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

Recruiting

Sponsor: Genentech, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03006172

Protocol Info

Short Description: Phase I of GDC-0077 in PIK3CA-Mutant Solid Tumors
Long Description: 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
MGH Status: Open
Sponsor: Genentech
Disease Program: Breast

Next Steps


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Purpose

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)).
Condition Title Intervention Phase
Breast Cancer Solid Tumor Inavolisib Fulvestrant Letrozole Palbociclib Metformin Trastuzumab Pertuzumab Phase 1
Study Type Interventional
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

Primary Outcome Measures

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

Percentage of Participants With Adverse Events and Serious Adverse Events [Time Frame: Day 1 up to 6 years] [Designated as safety issue: ]


Secondary Outcome Measures

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)] [Designated as safety issue: ]

AUC from Time Zero to Dosing Interval (AUC0-tau) of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Half-Life of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Maximum Plasma Concentration (Cmax) of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Minimum Plasma Concentration (Cmin) of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Time to Cmax (tmax) of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Apparent Clearance (CL/F) of Inavolisib [Time Frame: 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)] [Designated as safety issue: ]

Accumulation Ratio (AR) of Inavolisib at Steady-State [Time Frame: 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)] [Designated as safety issue: ]

AUC of Palbociclib [Time Frame: Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days] [Designated as safety issue: ]

Cmax of Palbociclib [Time Frame: Predose (0-2 hours before inavolisib) dosing) on Cycle 1 Day 1 up to Cycle 6; Cycle length=28 days] [Designated as safety issue: ]

AUC of Letrozole [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days] [Designated as safety issue: ]

Cmax of Letrozole [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days] [Designated as safety issue: ]

AUC of Fulvestrant [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days] [Designated as safety issue: ]

Cmax of Fulvestrant [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=28 days] [Designated as safety issue: ]

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 6 years)] [Designated as safety issue: ]

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 6 years)] [Designated as safety issue: ]

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 6 years)] [Designated as safety issue: ]

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 6 years)] [Designated as safety issue: ]

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 [Time Frame: Baseline, Week 2] [Designated as safety issue: ]

AUC of Pertuzumab [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days] [Designated as safety issue: ]

Cmax of Pertuzumab [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days] [Designated as safety issue: ]

AUC of Trastuzumab [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days] [Designated as safety issue: ]

Cmax of Trastuzumab [Time Frame: Predose (0-2 hours before inavolisib dosing) on Cycle 1 Day 1 up to EOS (up to approximately 6 years); Cycle length=21 days] [Designated as safety issue: ]

Estimated Enrollment: 256
Study Start Date: December 2016
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: November 2022
Arms Assigned Interventions

Experimental:Stage I Arm A: Inavolisib Single Agent

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.
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).

Experimental:Stage I Arm B: Inavolisib + Palbociclib + Letrozole

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

Experimental:Stage I Arm C: Inavolisib + Letrozole

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.

Experimental:Stage II Arm B: Inavolisib + Palbociclib + Letrozole

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.

Experimental:Stage II Arm C: Inavolisib + Letrozole

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.

Experimental:Stage II Arm D: Inavolisib + Fulvestrant

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.
Drug: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.

Experimental:Stage II Arm E: Inavolisib + Palbociclib + Fulvestrant

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.

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

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

Experimental:Stage II Arm G: Inavolisib + Trastuzumab + Pertuzumab

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.
Drug: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.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03006172

Locations

  • United States, Massachusetts
    • Massachusetts General Hospital. Boston, Massachusetts, United States, 02114
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, New York
    • Columbia University Medical Center New York, New York, United States, 10032
    • Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065
  • United States, Tennessee
    • Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203
  • Canada, Ontario
    • Philippe Bedard Clinic Toronto Toronto, Ontario, Canada, M5G 1L7
  • France,
    • Institut Bergonie Bordeaux, , France, 33076
    • Institut Gustave Roussy Villejuif, , France, 94805
  • Spain,
    • Hospital Universitari Vall d'Hebron Barcelona, , Spain, 08035
    • Hospital Clinico Universitario de Valencia Valencia, , Spain, 46010
  • United Kingdom,
    • Barts and the London NHS Trust. London, , United Kingdom, EC1A 7BE
    • Royal Marsden Hospital - London London, , United Kingdom, SW3 6JJ
    • Royal Marsden Hospital - Surrey Surrey, , United Kingdom, SM2 5PT

Sponsors and Collaborators

Genentech, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03006172
Other Study ID Numbers: 2016-003022-17
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Genentech, Inc.:

PIK3CA mutant, Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms

Metformin

Trastuzumab

Pertuzumab

Letrozole

Fulvestrant

Palbociclib

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on June 10, 2021