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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

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ClinicalTrials.gov Identifier: NCT03006172
Recruitment Status : Recruiting
First Posted : December 30, 2016
Last Update Posted : March 23, 2021
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

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)).

Condition or disease Intervention/treatment Phase
Breast Cancer Solid Tumor Drug: Inavolisib Drug: Fulvestrant Drug: Letrozole Drug: Palbociclib Drug: Metformin Drug: Trastuzumab Drug: Pertuzumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 256 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 13, 2016
Estimated Primary Completion Date : November 30, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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).
Other Name: RO7113755, GDC-0077

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: 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).
Other Name: RO7113755, GDC-0077

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

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.
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).
Other Name: RO7113755, GDC-0077

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

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.
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).
Other Name: RO7113755, GDC-0077

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

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

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.
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).
Other Name: RO7113755, GDC-0077

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

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: 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).
Other Name: RO7113755, GDC-0077

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.
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).
Other Name: RO7113755, GDC-0077

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.

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

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: 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).
Other Name: RO7113755, GDC-0077

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.

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

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: 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).
Other Name: RO7113755, GDC-0077

Drug: 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.

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.




Primary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. Percentage of Participants With Adverse Events and Serious Adverse Events [ Time Frame: Day 1 up to 6 years ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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) ]
  16. 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) ]
  17. 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) ]
  18. 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) ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03006172


Contacts
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Contact: Reference Study ID Number: GO39374 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
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United States, Massachusetts
Massachusetts General Hospital. Recruiting
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Canada, Ontario
Philippe Bedard Clinic Toronto Recruiting
Toronto, Ontario, Canada, M5G 1L7
France
Institut Bergonie Recruiting
Bordeaux, France, 33076
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Spain
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Hospital Clinico Universitario de Valencia Recruiting
Valencia, Spain, 46010
United Kingdom
Barts and the London NHS Trust. Active, not recruiting
London, United Kingdom, EC1A 7BE
Royal Marsden Hospital - London Recruiting
London, United Kingdom, SW3 6JJ
Royal Marsden Hospital - Surrey Recruiting
Surrey, United Kingdom, SM2 5PT
Sponsors and Collaborators
Genentech, Inc.
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT03006172    
Other Study ID Numbers: GO39374
2016-003022-17 ( EudraCT Number )
First Posted: December 30, 2016    Key Record Dates
Last Update Posted: March 23, 2021
Last Verified: March 2021
Keywords provided by Genentech, Inc.:
PIK3CA mutant, Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Metformin
Trastuzumab
Pertuzumab
Letrozole
Fulvestrant
Palbociclib
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Protein Kinase Inhibitors