Clinical trial NCT01296555: 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
Official title: An Open-Label, Phase I/II, Dose-Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Cancers
Non-Hodgkin's Lymphoma
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2011-02-15
Enrollment: 674
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* Phase I (Cohorts A through D, G, H, T, T2 and X): Histologically documented, locally advanced or metastatic solid malignancy or NHL that has progressed or failed to respond to at least one prior regimen and are not candidates for regimens known to provide clinical benefit
* Phase I (Cohorts E and F): Post-menopausal females with locally advanced or metastatic hormone receptor-positive breast cancer that has progressed or failed to respond to at least one prior endocrine therapy in the adjuvant or metastatic setting
* Phase I (Cohorts J through S): Post-menopausal females with HER2-negative, hormone-receptor positive breast cancer that has progressed or failed to response to at least one prior endocrine therapy in the adjuvant or metastatic setting
* Phase II: Post-menopausal female participants with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer
* Phase I (Cohorts A through S) and Phase II: Evaluable or measurable disease per RECIST version 1.1
* Phase I (Cohorts T, and T2): Greater than or equal to (\>/=) 1 bi-dimensionally measurable lesion on computed tomography (CT) scan
* Phase I (Cohort T): Participants with non-Hodgkin's lymphoma, regardless of PIK3CA mutation status
* Phase 1 (Cohort T2): Participants with diffuse large B-cell lymphoma (DLBCL), regardless of PIK3CA mutation status
* Phase I (Cohort X): Participants with PIK3CA-mutant tumors and measurable disease per RECIST v1.1
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Screening
* 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)

Primary outcomes:
measure: 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)
timeFrame: Baseline up to 35 days of Cycle 1
measure: Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0
timeFrame: Baseline up to 28 days of Cycle 1
measure: Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032
timeFrame: 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
measure: Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032
timeFrame: 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
measure: Phase I: Time to Reach Cmax (Tmax) of GDC-0032
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr
measure: Phase I: Terminal Half-life (t1/2) of GDC-0032
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr
measure: 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)
timeFrame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
measure: Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1
timeFrame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
measure: Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1
timeFrame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
measure: Percentage of Participants With BOR in Cohort T and T2
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
measure: DOR in Cohort T and T2
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
measure: PFS in Cohort T and T2
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
Secondary outcomes:
measure: Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade
timeFrame: 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)
measure: Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade
timeFrame: 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)
measure: Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade
timeFrame: 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)
measure: Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters
timeFrame: Baseline to a maximum of 67 months
measure: Cmax of GDC-0032 Under Fed Conditions
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
measure: Cmax of GDC-0032 Under Fasted Conditions
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
measure: AUC of GDC-0032 Under Fed Conditions
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
measure: AUC of GDC-0032 Under Fasted Conditions
timeFrame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
measure: Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone
timeFrame: 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
measure: Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone
timeFrame: 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
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: TGen Clinical Research Srvs
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Orange
country: United States
facility: University of California Irvine Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis; Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: Sutter Health
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - Fort Myers (New Hampshire Ct)
state: Florida
city: Sarasota
country: United States
facility: Sarah Cannon Res Inst; FL
state: Florida
city: Chicago
country: United States
facility: Univ of Chicago
state: Illinois
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Inst.
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University; Division of Oncology
state: Missouri
city: Albany
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Oklahoma City
country: United States
facility: Sarah Cannon Res Inst; OK
state: Oklahoma
city: Germantown
country: United States
facility: West Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Res Inst; TN Onc
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Breast Center; Vanderbilt Health Pharmacy
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt
state: Tennessee
city: Abilene
country: United States
facility: Texas Cancer Center
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Cancer Rsch Ctr
state: Texas
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Tyler
country: United States
facility: USO - Tyler Cancer Ctr
state: Texas
city: Vancouver
country: United States
facility: Northwest Cancer Specialists - Vancouver
state: Washington
city: Yakima
country: United States
facility: Yakima Valley Memorial Hospital/North Star Lodge
state: Washington
city: Toronto
country: Canada
facility: University Health Network; Princess Margaret Hospital; Medical Oncology Dept
state: Ontario
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Sant Andreu de La Barca
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
state: Barcelona
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References: