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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03006172
• Other study ID #: GO39374
• Secondary ID: 2016-003022-1720
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 13, 2016
• Est. completion date: November 30, 2024

Study information

• Verified date: March 2024
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 256
• Est. completion date: November 30, 2024
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Solid Tumor

Intervention

Drug:
• Inavolisib
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).
• 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.
• Letrozole
Participants will receive once daily oral doses of letrozole 2.5 mg on Days 1-28 of each cycle.
• Palbociclib
Participants will receive once daily oral doses of palbociclib 125 mg on Days 1-21 of each cycle.
• Metformin
Participants will receive oral metformin once daily, starting on Cycle 1, Day 1, as tolerated.
• Trastuzumab
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.
• Pertuzumab
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.

Locations

Country	Name	City	State
Canada	Philippe Bedard Clinic Toronto	Toronto	Ontario
France	Institut Bergonie	Bordeaux
France	Institut Gustave Roussy	Villejuif
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Clinico Universitario de Valencia	Valencia
United Kingdom	Barts and the London NHS Trust.	London
United Kingdom	Royal Marsden Hospital - London	London
United Kingdom	Royal Marsden Hospital - Surrey	Surrey
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital.	Boston	Massachusetts
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Countries where clinical trial is conducted

United States,  Canada,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stage 1: Percentage of Participants With Dose Limiting Toxicities		Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)
Primary	Recommended Phase II Dose of Inavolisib		Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)
Primary	Percentage of Participants With Adverse Events and Serious Adverse Events		Day 1 up to 6 years
Secondary	Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of Inavolisib		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)
Secondary	AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Half-Life of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Maximum Plasma Concentration (Cmax) of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Minimum Plasma Concentration (Cmin) of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Time to Cmax (tmax) of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Apparent Clearance (CL/F) of Inavolisib		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	Accumulation Ratio (AR) of Inavolisib at Steady-State		Predose (0-2 hours before dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days (Cycle 1 of Stage 1 Arm A=35 days)
Secondary	AUC of Palbociclib		Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days
Secondary	Cmax of Palbociclib		Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days
Secondary	AUC of Letrozole		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
Secondary	Cmax of Letrozole		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
Secondary	AUC of Fulvestrant		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
Secondary	Cmax of Fulvestrant		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
Secondary	Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (v1.1)		Baseline up to occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions >/=4 weeks apart (up to approximately 6 years)
Secondary	Duration of Response, as Assessed by RECIST v1.1		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 6 years)
Secondary	Percentage of Participants With Clinical Benefit as Assessed by RECIST v1.1		Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	Progression Free Survival (PFS) as Assessed by RECIST v1.1		Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	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		Baseline, Week 2
Secondary	AUC of Pertuzumab		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
Secondary	Cmax of Pertuzumab		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
Secondary	AUC of Trastuzumab		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
Secondary	Cmax of Trastuzumab		Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days