Study of GDC-0941 or GDC-0980 With Fulvestrant Versus Fulvestrant in Advanced or Metastatic Breast Cancer in Participants Resistant to Aromatase Inhibitor Therapy

A Phase II, Double-Blind, Placebo Controlled, Randomized Study of GDC-0941 or GDC-0980 With Fulvestrant Versus Fulvestrant in Advanced or Metastatic Breast Cancer in Patients Resistant to Aromatase Inhibitor Therapy

This is a multicenter, international, randomized, double-blinded, placebo-controlled, Phase II trial. Participants with advanced breast cancer (ABC) or Metastatic Breast Cancer (MBC) who have experienced recurrence or progression of their disease while receiving aromatase inhibitor (AI) therapy or who have relapsed within 6 months after completing adjuvant AI therapy will be enrolled in Part I of this study. Participants with ABC or MBC who have received prior AI therapy and who have PIK3CA-mutant tumors will be enrolled in Part II of this study. Part I of the study will assess the effect of the addition of GDC-0941 to fulvestrant (Arm A) and of GDC-0980 to fulvestrant (Arm B) on progression free survival (PFS) compared with fulvestrant + placebo (Arm C). Part II of the study will examine the safety and tolerability and to estimate the effect of GDC-0941 in combination with fulvestrant (Arm D) on PFS versus fulvestrant + placebo (Arm E) in participants who received prior treatment with an AI and whose tumors contain a PIK3CA mutation.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Fulvestrant; Drug: GDC-0941 Matching Placebo; Drug: GDC-0941; Drug: GDC-0980 Matching Placebo; Drug: GDC-0980

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1025
  • Santa Fe, Argentina, 03000
• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
    • Wahroonga, New South Wales, Australia, 2076
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
    • Woodville, South Australia, Australia, 5011
  • Victoria
    • Frankston, Victoria, Australia, 3199
    • Parkville, Victoria, Australia, 3050
• Belgium
  • Bruxelles, Belgium, 1070
  • Bruxelles, Belgium, 1000
  • Edegem, Belgium, 2650
  • Leuven, Belgium, 3000
  • Liège, Belgium, 4000
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
    • Quebec City, Quebec, Canada, G1R 2J6
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
• Chile
  • Santiago, Chile, 7630370
  • Temuco, Chile, 4810469
  • Valparaiso, Chile, 2341391
  • Vina del Mar, Chile, 2540364
• Czech Republic
  • Brno, Czech Republic, 656 53
  • Olomouc, Czech Republic, 775 20
  • Praha 2, Czech Republic, 128 08
• Denmark
  • Herlev, Denmark, 2730
  • København Ø, Denmark, 2100
  • Odense, Denmark, 5000
  • Roskilde, Denmark, 4000
  • Vejle, Denmark, 7100
  • Århus, Denmark, 8000
• France
  • Paris, France, 75231
• Germany
  • Berlin, Germany, 13125
  • Düsseldorf, Germany, 40225
  • Freiburg, Germany, 79106
  • Freiburg, Germany, 79110
  • Hamburg, Germany, 20246
  • Muenchen, Germany, 81675
  • Muenchen, Germany, 81377
  • München, Germany, 80336
  • Trier, Germany, 54290
• Hong Kong
  • Hong Kong, Hong Kong, 852
  • Pokfulam, Hong Kong
• Israel
  • Beer Sheva, Israel, 8410101
  • Holon, Israel, 58100
  • Jerusalem, Israel, 91120
  • Jerusalem, Israel, 9372212
  • Kfar-Saba, Israel, 4428164
  • Rehovot, Israel, 7610001
  • Tel Aviv, Israel, 6423906
  • Tel-Hashomer, Israel, 52621
  • Zerifin, Israel, 70300
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
  • Emilia-Romagna
    • Meldola, Emilia-Romagna, Italy, 47014
  • Lombardia
    • Milano, Lombardia, Italy, 20132
    • Milano, Lombardia, Italy, 20121
    • Milano, Lombardia, Italy, 20141
    • Monza, Lombardia, Italy, 20900
  • Toscana
    • Pisa, Toscana, Italy, 56100
    • Prato, Toscana, Italy, 59100
  • Umbria
    • Terni, Umbria, Italy, 05100
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
  • Kuala Lumpur, Malaysia, 56000
  • Penang, Malaysia, 10050
  • Penang, Malaysia, 10400
  • Tanjung Bungah, Malaysia, 11200
• Mexico
  • León, Mexico, 37000
• New Zealand
  • Christchurch, New Zealand
  • Hamilton, New Zealand, 3240
  • Wellington, New Zealand, 0621
• Peru
  • Lima, Peru, 34
  • Lima, Peru, 11
  • Lima, Peru, Lima 27
• Russian Federation
  • Chelyabinsk, Russian Federation, 454087
  • Kazan, Russian Federation, 420029
  • Moscow, Russian Federation, 115478
  • Voronezh, Russian Federation, 394000
• Singapore
  • Singapore, Singapore, 119074
• Spain
  • Barcelona, Spain, 08035
  • Lerida, Spain, 25198
  • Valencia, Spain, 46015
  • Zaragoza, Spain, 50009
• Thailand
  • Patumwan, Thailand, 10330
  • Songkhla, Thailand, 90110
• United Kingdom
  • Brighton, United Kingdom, BN1 9PX
  • Cardiff, United Kingdom, CF14 2TL
  • London, United Kingdom, SW3 6JJ
  • London, United Kingdom, W1G 6AD
  • Stoke on Trent, United Kingdom, ST4 7LN
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
  • California
    • Hayward, California, United States, 94545
    • Oakland, California, United States, 94611
    • Roseville, California, United States, 95661
    • Sacramento, California, United States, 95825
    • San Francisco, California, United States, 94115
    • San Jose, California, United States, 95119
    • Santa Clara, California, United States, 95051
    • South San Francisco, California, United States, 94080
    • Vallejo, California, United States, 94589
    • Walnut Creek, California, United States, 94596
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
  • Florida
    • Boca Raton, Florida, United States, 33428
    • Fort Myers, Florida, United States, 33916
    • Jacksonville, Florida, United States, 32224
    • Saint Petersburg, Florida, United States, 33705
  • Georgia
    • Marietta, Georgia, United States, 30060
  • Illinois
    • Joliet, Illinois, United States, 60435
    • Peoria, Illinois, United States, 61615
  • Kansas
    • Wichita, Kansas, United States, 67214-3728
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
    • Boston, Massachusetts, United States, 02115
  • Missouri
    • St. Louis, Missouri, United States, 63128
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
    • Hackensack, New Jersey, United States, 07601
  • New York
    • Commack, New York, United States, 11725
    • New York, New York, United States, 10065
    • Rockville Centre, New York, United States, 11570
    • Sleepy Hollow, New York, United States, 10591
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
  • South Carolina
    • Charleston, South Carolina, United States, 29425
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
    • Germantown, Tennessee, United States, 38138
    • Nashville, Tennessee, United States, 37232
    • Nashville, Tennessee, United States, 37211
  • Texas
    • Dallas, Texas, United States, 75246
    • Fort Worth, Texas, United States, 76104
    • Houston, Texas, United States, 77030
    • Houston, Texas, United States, 77030-4095
    • Tyler, Texas, United States, 75702
  • Virginia
    • Richmond, Virginia, United States, 23226

