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

NCT01296555 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: PMT4979gGO008862012-002042-21
• Study Type: interventional
• Target: 674
• Locations: 4 countries
• Sites: 31

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.

Conditions

Solid Cancers; Non-Hodgkin's Lymphoma

Outcome Measures

Primary Outcomes (12)

• 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.

  Baseline up to 35 days of Cycle 1

• 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.

  Baseline up to 28 days of Cycle 1

• 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.

  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

• 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.

  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

• 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)

  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.

  Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

• 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.

  Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

• 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).

  Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

• 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.

  Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

• 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.

  Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

• 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.

  Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

Secondary Outcomes (10)

• Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade

  From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 16 months)

• Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade

  From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 67 months)

• 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)

• Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters

  Baseline to a maximum of 67 months

• Cmax of GDC-0032 Under Fed Conditions

  Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr

Study Arms (6)

Phase I, Stage 1: GDC-0032 as Single Agent

EXPERIMENTAL

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.

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Fulvestrant

EXPERIMENTAL

Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.

Drug: Fulvestrant; Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Letrozole

EXPERIMENTAL

Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.

Drug: GDC-0032; Drug: Letrozole

Phase I, Stage 2: GDC-0032 as Single Agent

EXPERIMENTAL

Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression.

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Midazolam

EXPERIMENTAL

Participants (Cohort C) will receive GDC-0032 in combination with midazolam.

Drug: GDC-0032; Drug: Midazolam

Phase II: GDC-0032 + Fulvestrant

EXPERIMENTAL

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.

Drug: Fulvestrant; Drug: GDC-0032

Interventions

Fulvestrant DRUG

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).

Also known as: Faslodex®

Phase I, Stage 2: GDC-0032 + Fulvestrant; Phase II: GDC-0032 + Fulvestrant

GDC-0032 DRUG

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.

Phase I, Stage 1: GDC-0032 as Single Agent; Phase I, Stage 2: GDC-0032 + Fulvestrant; Phase I, Stage 2: GDC-0032 + Letrozole; Phase I, Stage 2: GDC-0032 + Midazolam; Phase I, Stage 2: GDC-0032 as Single Agent; Phase II: GDC-0032 + Fulvestrant

Letrozole DRUG

Participants will receive letrozole 2.5 mg orally (as per Package Insert or SmPC) once daily in 28-day cycles until disease progression.

Also known as: Femara®

Phase I, Stage 2: GDC-0032 + Letrozole

Midazolam DRUG

Participants will receive midazolam 5 mg (as per Package Insert or SmPC) in hydrochloride syrup on Days 1 and 16 of Cycle 1.

Phase I, Stage 2: GDC-0032 + Midazolam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (31)

TGen Clinical Research Srvs

Scottsdale, Arizona, 85258, United States

Location

University of Arizona Cancer Center

Tucson, Arizona, 85719, United States

Location

University of California Irvine Medical Center

Orange, California, 92868, United States

Location

UC Davis; Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

Sutter Health

San Francisco, California, 94109, United States

Location

Yale University

New Haven, Connecticut, 06510, United States

Location

Florida Cancer Specialists - Fort Myers (New Hampshire Ct)

Fort Myers, Florida, 33901-8101, United States

Location

Sarah Cannon Res Inst; FL

Sarasota, Florida, 34232, United States

Location

Univ of Chicago

Chicago, Illinois, 60637, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Maine, 48201-2013, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Inst.

Boston, Massachusetts, 02115, United States

Location

Washington University; Division of Oncology

St Louis, Missouri, 63110, United States

Location

New York Oncology Hematology, P.C.

Albany, New York, 12206, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Sarah Cannon Res Inst; OK

Oklahoma City, Oklahoma, 73104, United States

Location

West Cancer Center

Germantown, Tennessee, 38138, United States

Location

Sarah Cannon Res Inst; TN Onc

Nashville, Tennessee, 37203, United States

Location

Vanderbilt Breast Center; Vanderbilt Health Pharmacy

Nashville, Tennessee, 37204, United States

Location

Vanderbilt

Nashville, Tennessee, 37232, United States

Location

Texas Cancer Center

Abilene, Texas, 79606-5208, United States

Location

Mary Crowley Cancer Rsch Ctr

Dallas, Texas, 75230, United States

Location

Baylor Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

USO - Tyler Cancer Ctr

Tyler, Texas, 75702, United States

Location

Northwest Cancer Specialists - Vancouver

Vancouver, Washington, 98684, United States

Location

Yakima Valley Memorial Hospital/North Star Lodge

Yakima, Washington, 98902, United States

Location

University Health Network; Princess Margaret Hospital; Medical Oncology Dept

Toronto, Ontario, M5G 2M9, Canada

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Sant Andreu de la Barca, Barcelona, 08740, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

Related Publications (1)

• Moein A, Jin JY, Wright MR, Wong H. Quantitative characterization of the effects of fulvestrant alone or in combination with taselisib (PI3Kinase inhibitor) on longitudinal tumor growth in patients with estrogen receptor-positive, HER2-negative, PIK3CA-mutant, advanced or metastatic breast cancer. Cancer Chemother Pharmacol. 2024 Sep;94(3):421-436. doi: 10.1007/s00280-024-04690-4. Epub 2024 Jun 27.

  PMID: 38937298 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

Fulvestrant; 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; Letrozole; Midazolam

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2011
• First Posted: February 15, 2011
• Study Start: March 16, 2011
• Primary Completion: June 25, 2021
• Study Completion: June 25, 2021
• Last Updated: July 31, 2024
• Results First Posted: July 31, 2024

Record last verified: 2024-02

Locations

CA (1); FR (1); ES (2); US (27)