Non-Hodgkin's Lymphoma, Solid Cancers
Conditions
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.
Interventions
DRUGFulvestrant
Participants will receive fulvestrant 500 milligrams (mg) via intramuscular injection (as per package insert or Summary of Product Characteristics \[SmPC\]) on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent cycle, until disease progression (Cycle length: 28 days).
DRUGGDC-0032
Participants will receive GDC-0032 at escalating (Phase I, Stage 1) or fixed (Phase II and Phase I, Stage 2) doses until disease progression. Cycle 1 may be 35 days in length to allow for a 7-day washout following the initial dose; thereafter, GDC-0032 will be administered orally once daily in 28-day cycles.
DRUGLetrozole
Participants will receive letrozole 2.5 mg orally (as per Package Insert or SmPC) once daily in 28-day cycles until disease progression.
DRUGMidazolam
Participants will receive midazolam 5 mg (as per Package Insert or SmPC) in hydrochloride syrup on Days 1 and 16 of Cycle 1.
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Life expectancy of \>/= 12 weeks * Adequate hematologic and organ function within 28 days prior to initiation of study treatment * Documented willingness to use an effective means of contraception for both men and women while participating in the study
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 * Radiation therapy (other than radiation to bony metastases) as cancer therapy \</= 4 weeks before study treatment * Palliative radiation therapy to bony metastases \</= 2 weeks before study treatment * Major surgery \</= 4 weeks before study treatment * Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the participant at high risk from treatment complications (examples include but are not limited to clinically significant non-healing wound, active bleeding, or ongoing fistula or active tuberculosis infection)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS in Cohort T and T2 | 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. |
| Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0 | 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. |
| Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | 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 | 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: Time to Reach Cmax (Tmax) of GDC-0032 | Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr | — |
| Phase I: Terminal Half-life (t1/2) of GDC-0032 | 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) | 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. |
| Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1 | 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. |
| Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1 | 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). |
| Percentage of Participants With BOR in Cohort T and T2 | 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 | 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. |
| 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator. |
| 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) | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator. |
| Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Baseline to a maximum of 67 months | Laboratory parameters such as fasting glucose, absolute neutrophil count, hemoglobin, platelet count, lymphocytes, serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), leukocytes, fasting triglycerides and fasting cholesterol were assessed. A clinically relevant shift from baseline was defined as a shift from Grade 0, 1, or 2 at baseline to Grade 3 or 4 post baseline. |
| Cmax of GDC-0032 Under Fed Conditions | Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr | For dosing under fed conditions, participant fasted overnight for \>/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032. |
| Cmax of GDC-0032 Under Fasted Conditions | Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr | Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose. |
| AUC of GDC-0032 Under Fed Conditions | Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr | For dosing under fed conditions, participant fasted overnight for \>/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032. |
| AUC of GDC-0032 Under Fasted Conditions | Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr | Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose. |
| 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 | The geometric mean ratio (90% CI) for midazolam+ GDC-0032 relative to midazolam alone was reported. Geometric Mean Ratio of Cmax was determined by comparing Midazolam Geometric Mean on Day 16 to Midazolam Geometric Mean on Day 1 (GeoMeanD16/GeoMeanD1). |
| 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 | The geometric mean ratios (90% CIs) for midazolam + GDC-0032 relative to midazolam alone were reported. Geometric Mean Ratio is determined by comparing GeoMean of AUC D16 with GeoMean of AUC D1 (GeoMeanD16/GeoMeanD1). |
| 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) | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator. |
Countries
Canada, France, Spain, United States
Participant flow
Recruitment details
Participants took part in this study at 30 centers in Canada, France, Spain, and United States from 16 March 2011 to 25 June 2021.
