An Open-Label, Phase I/II, Dose-Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- GDC-0032
- Conditions
- Solid Cancers
- Sponsor
- Genentech, Inc.
- Enrollment
- 674
- Locations
- 31
- Primary Endpoint
- Phase I: Time to Reach Cmax (Tmax) of GDC-0032
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is an open-label, multicenter, Phase I/II study to assess the safety, tolerability, and pharmacokinetics of GDC-0032. The Phase I portion will be divided into two stages. During Stage 1, GDC-0032 will be administered every day orally and at escalating doses in participants with locally advanced or metastatic solid tumors. During Stage 2, GDC-0032 will be administered alone or as combination therapy within indication-specific cohorts. In Phase II of the study, the efficacy and safety of the combination GDC-0032 and fulvestrant will be evaluated in post-menopausal female participants with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Phase I (Cohorts A through D, G, H, T, T2 and X): Histologically documented, locally advanced or metastatic solid malignancy or NHL that has progressed or failed to respond to at least one prior regimen and are not candidates for regimens known to provide clinical benefit
- •Phase I (Cohorts E and F): Post-menopausal females with locally advanced or metastatic hormone receptor-positive breast cancer that has progressed or failed to respond to at least one prior endocrine therapy in the adjuvant or metastatic setting
- •Phase I (Cohorts J through S): Post-menopausal females with HER2-negative, hormone-receptor positive breast cancer that has progressed or failed to response to at least one prior endocrine therapy in the adjuvant or metastatic setting
- •Phase II: Post-menopausal female participants with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer
- •Phase I (Cohorts A through S) and Phase II: Evaluable or measurable disease per RECIST version 1.1
- •Phase I (Cohorts T, and T2): Greater than or equal to (\>/=) 1 bi-dimensionally measurable lesion on computed tomography (CT) scan
- •Phase I (Cohort T): Participants with non-Hodgkin's lymphoma, regardless of PIK3CA mutation status
- •Phase 1 (Cohort T2): Participants with diffuse large B-cell lymphoma (DLBCL), regardless of PIK3CA mutation status
- •Phase I (Cohort X): Participants with PIK3CA-mutant tumors and measurable disease per RECIST v1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Screening
Exclusion Criteria
- •Known and untreated, or active central nervous system (CNS) metastases (progressing or requiring treatment)
- •Active congestive heart failure or ventricular arrhythmia requiring medication
- •Participants requiring any daily supplemental oxygen
- •Active inflammatory disease requiring immunosuppressants, including small or large intestinal inflammation such as Crohn's disease or ulcerative colitis
- •Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- •Treatment with chemotherapy less than or equal to (\</=) 3 weeks before study treatment
- •Oral endocrine therapy \</= 2 weeks before study treatment
- •Treatment with investigational drug \</= 3 weeks or 5 half-lives before study treatment
- •Treatment with biologic therapy \</= 3 weeks before study treatment
- •Treatment with kinase inhibitors \</= 2 weeks before study treatment
Arms & Interventions
Phase I, Stage 1: GDC-0032 as Single Agent
Participants with locally advanced or metastatic solid tumors will receive increasing doses of GDC-0032 administered orally daily in 28-day cycles. Dose escalation decisions will be based upon the observed incidence of DLTs.
Intervention: GDC-0032
Phase I, Stage 2: GDC-0032 + Fulvestrant
Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.
Intervention: Fulvestrant
Phase I, Stage 2: GDC-0032 + Fulvestrant
Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.
Intervention: GDC-0032
Phase I, Stage 2: GDC-0032 + Letrozole
Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.
Intervention: GDC-0032
Phase I, Stage 2: GDC-0032 + Letrozole
Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.
Intervention: Letrozole
Phase I, Stage 2: GDC-0032 as Single Agent
Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression.
Intervention: GDC-0032
Phase I, Stage 2: GDC-0032 + Midazolam
Participants (Cohort C) will receive GDC-0032 in combination with midazolam.
Intervention: GDC-0032
Phase I, Stage 2: GDC-0032 + Midazolam
Participants (Cohort C) will receive GDC-0032 in combination with midazolam.
Intervention: Midazolam
Phase II: GDC-0032 + Fulvestrant
Post-menopausal females with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer will receive GDC-0032 in combination with fulvestrant until disease progression.
