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

Genentech

Status and phase: Active, not recruiting; Phase 1

Conditions: Solid Tumor; Breast Cancer

Treatments: Drug: Inavolisib; Drug: Palbociclib; Drug: Letrozole; Drug: Trastuzumab; Drug: Fulvestrant; Drug: Metformin; Drug: Pertuzumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03006172

2016-003022-17 (EudraCT Number)

GO39374

2023-508124-36-00 (Other Identifier)

Details and patient eligibility

About

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)).

Enrollment: 256 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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256 participants in 9 patient groups

Stage I Arm A: Inavolisib Single Agent

Experimental group

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.

Treatment:

Drug: Inavolisib

Stage I Arm B: Inavolisib + Palbociclib + Letrozole

Experimental group

Description:

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.

Treatment:

Drug: Palbociclib

Drug: Letrozole

Drug: Inavolisib

Stage I Arm C: Inavolisib + Letrozole

Experimental group

Description:

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.

Treatment:

Drug: Letrozole

Drug: Inavolisib

Stage II Arm B: Inavolisib + Palbociclib + Letrozole

Experimental group

Description:

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.

Treatment:

Drug: Palbociclib

Drug: Letrozole

Drug: Inavolisib

Stage II Arm C: Inavolisib + Letrozole

Experimental group

Description:

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.

Treatment:

Drug: Letrozole

Drug: Inavolisib

Stage II Arm D: Inavolisib + Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Inavolisib

Stage II Arm E: Inavolisib + Palbociclib + Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Palbociclib

Drug: Inavolisib

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

Experimental group

Description:

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.

Treatment:

Drug: Metformin

Drug: Fulvestrant

Drug: Palbociclib

Drug: Inavolisib

Stage II Arm G: Inavolisib + Trastuzumab + Pertuzumab

Experimental group

Description:

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.

Treatment:

Drug: Pertuzumab

Drug: Trastuzumab

Drug: Inavolisib