Participants by arm
| Arm | Count |
|---|---|
| Phase I, Stage 1: GDC-0032 3 Milligrams (mg) Once Participants received GDC-0032 3 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28-day cycles until disease progression. | 6 |
| Phase I, Stage 1: GDC-0032 5 mg QD Participants received GDC-0032 5 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28-day cycles until disease progression. | 3 |
| Phase I, Stage 1: GDC-0032 8 mg QD Participants received GDC-0032 8 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28-day cycles until disease progression. | 4 |
| Phase I, Stage 1: GDC-0032 12 mg QD Participants received GDC- 0032 12 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28- day cycles until disease progression. | 10 |
| Phase I, Stage 1: GDC-0032 16 mg QD Participants received GDC-0032 16 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28-day cycles until disease progression. | 11 |
| Phase I, Stage 2: Cohort A - GDC-0032 9 mg QD Participants with PIK3CA-mutant breast cancer were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, once on Day 1 and then QD on Days 8 to 35 of Cycle 1 (Cycle 1 duration=35 days) and in subsequent 28-day cycles until disease progression. | 20 |
| Phase I, Stage 2: Cohort B - GDC-0032 9 mg QD Participants with PIK3CA-mutant solid tumors other than breast cancer were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, QD in 28-day cycles until disease progression. | 20 |
| Phase I, Stage 2: Cohort C - GDC-0032 9 mg QD + Midazolam 5 mg Participants with any type of solid tumors were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, QD on Days 2 to 29 along with midazolam 5 mg syrup, orally, once on Days 1 and 16 of Cycle 1 (Cycle 1 duration=29 days) followed by GDC-0032 9 mg capsules, orally, QD in subsequent 28-day cycles until disease progression. | 13 |
| Phase I, Stage 2: Cohort D - GDC-0032 9 mg QD Participants with HER2-positive breast cancer were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, QD in 28-day cycles until disease progression. | 10 |
| Phase I, Stage 2: Cohort E - GDC-0032 6 mg QD + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 6 mg and letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression. | 20 |
| Phase I, Stage 2: Cohort E - GDC-0032 9 mg QD + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 9 mg and letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression | 8 |
| Phase I, Stage 2: Cohort F - GDC-0032 6 mg QD + Fulvestran t 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 6 mg capsules, orally, QD in 28-day cycles along with fulvestrant 500 mg, intramuscularly (IM) on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 21 |
| Phase I, Stage 2: Cohort F - GDC-0032 9 mg QD + Fulvestran t 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, QD in 28-day cycles along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 6 |
| Phase I, Stage 2: Cohort G - GDC-0032 9 mg QD Participants with solid tumors with increased PIK3CA copy number were enrolled in this cohort to receive GDC-0032 9 mg capsules, orally, QD in each 28-day cycle until disease progression. | 21 |
| Phase I, Stage 2: Cohort H - GDC-0032 6 mg QD Participants with PIK3CA-mutant solid tumors that are non-breast and non-colorectal cancer were enrolled in this cohort to receive GDC-0032 6 mg tablets, orally, QD on Days 1 to 21 of each 28-day cycle until disease progression. | 35 |
| Phase I, Stage 2: Cohort J - GDC-0032 4 mg + Fulvestrant 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD on Days 1 to 21 of each 28-day cycle along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 20 |
| Phase I, Stage 2: Cohort K - GDC-0032 4 mg + Fulvestrant 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 20 |
| Phase I, Stage 2: Cohort L - GDC-0032 4 mg + Fulvestrant 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD on Days 1-7 and 15-21 of each 28-day cycle along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 19 |
| Phase I, Stage 2: Cohort M - GDC-0032 2 mg QD + Fulvestrant 500 mg Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 2 mg tablets, orally, QD in each 28-day cycle along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle until disease progression | 20 |
| Phase I, Stage 2: Cohort N - GDC-0032 2 mg QD + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 2 mg tablets and letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression | 27 |
| Phase I, Stage 2: Cohort P - GDC-0032 4 mg QD + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets and letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression | 28 |
| Phase I, Stage 2: Cohort Q - GDC-0032 4 mg + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD on Days 1 to 21 along with letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression | 20 |
| Phase I, Stage 2: Cohort R - GDC-0032 4 mg + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally on Days 1-5, 8-12, 15-19, and 22-26 along with letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression | 20 |
| Phase I, Stage 2: Cohort S - GDC-0032 4 mg + Letrozole 2.5 mg QD Postmenopausal participants with hormone receptor-positive breast cancer were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally on Days 1-7 and 15-21 along with letrozole 2.5 mg capsules, orally, QD in 28-day cycles until disease progression. | 20 |
| Phase I, Stage 2: Cohort T - GDC-0032 4 mg QD Participants with non-Hodgkin's lymphoma that had progressed or had failed to respond to at least one prior regimen were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally QD in 28-day cycles until disease progression. | 10 |
| Phase I, Stage 2: Cohort T2 - GDC-0032 4 mg QD Participants with DLBCL who had progressed or had failed to respond to at least one prior regimen were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD in 28-day cycles until disease progression. | 10 |
| Phase I, Stage 2: Cohort X - GDC-0032 4 mg QD Participants with PIK3CA-mutant solid tumors that have progressed or failed to respond to at least one prior regimen were enrolled in this cohort to receive GDC-0032 4 mg tablets, orally, QD in 28-day cycles until disease progression. | 70 |
| Phase I, Stage 2: Cohort X - GDC-0032 6 mg QD Participants with PIK3CA-mutant solid tumors that had progressed or failed to respond to at least one prior regimen were enrolled in this cohort to receive GDC-0032 6 mg tablets, orally QD in 28-day cycles until disease progression. | 122 |
| Phase II: GDC-0032 6 mg QD + Fulvestrant 500 mg Postmenopausal participants with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer who had not previously received fulvestrant were enrolled in this cohort to receive GDC-0032 6 mg tablets, orally, QD in 28-day cycles along with fulvestrant 500 mg, IM on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycles until disease progression. | 60 |
| Total | 674 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 | FG020 | FG021 | FG022 | FG023 | FG024 | FG025 | FG026 | FG027 | FG028 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 2 | 4 | 1 | 4 | 3 | 1 | 0 | 4 | 1 | 4 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 2 | 1 | 0 | 2 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 27 | 15 | 11 | 11 | 17 | 12 | 13 | 12 | 12 | 13 | 7 | 7 | 35 | 92 | 44 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 2 | 0 | 2 | 3 | 2 | 0 | 0 | 0 | 0 | 3 | 13 | 5 |
| Overall Study | Non-Compliance With Study Drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 6 | 3 | 3 | 7 | 6 | 16 | 16 | 8 | 7 | 18 | 7 | 14 | 5 | 12 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 5 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 3 | 7 | 4 | 3 | 7 | 11 | 5 | 5 | 7 | 2 | 2 | 19 | 11 | 9 |
| Overall Study | Study Terminated By Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Use Of Another Anti-Cancer Therapy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 0 | 2 | 1 | 0 | 1 | 1 | 1 | 3 | 0 | 0 | 0 | 8 | 4 | 2 |
Baseline characteristics
| Characteristic | Phase I, Stage 1: GDC-0032 5 mg QD | Total | Phase II: GDC-0032 6 mg QD + Fulvestrant 500 mg | Phase I, Stage 2: Cohort X - GDC-0032 6 mg QD | Phase I, Stage 2: Cohort X - GDC-0032 4 mg QD | Phase I, Stage 2: Cohort T2 - GDC-0032 4 mg QD | Phase I, Stage 2: Cohort T - GDC-0032 4 mg QD | Phase I, Stage 2: Cohort S - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort R - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort Q - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort P - GDC-0032 4 mg QD + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort N - GDC-0032 2 mg QD + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort M - GDC-0032 2 mg QD + Fulvestrant 500 mg | Phase I, Stage 2: Cohort L - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I, Stage 2: Cohort K - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I, Stage 2: Cohort J - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I, Stage 1: GDC-0032 3 Milligrams (mg) Once | Phase I, Stage 2: Cohort H - GDC-0032 6 mg QD | Phase I, Stage 2: Cohort G - GDC-0032 9 mg QD | Phase I, Stage 2: Cohort F - GDC-0032 9 mg QD + Fulvestran t 500 mg | Phase I, Stage 2: Cohort F - GDC-0032 6 mg QD + Fulvestran t 500 mg | Phase I, Stage 2: Cohort