Clinical trial NCT03006172: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Breast Cancer
Solid Tumor
Keywords: PIK3CA mutant, Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2016-12-30
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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)).


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 (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

Primary outcomes:
measure: Stage 1: Percentage of Participants With Dose Limiting Toxicities
timeFrame: Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)
measure: Recommended Phase II Dose of Inavolisib
timeFrame: Day 1 up to Day 28 (for Stage 1 Arm A: Day 1 up to Day 35)
measure: Percentage of Participants With Adverse Events and Serious Adverse Events
timeFrame: Day 1 up to 6 years
Secondary outcomes:
measure: Area Under the Concentration Time-Curve (AUC) from Time Zero to Infinity (AUCinf) of Inavolisib
timeFrame: 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)
measure: AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib
timeFrame: 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)
measure: Half-Life of Inavolisib
timeFrame: 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)
measure: Maximum Plasma Concentration (Cmax) of Inavolisib
timeFrame: 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)
measure: Minimum Plasma Concentration (Cmin) of Inavolisib
timeFrame: 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)
measure: Time to Cmax (tmax) of Inavolisib
timeFrame: 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)
measure: Apparent Clearance (CL/F) of Inavolisib
timeFrame: 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)
measure: Accumulation Ratio (AR) of Inavolisib at Steady-State
timeFrame: 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)
measure: AUC of Palbociclib
timeFrame: Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days
measure: Cmax of Palbociclib
timeFrame: Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days
measure: AUC of Letrozole
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
measure: Cmax of Letrozole
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
measure: AUC of Fulvestrant
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
measure: Cmax of Fulvestrant
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days
measure: Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (v1.1)
timeFrame: Baseline up to occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions >/=4 weeks apart (up to approximately 6 years)
measure: Duration of Response, as Assessed by RECIST v1.1
timeFrame: 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)
measure: Percentage of Participants With Clinical Benefit as Assessed by RECIST v1.1
timeFrame: Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
measure: Progression Free Survival (PFS) as Assessed by RECIST v1.1
timeFrame: Baseline up to disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
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 Inavolisib Treatment
timeFrame: Baseline, Week 2
measure: AUC of Pertuzumab
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
measure: Cmax of Pertuzumab
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
measure: AUC of Trastuzumab
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
measure: Cmax of Trastuzumab
timeFrame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Bordeaux
country: France
facility: Institut Bergonie
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Surrey
country: United Kingdom
facility: Royal Marsden Hospital - Surrey
state: Sutton
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: