up to data cut-off date of 15-Nov-2021, approximately 8.7 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, postmenopausal women, estrogen-receptor positive, HER2 negative, locoregionally recurrent, metastatic, Palbociclib (PD-0332991), PALOMA-2