Clinical trial NCT00721409: Study Of Letrozole With Or Without Palbociclib (PD-0332991) For The First-Line Treatment Of Hormone-Receptor Positive Advanced Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: hormone-receptor positive advanced breast cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2008-07-24
Enrollment: 177
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1
timeFrame: Maximum treatment duration (approximately 55 months)
measure: Number of Participants With Treatment-Related Adverse Events at Phase 1
timeFrame: Maximum treatment duration (approximately 55 months)
measure: Number of Participants With Dose Limiting Toxicities at Phase 1
timeFrame: Cycle 2 (4 weeks)
measure: Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment
timeFrame: From randomization date to date of first documentation of progression or death (assessed up to 41 months)
Secondary outcomes:
measure: Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1
timeFrame: From Baseline up to end of study (assessed up to 55 months)
measure: Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1
timeFrame: From Baseline up to end of study (assessed up to 55 months)
measure: 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
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: 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
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: 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
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: 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
timeFrame: Cycle 1 Day 14, and Cycle 2 Day 14
measure: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1
timeFrame: Cycle 2 Day 14, Cycle 2 Day 28
measure: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1
timeFrame: Cycle 2 Day 14, and Cycle 2 Day 28
measure: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1
timeFrame: Cycle 2 Day 14, and Cycle 2 Day 28
measure: Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1
timeFrame: 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)
measure: Overall Survival (OS) at Phase 2
timeFrame: From randomization until death (assessed up to 86 months)
measure: Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment
timeFrame: From randomization up to the end of treatment (approximately 41 months)
measure: Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment
timeFrame: From randomization up to the end of treatment (approximately 41 months)
measure: Duration of Response at Phase 2 - Investigator Assessment
timeFrame: From randomization up to the end of treatment (approximately 41 months)
measure: Number of Participants With CBR at Phase 2 - Investigator Assessment
timeFrame: From randomization up to the end of treatment (approximately 41 months)
measure: Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment
timeFrame: From randomization up to the end of treatment (approximately 41 months)
measure: Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2
timeFrame: Baseline, End of treatment (approximately 41 months)
measure: Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2
timeFrame: Baseline, End of treatment (approximately 41 months)
measure: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1
timeFrame: Screening visit (≤ 28 Days prior to dosing)
measure: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67
timeFrame: Screening visit (≤ 28 Days prior to dosing)
measure: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1
timeFrame: Screening visit (≤ 28 Days prior to dosing)
measure: Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2
timeFrame: Screening visit (≤ 28 Days prior to dosing)
measure: Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2
timeFrame: Screening visit (≤ 28 Days prior to dosing)
measure: Number of Participants With TEAEs (All Causalities) at Phase 2
timeFrame: Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
measure: Number of Participants With Treatment-Related Adverse Events at Phase 2
timeFrame: Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: Central Hematology Oncology Medical group Inc.
state: California
city: Alhambra
country: United States
facility: UCLA Hematology/Oncology - Alhambra
state: California
city: Bakersfield
country: United States
facility: CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center
state: California
city: Fullerton
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: UCLA West Medical Pharmacy (Drug Management Only)
state: California
city: Los Angeles
country: United States
facility: UCLA West Medical Pharmacy
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA West Medical Pharmacy
state: California
city: Los Angeles
country: United States
facility: Drug Management Only: UCLA West Medical Pharmacy
state: California
city: Los Angeles
country: United States
facility: Drug Management Only
state: California
city: Los Angeles
country: United States
facility: Regulatory Managment
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: TORI -US Central Administration (Regulatory Management)
state: California
city: Los Angeles
country: United States
facility: TORI -US Central Administration
state: California
city: Los Angeles
country: United States
facility: TORI Central Administration (Regulatory Management)
state: California
city: Los Angeles
country: United States
facility: TORI Central Administration (Regulatory Managment Only)
state: California
city: Los Angeles
country: United States
facility: TRIO-US Central Administration
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology/Oncology
state: California
city: Los Angeles
country: United States
facility: UCLA, Hematology/Oncology
state: California
city: Los Angeles
country: United States
facility: Westwood Bowyer Clinic, Peter Morton Medical Building
state: California
city: Pasadena
country: United States
facility: Central Hematology Oncology Medical Group, Inc
state: California
city: Redondo Beach
country: United States
facility: Torrance Health Association, DBA Torrance Memorial Physician Network/Cancer Care Associates
state: California
city: Santa Barbara
country: United States
facility: Sansum Santa Barbara Medical Foundation Clinic
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation
state: California
city: Santa Monica
country: United States
facility: Santa Monica-UCLA Medical Center and Orthopaedic Hospital
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology Oncology-Santa Monica
state: California
city: Valencia
country: United States
facility: UCLA Hematology/Oncology - Santa Clarita
state: California
city: Duluth
country: United States
facility: Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care
state: Georgia
city: Lawrenceville
country: United States
facility: Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care
state: Georgia
city: Snellville
country: United States
facility: Gwinnett Hospital System Inc.-d/b/a-The Center for Cancer Care
state: Georgia
city: Chicago
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Chicago
country: United States
facility: Resurrection Medical Group
state: Illinois
city: Crystal Lake
country: United States
facility: North Shore Oncology-Hematology Associates
state: Illinois
city: Highland Park
country: United States
facility: North Shore Hematology Oncology
state: Illinois
city: Libertyville
country: United States
facility: North Shore Oncology-Hematology Associates
state: Illinois
city: Skokie
country: United States
facility: North Shore Hematology Oncology
state: Illinois
city: Henderson
country: United States
facility: Regulatory Office: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Dallas
country: United States
facility: Texas Oncology-Dallas Presbyterian Hospital
state: Texas
city: Dallas
country: United States
facility: Texas Oncology-Baylor Charles A. Sammons Cancer Center
state: Texas
city: Fort Worth
country: United States
facility: Investigational Products Center (IPC)
state: Texas
city: Fort Worth
country: United States
facility: US Oncology Research and Clinical Pharmacy
state: Texas
city: Arlington
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Gainesville
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Leesburg
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Woodbridge
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Vancouver
country: Canada
facility: BC Cancer Agency - Vancouver Centre
state: British Columbia
city: Greenfield Park
country: Canada
facility: CSSS Champlain-Charles-Le Moyne Local HS-0054
state: Quebec
city: ANGERS Cedex 9
country: France
facility: Centre Paul Papin, CRLCC
city: La Roche Sur Yon
country: France
facility: CHD Vendee
city: Berlin
country: Germany
facility: Gemeinschaftspraxis, Onkologischer Schwerpunkt am Oskar-Helene-Heim
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Haematologie-Onkologie
city: Halle/Saale
country: Germany
facility: Martin-Luther-Universitaet Halle-Wittenberg
city: Halle/Saale
country: Germany
facility: Universitaetsklinik und Poliklinik fuer Gynaekologie, Martin-Luther-Universitaet Halle-Wittenberg
city: Heidelberg
