Clinical Trial - NCT03006172

To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer

Recruiting

Sponsor: Genentech, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03006172

Protocol Info

Short Description: Phase I of GDC-0077 in PIK3CA-Mutant Solid Tumors
Long Description: A Phase I, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0077 as a Single Agent in Patients with Locally Advanced or Metastatic PIK3CA-Mutant Solid Tumors and in Combination with Endocrine and Targeted Therapies in Patients with Locally Advanced or Metastatic PIK3CA-Mutant Hormone-Receptor Positive Breast Cancer
MGH Status: Open
Sponsor: Genentech
Disease Program: Breast

Next Steps


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Purpose

This is an open-label, multicenter, Phase I study designed to evaluate the safety, tolerability, and pharmacokinetics of GDC-0077 administered orally as a single agent in participants with locally advanced or metastatic Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA)-mutant solid tumors, including breast cancer, and in combination with standard-of-care endocrine and targeted therapies for the treatment of locally advanced or metastatic PIK3CA-mutant hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Participants will be enrolled in two stages: a dose-escalation stage (Stage I) and an expansion stage (Stage II). Participants will be assigned to one of six regimens: GDC-0077 as a single agent (Arm A), GDC-0077 in combination with palbociclib and letrozole (Arm B), GDC-0077 in combination with letrozole (Arm C), GDC-0077 in combination with fulvestrant (Arm D), GDC-0077 in combination with palbociclib and fulvestrant (Arm E), and GDC-0077 in combination with palbociclib, fulvestrant, and metformin (Arm F).
Condition Title Intervention Phase
Breast Cancer Solid Tumor GDC-0077 Fulvestrant Letrozole Palbociclib Metformin Phase 1
Study Type Interventional
Official Title A Phase I, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0077 as a Single Agent in Patients With Locally Advanced or Metastatic PIK3CA-Mutant Solid Tumors and in Combination With Endocrine and Targeted Therapies in Patients With Locally Advanced or Metastatic PIK3CA-Mutant Hormone-Receptor Positive Breast Cancer

Primary Outcome Measures

Stage 1: Percentage of Participants With Dose Limiting Toxicities [Time Frame: Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)] [Designated as safety issue: ]

Recommended Phase II Dose of GDC-0077 [Time Frame: Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)] [Designated as safety issue: ]

Percentage of Participants With Adverse Events and Serious Adverse Events [Time Frame: Day 1 up to 5 years] [Designated as safety issue: ]


Secondary Outcome Measures

Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to end of study (EOS; up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

AUC from Time Zero to Dosing Interval (AUC0-tau) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Half-Life of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Maximum Plasma Concentration (Cmax) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Minimum Plasma Concentration (Cmin) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Time to Cmax (tmax) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Apparent Clearance (CL/F) of GDC-0077 [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

Accumulation Ratio (AR) of GDC-0077 at Steady-State [Time Frame: Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)] [Designated as safety issue: ]

AUC of Palbociclib [Time Frame: Predose (0-2 hours before GDC-0077) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days] [Designated as safety issue: ]

Cmax of Palbociclib [Time Frame: Predose (0-2 hours before GDC-0077) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days] [Designated as safety issue: ]

AUC of Letrozole [Time Frame: Predose (0-2 hours before GDC-0077 dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days] [Designated as safety issue: ]

Cmax of Letrozole [Time Frame: Predose (0-2 hours before GDC-0077 dosing) on Cycle 1 Day 1 up to EOS (up to approximately 5 years); Cycle length=28 days] [Designated as safety issue: ]

AUC of Fulvestrant [Time Frame: Cycle 1 Day 2 up to EOS (up to approximately 5 years); Cycle length=28 days.] [Designated as safety issue: ]

Cmax of Fulvestrant [Time Frame: Cycle 1 Day 2 up to EOS (up to approximately 5 years); Cycle length=28 days.] [Designated as safety issue: ]

Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (v1.1) [Time Frame: Baseline up to occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions >/=4 weeks apart (up to approximately 5 years)] [Designated as safety issue: ]

Duration of Response, as Assessed by RECIST v1.1 [Time Frame: From first occurrence of a documented objective response (CR or PR) to disease progression or death from any cause, whichever occurs first (up to approximately 5 years)] [Designated as safety issue: ]

Percentage of Participants With Clinical Benefit as Assessed by RECIST v1.1 [Time Frame: Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 5 years)] [Designated as safety issue: ]

Progression Free Survival (PFS) as Assessed by RECIST v1.1 [Time Frame: Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 5 years)] [Designated as safety issue: ]

Change in Maximum Standard Uptake Value (SUV) of Tumor Regions of Interest (as assessed by [18] F-fluorodeoxyglucose-positron emission tomography) From Baseline to Approximately 2 Weeks of GDC-0077 Treatment [Time Frame: Baseline, Week 2] [Designated as safety issue: ]

Estimated Enrollment: 236
Study Start Date: December 2016
Estimated Study Completion Date: December 2021
Estimated Primary Completion Date: December 2021
Arms Assigned Interventions

Experimental:Stage I Arm A: GDC-0077 Single Agent

Participants will receive GDC-0077 in escalating dose levels with starting dose of 6 milligrams (mg). Participants will receive single dose of GDC-0077 on Day 1 of Cycle 1 followed by once daily from Day 8 of Cycle 1. (Cycle length: 35 days for Cycle 1 and 28 days for all other cycles). Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.
Drug:GDC-0077
Participants will receive oral GDC-0077 once daily on Days 1-28 of each cycle.