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• As per national or local treatment guidelines, endocrine therapy (i.e., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not necessary for participants, at time of entry into the study.
• Part I: Postmenopausal women with locally ABC or MBC whose disease relapsed during treatment with (or within 6 months after discontinuation of) an AI in the adjuvant setting or progressed during treatment with an AI in the metastatic setting.
• Part II: Postmenopausal women with locally ABC or MBC whose disease has progressed during or after treatment with an AI. Participants who discontinued the AI for toxicity rather than completion of regimen or for disease progression are not eligible
• Estrogen receptor (ER)-positive disease and human epidermal receptor 2 (HER2)-negative disease
• Participants must have measurable disease by response evaluation criteria in solid tumors (RECIST) version (v) 1.1 or bone-only disease with radiologic scans
• Adequate hematologic and end-organ function

Exclusion Criteria:

• Prior treatment with fulvestrant, phosphoinositide 3-kinase (PI3K) inhibitor, or mechanistic target of rapamycin (mTOR) inhibitor for ABC or MBC
• Prior anti-cancer therapy or radiotherapy within 2 weeks prior to Day 1 of Cycle 1
• Prior treatment with greater than (>) one cytotoxic chemotherapy regimens or experienced recurrent or progressive disease on > two endocrine therapies for MBC
• Participants requiring anti-hyperglycemic therapy
• Clinically significant cardiac or pulmonary dysfunction
• History of malabsorption syndrome or other condition that would interfere with enteral absorption
• Clinically significant history of liver disease
• Active uncontrolled autoimmune disease or active inflammatory disease
• Immunocompromised status
• Need for current chronic corticosteroid therapy
• Pregnancy, lactation, or breastfeeding
• Current severe, uncontrolled systemic disease
• Symptomatic hypercalcemia
• Known untreated or active central nervous system (CNS) metastases
• History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or patients who have undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to be at low risk for recurrence

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: GDC-0941 Matching Placebo + Fulvestrant (Arm E); Participants with PIK3CA mutation will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle and GDC-0941 matching placebo QD orally starting on Day 1 of Cycle 1, each cycle of 28 days. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.	Drug: Fulvestrant; Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0941 Matching Placebo; Participants will receive GDC-0941 matching placebo QD orally from Day 1 or Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.
EXPERIMENTAL: GDC-0941-260 mg + Fulvestrant (Arm D); Participants with PIK3CA mutation will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle and GDC-0941 260 mg QD orally starting on Day 1 of Cycle 1, each cycle of 28 days. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.	Drug: Fulvestrant; Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0941; Participants will receive GDC-0941 260 mg (Part II) or 340 mg (Part I) QD orally from Day 1 or Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.
EXPERIMENTAL: GDC-0941-340 mg + Fulvestrant (Arm A); Participants will receive fulvestrant 500 milligrams (mg) as 2 intramuscular (IM) injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle and GDC-0941 340 mg once daily (QD) orally starting on Day 15 of Cycle 1, each cycle of 28 days. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.	Drug: Fulvestrant; Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0941; Participants will receive GDC-0941 260 mg (Part II) or 340 mg (Part I) QD orally from Day 1 or Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.
PLACEBO_COMPARATOR: GDC-0948 or GDC-0980 Matching Placebo + Fulvestrant (Arm C); Participants will be randomized in 1:1 ratio to receive GDC-0948 matching placebo or GDC-0980 matching placebo with fulvestrant. Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle and GDC-0948 or GDC-0980 matching placebo QD orally starting on Day 15 of Cycle 1, each cycle of 28 days. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.	Drug: Fulvestrant; Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0941 Matching Placebo; Participants will receive GDC-0941 matching placebo QD orally from Day 1 or Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0980 Matching Placebo; Participants will receive GDC-0980 matching placebo QD orally from Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.
EXPERIMENTAL: GDC-0980-30 mg + Fulvestrant (Arm B); Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle and GDC-0980 30 mg QD orally starting on Day 15 of Cycle 1, each cycle of 28 days. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.	Drug: Fulvestrant; Participants will receive fulvestrant 500 mg as 2 IM injections of 250 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle, each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.; Drug: GDC-0980; Participants will receive GDC-0980 30 mg (Part I) QD orally from Day 15 of Cycle 1 until disease progression, intolerable toxicity, elective withdrawal from the study, study completion or termination.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival as Assessed by the Investigator Per modified RECIST v 1.1	From Screening to up to approximately 5 years (assessed at Screening, after 8, 16, 24 and 32 weeks of treatment, every 12 weeks thereafter until disease progression or initiation of other anti-cancer therapy)
Percentage of Participants with Adverse Events	Baseline to up to 30 days after the last dose of study drug (Approximately 5 years)

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants with Objective Tumor Response (Complete Response [CR] or Partial Response [PR] as Assessed by the Investigator Per Modified RECIST v 1.1	From Screening to up to approximately 5 years (assessed at Screening, after 8, 16, 24 and 32 weeks of treatment, every 12 weeks thereafter until disease progression or initiation of other anti-cancer therapy)
Percentage of Participants with Clinical Benefit Response Defined as PR, CR, or SD Per Modified RECIST v 1.1	From Screening to up to approximately 5 years (assessed at Screening, after 8, 16, 24 and 32 weeks of treatment, every 12 weeks thereafter until disease progression or initiation of other anti-cancer therapy)
Duration of Confirmed Objective Response as Assessed by the investigator Per Modified RECIST v 1.1	From Screening to up to approximately 5 years (assessed at Screening, after 8, 16, 24 and 32 weeks of treatment, every 12 weeks thereafter until disease progression or initiation of other anti-cancer therapy)
Percentage of Participants with PIK3CA Mutant Tumors	Baseline
Time to Maximum Plasma Concentration (Tmax) of GDC-0941 and GDC-0948	Part 1:0-4 hour (hr) predose (PrD), 1,2,4 hr postdose (PoD) on Day 15 of Cycles 1 & 2, PrD on Cycle 1 Day 16, 0-4 hr PrD & 2 hr PoD on Cycle 6 Day 1; Part II:0-4 hr PrD, 2 hr PoD on Day 1 of Cycles 1 & 6, 0-4 hr PrD, 1, 2, 4 hr PoD on Cycle 2 Day 1
Maximum Plasma Concentration (Cmax) of GDC-0941 and GDC-0948	Part 1:0-4 hr PrD, 1,2,4 hr PoD on Day 15 of Cycles 1 & 2, PrD on Cycle 1 Day 16, 0-4 hr PrD & 2 hr PoD on Cycle 6 Day 1; Part II:0-4 hr PrD, 2 hr PoD on Day 1 of Cycles 1 & 6, 0-4 hr PrD, 1, 2, 4 hr PoD on Cycle 2 Day 1
Area Under the Concentration Time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of GDC-0941 and GDC-0948	Part 1:0-4 hr PrD, 1,2,4 hr PoD on Day 15 of Cycles 1 & 2, PrD on Cycle 1 Day 16, 0-4 hr PrD & 2 hr PoD on Cycle 6 Day 1; Part II:0-4 hr PrD, 2 hr PoD on Day 1 of Cycles 1 & 6, 0-4 hr PrD, 1, 2, 4 hr PoD on Cycle 2 Day 1

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Gallia Levy, M.D., Ph.D., Genentech, Inc.

Publications and helpful links

General Publications

• Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016 Jun;17(6):811-821. doi: 10.1016/S1470-2045(16)00106-6. Epub 2016 May 4.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): April 1, 2016
• Study Completion (ACTUAL): April 1, 2016

Study Registration Dates

• First Submitted: September 8, 2011
• First Submitted That Met QC Criteria: September 19, 2011
• First Posted (ESTIMATE): September 21, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: GDC4950g; GO00769 (OTHER: Hoffmann-La Roche); 2010-023763-17 (EUDRACT_NUMBER)