E - GDC-0032 9 mg QD + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort E - GDC-0032 6 mg QD + Letrozole 2.5 mg QD | Phase I, Stage 2: Cohort D - GDC-0032 9 mg QD | Phase I, Stage 2: Cohort C - GDC-0032 9 mg QD + Midazolam 5 mg | Phase I, Stage 2: Cohort B - GDC-0032 9 mg QD | Phase I, Stage 2: Cohort A - GDC-0032 9 mg QD | Phase I, Stage 1: GDC-0032 16 mg QD | Phase I, Stage 1: GDC-0032 12 mg QD | Phase I, Stage 1: GDC-0032 8 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.0 Years STANDARD_DEVIATION 12.5 | 59.8 Years STANDARD_DEVIATION 11.9 | 60.3 Years STANDARD_DEVIATION 12.2 | 58.9 Years STANDARD_DEVIATION 11.9 | 60.6 Years STANDARD_DEVIATION 13.4 | 53.9 Years STANDARD_DEVIATION 19.3 | 66.1 Years STANDARD_DEVIATION 7.8 | 59.5 Years STANDARD_DEVIATION 10.6 | 58.3 Years STANDARD_DEVIATION 8.9 | 57.2 Years STANDARD_DEVIATION 13.9 | 59.7 Years STANDARD_DEVIATION 12.5 | 63.1 Years STANDARD_DEVIATION 9.1 | 55.7 Years STANDARD_DEVIATION 11.9 | 54.3 Years STANDARD_DEVIATION 12.7 | 62.8 Years STANDARD_DEVIATION 9.1 | 61.8 Years STANDARD_DEVIATION 7.7 | 51.0 Years STANDARD_DEVIATION 9.2 | 64.3 Years STANDARD_DEVIATION 11.8 | 64.4 Years STANDARD_DEVIATION 10 | 55.0 Years STANDARD_DEVIATION 9.7 | 59.8 Years STANDARD_DEVIATION 11.9 | 59.1 Years STANDARD_DEVIATION 7.6 | 63.5 Years STANDARD_DEVIATION 9.7 | 50.4 Years STANDARD_DEVIATION 9.5 | 61.7 Years STANDARD_DEVIATION 9.6 | 62.6 Years STANDARD_DEVIATION 11.9 | 56.8 Years STANDARD_DEVIATION 11.6 | 57.9 Years STANDARD_DEVIATION 11.9 | 60.7 Years STANDARD_DEVIATION 15.4 | 66.3 Years STANDARD_DEVIATION 12.8 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants | 26 Participants | 0 Participants | 6 Participants | 5 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 3 Participants | 611 Participants | 56 Participants | 108 Participants | 61 Participants | 8 Participants | 10 Participants | 20 Participants | 19 Participants | 18 Participants | 25 Participants | 24 Participants | 18 Participants | 17 Participants | 20 Participants | 17 Participants | 5 Participants | 31 Participants | 18 Participants | 6 Participants | 20 Participants | 8 Participants | 18 Participants | 9 Participants | 12 Participants | 20 Participants | 19 Participants | 10 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 0 Participants | 26 Participants | 3 Participants | 6 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 0 Participants | 11 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 18 Participants | 3 Participants | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 19 Participants | 3 Participants | 4 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Multiple | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Island | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 20 Participants | 0 Participants | 5 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 3 Participants | 612 Participants | 53 Participants | 109 Participants | 57 Participants | 9 Participants | 10 Participants | 20 Participants | 18 Participants | 18 Participants | 27 Participants | 26 Participants | 17 Participants | 17 Participants | 20 Participants | 19 Participants | 6 Participants | 30 Participants | 20 Participants | 6 Participants | 19 Participants | 8 Participants | 20 Participants | 10 Participants | 12 Participants | 20 Participants | 18 Participants | 8 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 544 Participants | 60 Participants | 83 Participants | 37 Participants | 2 Participants | 6 Participants | 19 Participants | 20 Participants | 20 Participants | 28 Participants | 27 Participants | 20 Participants | 19 Participants | 20 Participants | 20 Participants | 4 Participants | 22 Participants | 16 Participants | 6 Participants | 21 Participants | 8 Participants | 20 Participants | 10 Participants | 6 Participants | 12 Participants | 19 Participants | 6 Participants | 9 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 130 Participants | 0 Participants | 39 Participants | 33 Participants | 8 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 13 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 8 Participants | 1 Participants | 5 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk | EG022 affected / at risk | EG023 affected / at risk | EG024 affected / at risk | EG025 affected / at risk | EG026 affected / at risk | EG027 affected / at risk | EG028 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 4 | 2 / 10 | 1 / 11 | 0 / 20 | 2 / 20 | 0 / 13 | 0 / 10 | 1 / 20 | 0 / 8 | 1 / 21 | 0 / 6 | 3 / 21 | 27 / 35 | 15 / 20 | 11 / 20 | 11 / 19 | 17 / 20 | 12 / 27 | 13 / 28 | 12 / 20 | 12 / 20 | 13 / 20 | 7 / 10 | 7 / 10 | 35 / 70 | 92 / 122 | 44 / 60 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 4 / 4 | 10 / 10 | 11 / 11 | 20 / 20 | 19 / 20 | 12 / 13 | 10 / 10 | 20 / 20 | 7 / 8 | 21 / 21 | 6 / 6 | 21 / 21 | 35 / 35 | 19 / 20 | 19 / 20 | 19 / 19 | 20 / 20 | 27 / 27 | 27 / 28 | 20 / 20 | 20 / 20 | 19 / 20 | 10 / 10 | 10 / 10 | 69 / 70 | 117 / 122 | 60 / 60 |