Intervention: Fulvestrant
Phase II: GDC-0032 + Fulvestrant
Post-menopausal females with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer will receive GDC-0032 in combination with fulvestrant until disease progression.
Intervention: GDC-0032
Outcomes
Primary Outcomes
Phase I: Time to Reach Cmax (Tmax) of GDC-0032
Time Frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr
Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1
Time Frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Phase I Stage 1: Percentage of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)
Time Frame: Baseline up to 35 days of Cycle 1
A DLT is defined as any one of the following toxicities occurring within the DLT Assessment Window (Days 1-35 of Cycle 1 in Stage 1) assessed by the investigator: Grade ≥ 3 non-hematologic, non-hepatic organ system, non-metabolic (hyperglycemia and hyperlipidemia) toxicity, excluding alopecia of any grade, Grade 3 diarrhea, Grade 3 nausea or vomiting; Grade ≥ 4 thrombocytopenia; Grade ≥ 4 neutropenia lasting \> 5 days or accompanied by fever; Fasting Grade ≥ 4 hyperglycemia or ≥ 3 hyperglycemia for ≥ 1 week; Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 2 weeks; Grade ≥ 3 serum bilirubin or hepatic transaminase (ALT or AST); For participants abnormal at baseline: hepatic transaminase ≥ 7.5 × the upper limit of normal (ULN) or total bilirubin ≥ 5 × the ULN or 10 × the ULN or alkaline phosphatase ≥ 10 times the ULN.
Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0
Time Frame: Baseline up to 28 days of Cycle 1
A DLT is defined as any one of the following toxicities occurring within the DLT Assessment Window (Days 1-28 of Cycle 1 in Stage 1) assessed by the investigator: Grade ≥ 3 non-hematologic, non-hepatic organ system, non-metabolic (hyperglycemia and hyperlipidemia) toxicity, excluding alopecia of any grade, Grade 3 diarrhea, Grade 3 nausea or vomiting; Grade ≥ 4 thrombocytopenia; Grade ≥ 4 neutropenia lasting \> 5 days or accompanied by fever; Fasting Grade ≥ 4 hyperglycemia or ≥ 3 hyperglycemia for ≥ 1 week; Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 2 weeks; Grade ≥ 3 serum bilirubin or hepatic transaminase (ALT or AST); For participants abnormal at baseline: hepatic transaminase ≥ 7.5 × ULN or total bilirubin ≥ 5 × the ULN or 10 × the ULN or alkaline phosphatase ≥ 10 times the ULN.
Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1
Time Frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
DOR was defined as the time from the first occurrence of a documented objective response (OR) to progressive disease (PD) or death from any cause (whichever occurred first) as determined by the investigator according to RECIST v1.1. OR=CR+PR. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. Number of participants analyzed signifies the number of responders.
Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032
Time Frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032
Time Frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
Phase I: Terminal Half-life (t1/2) of GDC-0032
Time Frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr
Across All Cohorts (Except Cohorts T and T2): Percentage of Participants With Best Overall Response (BOR) as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time Frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
BOR was defined as having best objective response as complete response (CR) or partial response (PR), as assessed by RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
PFS in Cohort T and T2
Time Frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
PFS in Cohort T was assessed using the 2007 Revised IWG Response Criteria in Malignant Lymphoma while in Cohort T2, it was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma.
Percentage of Participants With BOR in Cohort T and T2
Time Frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
BOR in Cohort T was assessed using the 2007 Revised International Working Group (IWG) Response Criteria in Malignant Lymphoma while in Cohort T2, BOR was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma.
DOR in Cohort T and T2
Time Frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
DOR in Cohort T was assessed using the 2007 Revised IWG Response Criteria in Malignant Lymphoma while in Cohort T2, it was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma. Number of participants analyzed signifies the number of responders.
Secondary Outcomes
- Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade(From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 16 months))
- Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade(From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 67 months))
- Cmax of GDC-0032 Under Fed Conditions(Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr)
- Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone(Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr)
- Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters(Baseline to a maximum of 67 months)
- Cmax of GDC-0032 Under Fasted Conditions(Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr)
- AUC of GDC-0032 Under Fed Conditions(Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr)
- Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade(From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 54 months))
- AUC of GDC-0032 Under Fasted Conditions(Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr)
- Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone(Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr)