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

Primary Purpose

Breast Cancer, Solid Tumor

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Inavolisib

Fulvestrant

Letrozole

Palbociclib

Metformin

Trastuzumab

Pertuzumab

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring PIK3CA mutant, Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 (Inavolisib):

- 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 Arm D:

- Prior treatment with CDK4/6 inhibitor

Stage II Arm G:

Female participants with locally advanced or metastatic PIK3CA-mutant HER2+ breast cancer
Left ventricular ejection fraction 50% or greater

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:

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
Any active infection that could impact patient safety or serious infection requiring intravenous antibiotics
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

Stage II Arm G only:

Current uncontrolled hypertension or unstable angina
History of congestive heart failure, serious cardiac arrhythmia, or recent myocardial infarction
Prior ejection fraction decrease on trastuzumab
Prior cumulative doxorubicin greater than 360 mg/m2
Symptomatic active lung disease
History of significant toxicity related to trastuzumab and/or pertuzumab requiring discontinuation of treatment

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Arm Label

Stage I Arm A: Inavolisib Single Agent

Stage I Arm B: Inavolisib + Palbociclib + Letrozole

Stage I Arm C: Inavolisib + Letrozole

Stage II Arm B: Inavolisib + Palbociclib + Letrozole

Stage II Arm C: Inavolisib + Letrozole

Stage II Arm D: Inavolisib + Fulvestrant

Stage II Arm E: Inavolisib + Palbociclib + Fulvestrant

Stage II Arm F: Inavolisib + Palbociclib + Fulvestrant + Metformin

Stage II Arm G: Inavolisib + Trastuzumab + Pertuzumab

Arm Description

Participants will receive inavolisib in escalating dose levels with starting dose of 6 milligrams (mg). Participants will receive single dose of inavolisib 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.

Participants will receive inavolisib 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.

Participants will receive inavolisib in escalating dose levels along with letrozole on Days 1-28 of each 28-day cycle. The starting dose of inavolisib 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.

Participants will receive inavolisib 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 inavolisib 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.

Participants will receive inavolisib in combination with letrozole on Days 1-28 of each 28-day cycle. Dose of inavolisib 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.

Participants will receive inavolisib 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 inavolisib 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.

Participants will receive inavolisib (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 inavolisib 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.

Participants will receive inavolisib (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 inavolisib 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.

Participants will receive inavolisib in combination with trastuzumab and pertuzumab (Days 1-21). Dose of inavolisib will be determined from the results of Stage I Arm A. Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

Outcomes

Primary Outcome Measures

Stage 1: Percentage of Participants With Dose Limiting Toxicities

Recommended Phase II Dose of Inavolisib

Percentage of Participants With Adverse Events and Serious Adverse Events

Secondary Outcome Measures

Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of Inavolisib

AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib

Half-Life of Inavolisib

Maximum Plasma Concentration (Cmax) of Inavolisib

Minimum Plasma Concentration (Cmin) of Inavolisib

Time to Cmax (tmax) of Inavolisib

Apparent Clearance (CL/F) of Inavolisib

Accumulation Ratio (AR) of Inavolisib at Steady-State

AUC of Palbociclib

Cmax of Palbociclib

AUC of Letrozole

Cmax of Letrozole

AUC of Fulvestrant

Cmax of Fulvestrant

Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (v1.1)

Duration of Response, as Assessed by RECIST v1.1

Percentage of Participants With Clinical Benefit as Assessed by RECIST v1.1

Progression Free Survival (PFS) as Assessed by RECIST v1.1

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 Inavolisib Treatment

AUC of Pertuzumab

Cmax of Pertuzumab

AUC of Trastuzumab

Cmax of Trastuzumab

Full Information

NCT ID

NCT03006172

First Posted

December 22, 2016

Last Updated

October 18, 2023

Sponsor

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03006172

Brief Title

To Evaluate the Safety, Tolerability, and Pharmacokinetics of Inavolisib 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 Breast Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 13, 2016 (Actual)

Primary Completion Date

November 30, 2024 (Anticipated)

Study Completion Date

November 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Genentech, Inc.

4. Oversight

5. Study Description

Brief Summary

This is an open-label, multicenter, Phase I study designed to evaluate the safety, tolerability, and pharmacokinetics of inavolisib 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: inavolisib as a single agent (Arm A), inavolisib in combination with palbociclib and letrozole (Arm B), inavolisib in combination with letrozole (Arm C), inavolisib in combination with fulvestrant (Arm D), inavolisib in combination with palbociclib and fulvestrant (Arm E), inavolisib in combination with palbociclib, fulvestrant, and metformin (Arm F), and inavolisib in combination with trastuzumab and pertuzumab (and letrozole or fulvestrant, if applicable (Arm G)).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer, Solid Tumor

Keywords

PIK3CA mutant, Breast Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

256 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Stage I Arm A: Inavolisib Single Agent

Arm Type

Experimental

Arm Description

Arm Title

Stage I Arm B: Inavolisib + Palbociclib + Letrozole

Arm Type

Experimental

Arm Description

Arm Title

Stage I Arm C: Inavolisib + Letrozole

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm B: Inavolisib + Palbociclib + Letrozole

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm C: Inavolisib + Letrozole

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm D: Inavolisib + Fulvestrant

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm E: Inavolisib + Palbociclib + Fulvestrant

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm F: Inavolisib + Palbociclib + Fulvestrant + Metformin

Arm Type

Experimental

Arm Description

Arm Title

Stage II Arm G: Inavolisib + Trastuzumab + Pertuzumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Inavolisib

Other Intervention Name(s)

RO7113755, GDC-0077

Intervention Description

Participants will receive oral inavolisib once daily on Days 1-28 of each 28-day cycle (Arms A, B, C, D, E, F) or Days 1-21 of each 21-day cycle (Arm G).

Intervention Type

Drug

Intervention Name(s)

Fulvestrant

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Letrozole

Intervention Description

Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.

Intervention Type

Drug

Intervention Name(s)

Palbociclib

Intervention Description

Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

Participants will receive oral metformin once daily, starting on Cycle 1, Day 1, as tolerated.

Intervention Type

Drug

Intervention Name(s)

Trastuzumab

Intervention Description

Participants will receive trastuzumab, administered by IV infusion on Day 1 of each 21-day cycle, at a loading dose of 8 mg/kg for Cycle 1 and a dose of 6 mg/kg for subsequent cycles, until disease progression or unacceptable toxicity.

Intervention Type

Drug

Intervention Name(s)

Pertuzumab

Intervention Description

Participants will receive pertuzumab, administered by IV infusion on Day 1 of each 21-day cycle, at a loading dose of 840 mg for Cycle 1 and a dose of 420 mg for subsequent cycles, until disease progression or unacceptable toxicity.

Primary Outcome Measure Information:

Title

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)

Title

Recommended Phase II Dose of Inavolisib

Time Frame

Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)

Title

Percentage of Participants With Adverse Events and Serious Adverse Events

Time Frame

Day 1 up to 6 years

Secondary Outcome Measure Information:

Title

Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of Inavolisib

Time Frame

Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to end of study (EOS; up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)

Title

AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib

Time Frame