| serious Total, serious adverse events | 1 / 6 | 0 / 3 | 2 / 4 | 4 / 10 | 9 / 11 | 9 / 20 | 7 / 20 | 7 / 13 | 4 / 10 | 11 / 20 | 2 / 8 | 5 / 21 | 3 / 6 | 9 / 21 | 19 / 35 | 4 / 20 | 7 / 20 | 3 / 19 | 6 / 20 | 6 / 27 | 10 / 28 | 2 / 20 | 5 / 20 | 2 / 20 | 7 / 10 | 4 / 10 | 40 / 70 | 63 / 122 | 19 / 60 |
Outcome results
Primary
Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1
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.
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1 | NA months |
Primary
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)
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.
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | 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) | 11.4 percentage of participants |
Primary
Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1
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).
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1 | 3.7 months |
Primary
DOR in Cohort T and T2
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.
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | DOR in Cohort T and T2 | NA months |
Primary
Percentage of Participants With BOR in Cohort T and T2
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.
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With BOR in Cohort T and T2 | 20.0 percentage of participants |
Primary
PFS in Cohort T and T2
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.
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | PFS in Cohort T and T2 | 4.2 months |
Primary
Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant. 'Number Analyzed' signifies number of participants analyzed for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 1 | 0.441 micromolar per hour (µM*h) | Standard Deviation 0.142 |
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 15 | 1.79 micromolar per hour (µM*h) | Standard Deviation 0.962 |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 1 | 0.547 micromolar per hour (µM*h) | Standard Deviation 0.233 |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 15 | 1.49 micromolar per hour (µM*h) | Standard Deviation 0.786 |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 1 | 1.34 micromolar per hour (µM*h) | Standard Deviation 0.411 |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 15 | 3.21 micromolar per hour (µM*h) | Standard Deviation 1.636 |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 15 | 5.1 micromolar per hour (µM*h) | Standard Deviation 2.035 |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 1 | 1.8 micromolar per hour (µM*h) | Standard Deviation 0.631 |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 1 | 2.26 micromolar per hour (µM*h) | Standard Deviation 0.806 |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032 | Day 15 | 8.1 micromolar per hour (µM*h) | Standard Deviation 4.79 |
Primary
Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant. 'Number Analyzed' signifies number of participants analyzed for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 1 | 0.0256 micromolar (µM) | Standard Deviation 0.0094 |
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 15 | 0.111 micromolar (µM) | Standard Deviation 0.072 |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 1 | 0.0304 micromolar (µM) | Standard Deviation 0.0122 |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 15 | 0.091 micromolar (µM) | Standard Deviation 0.048 |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 1 | 0.0764 micromolar (µM) | Standard Deviation 0.0328 |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 15 | 0.188 micromolar (µM) | Standard Deviation 0.119 |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 15 | 0.302 micromolar (µM) | Standard Deviation 0.1 |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 1 | 0.127 micromolar (µM) | Standard Deviation 0.0529 |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 1 | 0.134 micromolar (µM) | Standard Deviation 0.0535 |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032 | Day 15 | 0.441 micromolar (µM) | Standard Deviation 0.251 |
Primary
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)
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.
Time frame: Baseline up to 35 days of Cycle 1
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | 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) | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | 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) | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | 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) | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | 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) | 10.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 16 mg QD | 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) | 18.1 percentage of participants |
Primary
Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0
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.
Time frame: Baseline up to 28 days of Cycle 1
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0 | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0 | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0 | 0.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0 | 0.0 percentage of participants |
Primary
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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: Terminal Half-life (t1/2) of GDC-0032 | 43.8 hr | Standard Deviation 11.6 |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: Terminal Half-life (t1/2) of GDC-0032 | 40 hr | Standard Deviation 21 |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: Terminal Half-life (t1/2) of GDC-0032 | 38.2 hr | Standard Deviation 9.1 |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: Terminal Half-life (t1/2) of GDC-0032 | 36.7 hr | Standard Deviation 8.3 |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: Terminal Half-life (t1/2) of GDC-0032 | 39.7 hr | Standard Deviation 8 |
Primary
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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I: Time to Reach Cmax (Tmax) of GDC-0032 | 4 hours (hr) |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I: Time to Reach Cmax (Tmax) of GDC-0032 | 8 hours (hr) |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I: Time to Reach Cmax (Tmax) of GDC-0032 | 4 hours (hr) |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I: Time to Reach Cmax (Tmax) of GDC-0032 | 3 hours (hr) |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I: Time to Reach Cmax (Tmax) of GDC-0032 | 4 hours (hr) |
Secondary
AUC of GDC-0032 Under Fasted Conditions
Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose.
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | AUC of GDC-0032 Under Fasted Conditions | 1.247 µM*hr | Standard Deviation 0.911 |
Secondary
AUC of GDC-0032 Under Fed Conditions
For dosing under fed conditions, participant fasted overnight for \>/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032.
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | AUC of GDC-0032 Under Fed Conditions | 1.404 µM*hr | Standard Deviation 0.656 |
Secondary
Cmax of GDC-0032 Under Fasted Conditions
Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose.
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Cmax of GDC-0032 Under Fasted Conditions | 0.085 µM | Standard Deviation 0.046 |
Secondary
Cmax of GDC-0032 Under Fed Conditions
For dosing under fed conditions, participant fasted overnight for \>/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032.
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Cmax of GDC-0032 Under Fed Conditions | 0.082 µM | Standard Deviation 0.038 |
Secondary
Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone
The geometric mean ratios (90% CIs) for midazolam + GDC-0032 relative to midazolam alone were reported. Geometric Mean Ratio is determined by comparing GeoMean of AUC D16 with GeoMean of AUC D1 (GeoMeanD16/GeoMeanD1).
Time frame: 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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone | 1.04 ratio |
Secondary
Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone
The geometric mean ratio (90% CI) for midazolam+ GDC-0032 relative to midazolam alone was reported. Geometric Mean Ratio of Cmax was determined by comparing Midazolam Geometric Mean on Day 16 to Midazolam Geometric Mean on Day 1 (GeoMeanD16/GeoMeanD1).
Time frame: 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
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone | 0.98 ratio |
Secondary
Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters
Laboratory parameters such as fasting glucose, absolute neutrophil count, hemoglobin, platelet count, lymphocytes, serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), leukocytes, fasting triglycerides and fasting cholesterol were assessed. A clinically relevant shift from baseline was defined as a shift from Grade 0, 1, or 2 at baseline to Grade 3 or 4 post baseline.
