NCT01942135 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2024-04-04

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).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

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

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outcome · POSTED

Overall Survival (OS)-Number of Participants Who Died

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

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

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outcome · POSTED

Objective Response (OR)

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outcome · POSTED

Duration of Response (DR)

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outcome · POSTED

Clinical Benefit Response (CBR)

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outcome · POSTED

Observed Plasma Trough Concentration (Ctrough) for Palbociclib

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outcome · POSTED

Ctrough for Fulvestrant

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outcome · POSTED

Ctrough for Goserelin

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Time to Deterioration (TTD)

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Women 18 years or older with metastatic or locally advanced disease, not amenable to curative therapy * Confirmed diagnosis of HR+/HER2- breast cancer * Any menopausal status * Progressed within 12 months from prior adjuvant or progressed within 1 month from prior advanced/metastatic endocrine breast cancer therapy * On an LHRH agonist for at least 28 days, if pre-/peri-menopausal, and willing to switch to goserelin (Zoladex ®) at time of randomization. * Measurable disease defined by RECIST version 1.1, or bone-only disease * Eastern Cooperative Oncology Group (ECOG) PS 0-1 * Adequate organ and marrow function, resolution of all toxic effects of prior therapy or surgical procedures * Patient must agree to provide tumor tissue from metastatic tissue at baseline Exclusion Criteria: * Prior treatment with any CDK inhibitor, fulvestrant, everolimus, or agent that inhibits the PI3K-mTOR pathway * Patients with extensive advanced/metastatic, symptomatic visceral disease, or known uncontrolled or symptomatic CNS metastases * Major surgery or any anti-cancer therapy within 2 weeks of randomization * Prior stem cell or bone marrow transplantation * Use of potent CYP3A4 inhibitors or inducers
gender Based: true
healthy Volunteers: false
minimum Age: 18 Years
sex: FEMALE
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.
intervention Names
Drug: Palbociclib
Drug: Fulvestrant
label
Arm A
type
EXPERIMENTAL
description
Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.
intervention Names
Drug: Placebo
Drug: Fulvestrant
label
Arm B
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Arm A
description
Palbociclib 125 mg/day orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle.
name
Palbociclib
type
DRUG
arm Group Labels
Arm A
description
Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle.
name
Fulvestrant
type
DRUG
arm Group Labels
Arm B
description
Placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle.
name
Placebo
type
DRUG
arm Group Labels
Arm B
description
Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle.
name
Fulvestrant
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: TRIPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR

primary Purpose

TREATMENT

Enrollment

count: 521
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Progression-Free Survival (PFS) as Assessed by the Investigator
time Frame
From randomization date to date of first documentation of progression or death (assessed up to 12 months)

secondary Outcomes

description
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.
measure
Overall Survival (OS)-Number of Participants Who Died
time Frame
From randomization until death (up to 4.5 years)
description
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.
measure
Overall Survival (OS)
time Frame
From randomization until death (up to 4.5 years)
description
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.
measure
Survival Probabilities at Year 1, Year 2, and Year 3
time Frame
From randomization until death (assessed up to 36 months)
description
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.
measure
Objective Response (OR)
time Frame
From randomization until end of treatment (assessed up to 2 years)
description
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.
measure
Duration of Response (DR)
time Frame
From randomization until end of treatment (assessed up to 2 years)
description
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.
measure
Clinical Benefit Response (CBR)
time Frame
From randomization until end of treatment (assessed up to 2 years)
description
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.
measure
Observed Plasma Trough Concentration (Ctrough) for Palbociclib
time Frame
Cycle 1/Day 15 and Cycle 2/Day 15
description
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.
measure
Ctrough for Fulvestrant
time Frame
Cycles 2/Day 1 and Cycle 3/Day 1
description
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.
measure
Ctrough for Goserelin
time Frame
Cycles 2/ Day 1 and Cycle 3/ Day 1
description
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.
measure
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
time Frame
From Cycle 1 to 14, as of 05 December 2014.
description
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.
measure
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores
time Frame
From Cycle 1 to 14, as of 05 December 2014.
description
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.
measure
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
time Frame
From Cycle 1 to 14, as of 05 December 2014.

Full study description

brief Summary: 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).

Source references

references

citation
Li H, Wu Y, Zou H, Koner S, Plichta JK, Tolaney SM, Zhang J, He YW, Wei Q, Tang L, Zhang H, Zhang B, Guo Y, Chen X, Li K, Lian L, Ma F, Luo S. Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials. EBioMedicine. 2024 Jul;105:105186. doi: 10.1016/j.ebiom.2024.105186. Epub 2024 Jun 10.
pmid
38861871
type
DERIVED
citation
Rugo HS, Im SA, Joy AA, Shparyk Y, Walshe JM, Sleckman B, Loi S, Theall KP, Kim S, Huang X, Bananis E, Mahtani R, Finn RS, Dieras V. Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3. Breast. 2022 Dec;66:324-331. doi: 10.1016/j.breast.2022.11.005. Epub 2022 Nov 15.
pmid
36463643
type
DERIVED
citation
Zhu Z, Turner NC, Loi S, Andre F, Martin M, Dieras V, Gelmon KA, Harbeck N, Zhang C, Cao JQ, Yan Z, Lu DR, Wei P, VanArsdale TL, Rejto PA, Huang X, Rugo HS, Loibl S, Cristofanilli M, Finn RS, Liu Y. Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib. NPJ Precis Oncol. 2022 Aug 16;6(1):56. doi: 10.1038/s41698-022-00297-1.
pmid
35974168
type
DERIVED
citation
Rugo HS, Cristofanilli M, Loibl S, Harbeck N, DeMichele A, Iwata H, Park YH, Brufsky A, Theall KP, Huang X, McRoy L, Bananis E, Turner NC. Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3. Oncologist. 2021 Aug;26(8):e1339-e1346. doi: 10.1002/onco.13833. Epub 2021 Jun 12.
pmid
34037282
type
DERIVED
citation
Iwata H, Umeyama Y, Liu Y, Zhang Z, Schnell P, Mori Y, Fletcher O, Marshall JC, Johnson JG, Wood LS, Toi M, Finn RS, Turner NC, Bartlett CH, Cristofanilli M. Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3. Oncologist. 2021 Jul;26(7):e1143-e1155. doi: 10.1002/onco.13811. Epub 2021 Jun 7.
pmid
33955129
type
DERIVED
citation
Finn RS, Rugo HS, Gelmon KA, Cristofanilli M, Colleoni M, Loi S, Schnell P, Lu DR, Theall KP, Mori A, Gauthier E, Bananis E, Turner NC, Dieras V. Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up. Oncologist. 2021 May;26(5):e749-e755. doi: 10.1002/onco.13684. Epub 2021 Mar 10.
pmid
33486783
type
DERIVED
citation
Finn RS, Cristofanilli M, Ettl J, Gelmon KA, Colleoni M, Giorgetti C, Gauthier E, Liu Y, Lu DR, Zhang Z, Bartlett CH, Slamon DJ, Turner NC, Rugo HS. Treatment effect of palbociclib plus endocrine therapy by prognostic and intrinsic subtype and biomarker analysis in patients with bone-only disease: a joint analysis of PALOMA-2 and PALOMA-3 clinical trials. Breast Cancer Res Treat. 2020 Nov;184(1):23-35. doi: 10.1007/s10549-020-05782-4. Epub 2020 Aug 11.
pmid
32783178
type
DERIVED
citation
Ettl J, Im SA, Ro J, Masuda N, Colleoni M, Schnell P, Bananis E, Lu DR, Cristofanilli M, Rugo HS, Finn RS. Hematologic adverse events following palbociclib dose reduction in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: pooled analysis from randomized phase 2 and 3 studies. Breast Cancer Res. 2020 Mar 12;22(1):27. doi: 10.1186/s13058-020-01263-0.
pmid
32164785
type
DERIVED
citation
Masuda N, Mukai H, Inoue K, Rai Y, Ohno S, Mori Y, Hashigaki S, Muramatsu Y, Umeyama Y, Iwata H, Toi M. Neutropenia management with palbociclib in Japanese patients with advanced breast cancer. Breast Cancer. 2019 Sep;26(5):637-650. doi: 10.1007/s12282-019-00970-7. Epub 2019 May 24.
pmid
31127500
type
DERIVED
citation
Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, DeMichele A, Harbeck N, Andre F, Bayar MA, Michiels S, Zhang Z, Giorgetti C, Arnedos M, Huang Bartlett C, Cristofanilli M. Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019 May 10;37(14):1169-1178. doi: 10.1200/JCO.18.00925. Epub 2019 Feb 26.
pmid
30807234
type
DERIVED
citation
Masuda N, Inoue K, Nakamura R, Rai Y, Mukai H, Ohno S, Hara F, Mori Y, Hashigaki S, Muramatsu Y, Nagasawa T, Umeyama Y, Huang X, Iwata H. Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. Int J Clin Oncol. 2019 Mar;24(3):262-273. doi: 10.1007/s10147-018-1359-3. Epub 2018 Nov 3.
pmid
30392115
type
DERIVED
citation
Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Andre F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20.
pmid
30345905
type
DERIVED