A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma (NHL) and in Combination With Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer

Phase 1

Terminated

Conditions: Solid Cancers
Non-Hodgkin's Lymphoma

Interventions: Drug: GDC-0032
Drug: Fulvestrant
Drug: Midazolam
Drug: Letrozole

Registration Number: NCT01296555

Lead Sponsor: Genentech, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 674

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I, Stage 2: GDC-0032 + Letrozole	GDC-0032	Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.
Phase I, Stage 2: GDC-0032 + Midazolam	GDC-0032	Participants (Cohort C) will receive GDC-0032 in combination with midazolam.
Phase I, Stage 2: GDC-0032 + Midazolam	Midazolam	Participants (Cohort C) will receive GDC-0032 in combination with midazolam.
Phase II: GDC-0032 + Fulvestrant	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.
Phase I, Stage 1: GDC-0032 as Single Agent	GDC-0032	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.
Phase I, Stage 2: GDC-0032 + Fulvestrant	GDC-0032	Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.
Phase I, Stage 2: GDC-0032 as Single Agent	GDC-0032	Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression.
Phase II: GDC-0032 + Fulvestrant	GDC-0032	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.
Phase I, Stage 2: GDC-0032 + Fulvestrant	Fulvestrant	Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.
Phase I, Stage 2: GDC-0032 + Letrozole	Letrozole	Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.

Primary Outcome Measures

Name	Time	Method
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
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).
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.
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.
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.
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: 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.
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.
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.
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.

Secondary Outcome Measures

Name	Time	Method
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.
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.
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.
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).
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 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.
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.
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 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).

Trial Locations

Locations (31): Univ of Chicago
🇺🇸
Chicago, Illinois, United States
Mary Crowley Cancer Rsch Ctr
🇺🇸
Dallas, Texas, United States
Baylor Sammons Cancer Center
🇺🇸
Dallas, Texas, United States
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
🇨🇦
Toronto, Ontario, Canada
Dana Farber Cancer Inst.
🇺🇸
Boston, Massachusetts, United States
Sutter Health
🇺🇸
San Francisco, California, United States
Vanderbilt Breast Center; Vanderbilt Health Pharmacy
🇺🇸
Nashville, Tennessee, United States
Vanderbilt
🇺🇸
Nashville, Tennessee, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Arizona Cancer Center
🇺🇸
Tucson, Arizona, United States
University of California Irvine Medical Center
🇺🇸
Orange, California, United States
Florida Cancer Specialists - Fort Myers (New Hampshire Ct)
🇺🇸
Fort Myers, Florida, United States
Sarah Cannon Res Inst; FL
🇺🇸
Sarasota, Florida, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Sarah Cannon Res Inst; TN Onc
🇺🇸
Nashville, Tennessee, United States
West Cancer Center
🇺🇸
Germantown, Tennessee, United States
Northwest Cancer Specialists - Vancouver
🇺🇸
Vancouver, Washington, United States
Institut Gustave Roussy
🇫🇷
Villejuif, France
Barbara Ann Karmanos Cancer Institute
🇺🇸
Detroit, Maine, United States
Texas Cancer Center
🇺🇸
Abilene, Texas, United States
TGen Clinical Research Srvs
🇺🇸
Scottsdale, Arizona, United States
Washington University; Division of Oncology
🇺🇸
Saint Louis, Missouri, United States
USO - Tyler Cancer Ctr
🇺🇸
Tyler, Texas, United States
Yakima Valley Memorial Hospital/North Star Lodge
🇺🇸
Yakima, Washington, United States
Hospital Univ Vall d'Hebron; Servicio de Oncologia
🇪🇸
Sant Andreu de La Barca, Barcelona, Spain
Hospital Clinico Universitario de Valencia
🇪🇸
Valencia, Spain
New York Oncology Hematology, P.C.
🇺🇸
Albany, New York, United States
Sarah Cannon Res Inst; OK
🇺🇸
Oklahoma City, Oklahoma, United States
UC Davis; Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Yale University
🇺🇸
New Haven, Connecticut, United States