Time frame: Baseline to a maximum of 67 months
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Platelet Count | 1.5 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Absolute Neutrophil Count | 4.8 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High ALT | 2.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Lymphocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Fasting Glucose | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High AST | 2.6 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Lymphocytes | 13.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Leukocytes | 2.1 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Serum Creatinine | 0.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Hemoglobin | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Cholesterol | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Glucose | 9.3 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Hemoglobin | 5.2 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Triglycerides | 0.4 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Leukocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Leukocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Glucose | 4.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Fasting Glucose | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Absolute Neutrophil Count | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Hemoglobin | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Hemoglobin | 0.7 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Platelet Count | 0.7 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Lymphocytes | 0.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Lymphocytes | 7.3 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Serum Creatinine | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High AST | 6.3 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High ALT | 4.2 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Leukocytes | 1.4 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Triglycerides | 0.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Cholesterol | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Platelet Count | 0.6 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Glucose | 3.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High ALT | 5.2 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Hemoglobin | 1.2 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Hemoglobin | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Leukocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Absolute Neutrophil Count | 0.7 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Leukocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Fasting Glucose | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | Low Lymphocytes | 2.9 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Cholesterol | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Serum Creatinine | 2.5 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Lymphocytes | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High Fasting Triglycerides | 0.8 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters | High AST | 7.0 percentage of participants |
Secondary
Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator.
Time frame: 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)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 31.7 percentage of participants |
Secondary
Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator.
Time frame: 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)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | SAEs | 16.7 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | SAEs | 0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | SAEs | 50.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | SAEs | 40.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade | SAEs | 81.8 percentage of participants |
Secondary
Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator.
Time frame: 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)
Population: The safety-evaluable population was defined as all participants who received at least one dose of GDC-0032, letrozole, or fulvestrant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 45.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 3 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 35.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 53.8 percentage of participants |
| Phase I, Stage 1: GDC-0032 8 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 92.3 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 40.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 12 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 1: GDC-0032 16 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 55.0 percentage of participants |
| Phase I, Stage 2: Cohort E - GDC-0032 9 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 87.5 percentage of participants |
| Phase I, Stage 2: Cohort E - GDC-0032 9 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 25.0 percentage of participants |
| Phase I, Stage 2: Cohort F - GDC-0032 6 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 23.8 percentage of participants |
| Phase I, Stage 2: Cohort F - GDC-0032 6 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort F - GDC-0032 9 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort F - GDC-0032 9 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 50.0 percentage of participants |
| Phase I, Stage 2: Cohort G - GDC-0032 9 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 42.9 percentage of participants |
| Phase I, Stage 2: Cohort G - GDC-0032 9 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort H - GDC-0032 6 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 54.3 percentage of participants |
| Phase I, Stage 2: Cohort H - GDC-0032 6 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort J - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 95.0 percentage of participants |
| Phase I, Stage 2: Cohort J - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 20.0 percentage of participants |
| Phase I, Stage 2: Cohort K - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 35.0 percentage of participants |
| Phase I, Stage 2: Cohort K - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 95.0 percentage of participants |
| Phase I, Stage 2: Cohort L - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 15.8 percentage of participants |
| Phase I, Stage 2: Cohort L - GDC-0032 4 mg + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort M - GDC-0032 2 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort M - GDC-0032 2 mg QD + Fulvestrant 500 mg | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 30.0 percentage of participants |
| Phase I, Stage 2: Cohort N - GDC-0032 2 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 22.2 percentage of participants |
| Phase I, Stage 2: Cohort N - GDC-0032 2 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort P - GDC-0032 4 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 96.4 percentage of participants |
| Phase I, Stage 2: Cohort P - GDC-0032 4 mg QD + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 35.7 percentage of participants |
| Phase I, Stage 2: Cohort Q - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort Q - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 10.0 percentage of participants |
| Phase I, Stage 2: Cohort R - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort R - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 25.0 percentage of participants |
| Phase I, Stage 2: Cohort S - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 95.0 percentage of participants |
| Phase I, Stage 2: Cohort S - GDC-0032 4 mg + Letrozole 2.5 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 10.0 percentage of participants |
| Phase I, Stage 2: Cohort T - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort T - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 70.0 percentage of participants |
| Phase I, Stage 2: Cohort T2 - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort T2 - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 40.0 percentage of participants |
| Phase I, Stage 2: Cohort X - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 100.0 percentage of participants |
| Phase I, Stage 2: Cohort X - GDC-0032 4 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 57.1 percentage of participants |
| Phase I, Stage 2: Cohort X - GDC-0032 6 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | SAEs | 51.6 percentage of participants |
| Phase I, Stage 2: Cohort X - GDC-0032 6 mg QD | Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade | AEs | 99.2 percentage of participants |