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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

NCT03006172

Description:

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)).

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: GO39374
  • SECONDARY ID: 2016-003022-17
  • NCT ID: NCT03006172

Conditions

  • Breast Cancer
  • Solid Tumor

Interventions

DrugSynonymsArms
InavolisibRO7113755, GDC-0077Stage I Arm A: Inavolisib Single Agent
FulvestrantStage II Arm D: Inavolisib + Fulvestrant
LetrozoleStage I Arm B: Inavolisib + Palbociclib + Letrozole
PalbociclibStage I Arm B: Inavolisib + Palbociclib + Letrozole
MetforminStage II Arm F: Inavolisib + Palbociclib + Fulvestrant + Metformin
TrastuzumabStage II Arm G: Inavolisib + Trastuzumab + Pertuzumab
PertuzumabStage II Arm G: Inavolisib + Trastuzumab + Pertuzumab

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)).

Trial Arms

NameTypeDescriptionInterventions
Stage I Arm A: Inavolisib Single AgentExperimentalParticipants 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.
  • Inavolisib
Stage I Arm B: Inavolisib + Palbociclib + LetrozoleExperimentalParticipants 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.
  • Inavolisib
  • Letrozole
  • Palbociclib
Stage I Arm C: Inavolisib + LetrozoleExperimentalParticipants 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.
  • Inavolisib
  • Letrozole
Stage II Arm B: Inavolisib + Palbociclib + LetrozoleExperimentalParticipants 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.
  • Inavolisib
  • Letrozole
  • Palbociclib
Stage II Arm C: Inavolisib + LetrozoleExperimentalParticipants 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.
  • Inavolisib
  • Letrozole
Stage II Arm D: Inavolisib + FulvestrantExperimentalParticipants 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.
  • Inavolisib
  • Fulvestrant
Stage II Arm E: Inavolisib + Palbociclib + FulvestrantExperimentalParticipants 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.
  • Inavolisib
  • Fulvestrant
  • Palbociclib
Stage II Arm F: Inavolisib + Palbociclib + Fulvestrant + MetforminExperimentalParticipants 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.
  • Inavolisib
  • Fulvestrant
  • Palbociclib
  • Metformin
Stage II Arm G: Inavolisib + Trastuzumab + PertuzumabExperimentalParticipants 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.
  • Inavolisib
  • Trastuzumab
  • Pertuzumab

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
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
Time Frame:Baseline, Week 2
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Genentech, Inc.

Trial Keywords

  • PIK3CA mutant, Breast Cancer

Last Updated

August 4, 2021