country: Germany
facility: Nationales Centrum fuer Tumorerkrankungen
city: Kiel
country: Germany
facility: Frauenaerzte Pruener Gang Abts & Partner
city: Mainz
country: Germany
facility: Klinik und Poliklinik fuer Frauenheilkunde und Geburtshilfe Universitaetsklinik Mainz
city: Muenchen
country: Germany
facility: Onkolog. Gemeinschaftspraxis
city: Muenchen
country: Germany
facility: Frauenklinik vom Roten Kreuz
city: Muenchen
country: Germany
facility: Frauenklinik und Poliklinik Klinikum rechts der Isar, Technische Universitaet Muenchen
city: Trier
country: Germany
facility: Mutterhaus der Borromaeerinnen, Innere Medizin I
city: Budapest
country: Hungary
facility: Szent Margit Korhaz, Onkologia
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet, Kemoterapia B
city: Budapest
country: Hungary
facility: Fovarosi Onkormanyzat Uzsoki Utcai Korhaz
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz, Onkoradiologia
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen Megyei Korhaz és Egyetemi Oktato Korhaz, Onkologia
city: Nyiregyhaza
country: Hungary
facility: Szabolcs-Szatmar-Bereg Megyei Korhazak es
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatokorhaz, Onkoradiologiai Osztaly
city: Cork
country: Ireland
facility: Bon Secours Hospital
city: Dublin 8
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Meldola
country: Italy
facility: Divisione Oncologia Medica Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST
state: FC
city: Cattolica
country: Italy
facility: M.O. di Oncologia - Azienda USL di Rimini - Ospedale "Cervesi"
city: Faenza, RA
country: Italy
facility: Ospedale Civile di Faenza Centro Oncologico
city: Lugo, RA
country: Italy
facility: Unita' Operativa di Oncologia, Ospedale Civile di Lugo
city: Ravenna
country: Italy
facility: Ospedale Civile di Ravenna
city: Rimini
country: Italy
facility: Azienda Unita Sanitaria Locale di Rimini, U.O. di Oncologia ed Oncoematologia Ospedale degli Infermi
city: Roma
country: Italy
facility: Ospedale Villa San Pietro
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center, Center for Breast Cancer
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Scientific Institution
city: Pyatigorsk
country: Russian Federation
facility: Pyatigorsk Oncology Center
city: Samara
country: Russian Federation
facility: State Budgetary Healthcare Institution "Samara Regional Clinical Oncology Dispensary"
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of the Ministry of Health of Bashkortostan Republic
city: Bloemfontein
country: South Africa
facility: Department of Oncotherapy, National Hospital
city: Pretoria
country: South Africa
facility: Eastleigh Breast Care Centre
city: Hospitalet de Llobregat
country: Spain
facility: Ico-Hospitalet
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital General Universitario Vall D'Hebron
city: La Coruña
country: Spain
facility: Centro Oncologico de Galicia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: Dnipropetrovsk
country: Ukraine
facility: Department of Oncology and Medical Radiology, SI "DMA of MOH, Ukraine, "MI "Dnipropetrovsk City
city: Donetsk
country: Ukraine
facility: Municipal Treatment-and-Prophylactic Institution 'Donetsk City Oncological Dispensary' Radiology dep
city: Donetsk
country: Ukraine
facility: Municipal clinical treatment-and-propyilactic institution "Donetsk regional oncology center',
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Oncologic Center
city: Lviv
country: Ukraine
facility: Lviv State Oncologic Regional Treatment and Diagnostic Centre
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
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.
citation: Finn RS, Boer K, Bondarenko I, Patel R, Pinter T, Schmidt M, Shparyk YV, Thummala A, Voitko N, Bananis E, McRoy L, Wilner K, Huang X, Kim S, Slamon DJ, Ettl J. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat. 2020 Sep;183(2):419-428. doi: 10.1007/s10549-020-05755-7. Epub 2020 Jul 18.
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.
citation: Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, Masuda N, Im SA, Huang X, Kim S, Sun W, Iyer S, Schnell P, Bartlett CH, Johnston S. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018 Sep;101:123-133. doi: 10.1016/j.ejca.2018.05.017. Epub 2018 Jul 25.
citation: Dieras V, Rugo HS, Schnell P, Gelmon K, Cristofanilli M, Loi S, Colleoni M, Lu DR, Mori A, Gauthier E, Huang Bartlett C, Slamon DJ, Turner NC, Finn RS. Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer. J Natl Cancer Inst. 2019 Apr 1;111(4):419-430. doi: 10.1093/jnci/djy109.
citation: Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.
citation: Bell T, Crown JP, Lang I, Bhattacharyya H, Zanotti G, Randolph S, Kim S, Huang X, Huang Bartlett C, Finn RS, Slamon D. Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment. Curr Med Res Opin. 2016 May;32(5):959-65. doi: 10.1185/03007995.2016.1157060. Epub 2016 Mar 2.
citation: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16.