Abstract OT3-2-10: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of fulvestrant with or without PD-0332991 (palbociclib) ± goserelin in women with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) whose disease progressed after prior endocrine therapy
Authors: Turner N , André F , Loibl S , Ro J , Iwata H , Harbeck N , Glück S , Verma S , Loi S , Huang Bartlett C , Thiele A , Zhang K , Koehler M , Cristofanilli M 
Published: August 2014

Abstract
Background: Palbociclib (P) is a selective inhibitor of CDK 4/6 that prevents DNA synthesis by blocking G1-S phase cell cycle progression. Blockade of hormone signaling is synergistic with cell cycle arrest induction and results in significant clinical benefit. Combining P with anti-endocrine therapy is expected to have additive or synergistic effect on tumor growth and metastasis. In a randomized phase 2 study, postmenopausal women with hormone- sensitive ER+/HER2– advanced breast cancer had significantly longer progression-free survival (PFS) with P + letrozole (L) versus L. This study will assess efficacy of P + fulvestrant (F) in patients with endocrine-resistant MBC.
Trial Design: In this double-blind phase 3 study, patients will receive F (500 mg given IM per standard of care) and be randomized 2:1 to receive P (125 mg/d orally for 3 wk followed by 1 wk off) + F (500 mg given per standard of care) or matched placebo + F. Pre- and perimenopausal women must also receive goserelin. Randomization will be stratified by documented sensitivity to prior endocrine therapy (yes vs no), menopausal status at study entry (pre-/peri- vs postmenopausal), and presence of visceral metastases (yes vs no). An external data monitoring committee will perform an early review of safety data from the first 40 randomized patients to confirm safety/tolerability, including pharmacokinetic data to explore potential drug-drug interactions.
Eligibility Criteria: Eligible women are aged ≥18 y with ER+ and/or PR+, HER2– MBC, whose cancer has progressed during or within 12 mo of completing adjuvant therapy (with an aromatase inhibitor or tamoxifen if post-menopausal or pre-/perimenopausal, respectively) or while on or within 1 mo after the end of prior aromatase inhibitor therapy for their metastatic disease. One previous line of chemotherapy for metastatic disease is permitted. Patients must have measureable disease (per RECIST v1.1) or bone-only metastatic disease and be willing and able to provide tumor tissue for biomarker research.
Aims: The primary endpoint will assess whether P + F vs placebo + F prolongs investigator-assessed PFS. Secondary endpoints include overall survival, objective response, duration of response, trough drug concentrations, patient-reported outcomes, biomarkers, and safety and tolerability.
Statistical Methods: This study will have 90% power to detect an increase in PFS using 1-sided significance testing. One interim analysis is planned to re-estimate the sample size and assess patient safety as well as preliminary efficacy.
Accrual: Target accrual is 417 patients (P + F, n = 278; placebo + F, n = 139).
Contact Information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc (marla.brickman@pfizer.com).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-10.