Clinical Trials /

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

NCT03006172

Description:

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).

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: GO39374
  • SECONDARY ID: 2016-003022-17
  • NCT ID: NCT03006172

Conditions

  • Breast Cancer
  • Solid Tumor

Interventions

DrugSynonymsArms
GDC-0077RO7113755Stage I Arm A: GDC-0077 Single Agent
FulvestrantStage II Arm D: GDC-0077 + Fulvestrant
LetrozoleStage I Arm B: GDC-0077 + Palbociclib + Letrozole
PalbociclibStage I Arm B: GDC-0077 + Palbociclib + Letrozole
MetforminStage II Arm F: GDC-0077+Palbociclib+Fulvestrant+Metformin

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).

Trial Arms

NameTypeDescriptionInterventions
Stage I Arm A: GDC-0077 Single AgentExperimentalParticipants 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.
  • GDC-0077
Stage I Arm B: GDC-0077 + Palbociclib + LetrozoleExperimentalParticipants 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.
  • GDC-0077
  • Letrozole
  • Palbociclib
Stage I Arm C: GDC-0077 + LetrozoleExperimentalParticipants 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.
  • GDC-0077
  • Letrozole
Stage II Arm B: GDC-0077 + Palbociclib + LetrozoleExperimentalParticipants 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.
  • GDC-0077
  • Letrozole
  • Palbociclib
Stage II Arm C: GDC-0077 + LetrozoleExperimentalParticipants 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.
  • GDC-0077
  • Letrozole
Stage II Arm D: GDC-0077 + FulvestrantExperimentalParticipants 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.
  • GDC-0077
  • Fulvestrant
Stage II Arm E: GDC-0077 + Palbociclib + FulvestrantExperimentalParticipants 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.
  • GDC-0077
  • Fulvestrant
  • Palbociclib
Stage II Arm F: GDC-0077+Palbociclib+Fulvestrant+MetforminExperimentalParticipants 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.
  • GDC-0077
  • Fulvestrant
  • Palbociclib
  • Metformin

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:AUC of Fulvestrant
Time Frame:Cycle 1 Day 2 up to EOS (up to approximately 5 years); Cycle length=28 days.
Safety Issue:
Description:
Measure:Cmax of Fulvestrant
Time Frame:Cycle 1 Day 2 up to EOS (up to approximately 5 years); Cycle length=28 days.
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Genentech, Inc.

Last Updated

December 26, 2019