Experimental:Stage I Arm B: GDC-0077 + Palbociclib + Letrozole

Participants will receive GDC-0077 in escalating dose levels (starting dose 3 mg) on Days 1-28, palbociclib on Days 1−21, and letrozole on Days 1−28 of each 28-day cycle. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.
Drug:Palbociclib
Participants will receive once daily oral doses of palbociclib 125 mg on Days 1−21 of each cycle.

Experimental:Stage I Arm C: GDC-0077 + Letrozole

Participants will receive GDC-0077 in escalating dose levels along with letrozole on Days 1−28 of each 28-day cycle. The starting dose of GDC-0077 will not exceed the starting dose in Stage I Arm A. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

Experimental:Stage II Arm B: GDC-0077 + Palbociclib + Letrozole

Participants will receive GDC-0077 on Days 1-28 in combination with palbociclib on Days 1-21 and letrozole on Days 1-28 of each 28-day cycle. Dose of GDC-0077 will be decided based on the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

Experimental:Stage II Arm C: GDC-0077 + Letrozole

Participants will receive GDC-0077 in combination with letrozole on Days 1-28 of each 28-day cycle. Dose of GDC-0077 will be decided based on the results of Stage I Arm C. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

Experimental:Stage II Arm D: GDC-0077 + Fulvestrant

Participants will receive GDC-0077 on Days 1-28 in combination with fulvestrant on Day 1 and 15 of Cycle 1 and then on Day 1 from Cycle 2 (cycle length: 28 days). Dose of GDC-0077 will be decided based on the results of Stage I Arm C. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.
Drug:Fulvestrant
Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1 and 15 of Cycle 1. For subsequent cycles, participants will receive fulvestrant intramuscularly on Day 1 of each cycle.

Experimental:Stage II Arm E: GDC-0077 + Palbociclib + Fulvestrant

Participants will receive GDC-0077 (Days 1-28) in combination with palbociclib (Days 1-21) and fulvestrant (Days 1 and 15 of Cycle 1; Day 1 for subsequent cycles)(Cycle = 28 days). Dose of GDC-0077 will be determined from the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

Experimental:Stage II Arm F: GDC-0077+Palbociclib+Fulvestrant+Metformin

Participants will receive GDC-0077 (Days 1-28) in combination with palbociclib (Days 1-21), fulvestrant (Days 1 and 15 of Cycle 1; Day 1 for subsequent cycles) and metformin (Days 1-28)(Cycle = 28 days). Dose of GDC-0077 will be determined from the results of Stage I Arm B. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.
Drug:Metformin
Participants will receive oral metformin once daily, starting on Cycle 1, Day 1, as tolerated.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

  • Evaluable or measurable disease per RECIST, Version 1.1 (measurable disease only for Arm D)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy of greater than or equal to (≥) 12 weeks
  • Adequate hematologic and organ function, including blood counts, liver and kidney function

Stage I Arm A (GDC-0077):

  • Locally advanced, recurrent, or metastatic, PIK3CA mutant, incurable solid tumor malignancy, including breast cancer

Stages I and II, Arms B and C:

  • Postmenopausal female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer

Stage II, Arms D, E, or F:

  • Female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer

Stage II Arms D:

  • Prior treatment with CDK4/6 inhibitor

Stages I and II:

  • All participants must provide tumor tissue from the primary or metastatic tumor site obtained from a prior or new biopsy or surgical procedure for detection of PIK3CA mutation by central laboratory test.

Exclusion Criteria:

  • Inflammatory or metaplastic breast cancer
  • History of leptomeningeal disease
  • Type 1 or 2 diabetes requiring anti-hyperglycemic medication
  • Inability or unwillingness to swallow pills
  • Malabsorption syndrome or other condition that would interfere with enteral absorption
  • Known and untreated, or active central nervous system metastases
  • Uncontrolled pleural effusion or ascites
  • History of other malignancy within 5 years, except for treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
  • History of or active ventricular dysrhythmias or congestive heart failure requiring medication or symptomatic coronary heart disease
  • Congenital long QT syndrome, prolonged QT interval, or family history of sudden unexplained death or long QT syndrome

Stage II:

  • Stage II Arms B, C, D, and E only: Prior treatment with >1 chemotherapy regimen for metastatic disease
  • Prior treatment with PI3K inhibitor
  • History of significant toxicity related to mTOR inhibitor requiring treatment discontinuation
  • Stage II Arms B and E only: prior CDK4/6 inhibitor treatment

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03006172

Locations

  • United States, Massachusetts
    • Massachusetts General Hospital. Boston, Massachusetts, United States, 02114
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, New York
    • Columbia University Medical Center New York, New York, United States, 10032
    • Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065
  • United States, Tennessee
    • Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203
  • Canada, Ontario
    • Philippe Bedard Clinic Toronto Toronto, Ontario, Canada, M5G 1L7
  • France,
    • Institut Bergonie Bordeaux, , France, 33076
    • Institut Gustave Roussy Villejuif, , France, 94805
  • Spain,
    • Hospital Universitari Vall d'Hebron Barcelona, , Spain, 08035
    • Hospital Clinico Universitario de Valencia Valencia, , Spain, 46010
  • United Kingdom,
    • Barts and the London NHS Trust. London, , United Kingdom, EC1A 7BE
    • Royal Marsden Hospital - London London, , United Kingdom, SW3 6JJ
    • Royal Marsden Hospital - Surrey Surrey, , United Kingdom, SM2 5PT

Sponsors and Collaborators

Genentech, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03006172
Other Study ID Numbers: 2016-003022-17
Study First Received:
Last Updated:
Health Authority:

Additional relevant MeSH terms:

Breast Neoplasms

Metformin

Letrozole

Fulvestrant

Palbociclib

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019