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
patients with locally advanced or metastatic PIK3CA-mutant solid tumors, including breast
cancer, and in combination with standard-of-care endocrine and/or targeted therapies for the
treatment of locally advanced or metastatic PIK3CA-mutant 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 seven 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), GDC-0077 in combination with palbociclib,
fulvestrant, and metformin (Arm F), and GDC-0077 in combination with trastuzumab and
pertuzumab (and letrozole or fulvestrant, if applicable (Arm G)).
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
Interventions
Drug | Synonyms | Arms |
---|
GDC-0077 | RO7113755 | Stage I Arm A: GDC-0077 Single Agent |
Fulvestrant | | Stage II Arm D: GDC-0077 + Fulvestrant |
Letrozole | | Stage I Arm B: GDC-0077 + Palbociclib + Letrozole |
Palbociclib | | Stage I Arm B: GDC-0077 + Palbociclib + Letrozole |
Metformin | | Stage 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
Name | Type | Description | Interventions |
---|
Stage I Arm A: GDC-0077 Single Agent | Experimental | 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. | |
Stage I Arm B: GDC-0077 + Palbociclib + Letrozole | Experimental | 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. | - GDC-0077
- Letrozole
- Palbociclib
|
Stage I Arm C: GDC-0077 + Letrozole | Experimental | 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. | |
Stage II Arm B: GDC-0077 + Palbociclib + Letrozole | Experimental | 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. | - GDC-0077
- Letrozole
- Palbociclib
|
Stage II Arm C: GDC-0077 + Letrozole | Experimental | 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. | |
Stage II Arm D: GDC-0077 + Fulvestrant | Experimental | 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. | |
Stage II Arm E: GDC-0077 + Palbociclib + Fulvestrant | Experimental | 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. | - GDC-0077
- Fulvestrant
- Palbociclib
|
Stage II Arm F: GDC-0077+Palbociclib+Fulvestrant+Metformin | Experimental | 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. | - 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, F:
- Female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast
cancer
Stage II Arm 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 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
August 26, 2020