GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

NCT00607724 | Completed Phase 1 Results

• 3 other identifiers: CDR0000585468JHOC-J06131GENETECH-SHH3925g
• Study Type: interventional
• Target: 68
• Locations: 0 countries
• Sites: N/A

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as GDC-0449, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I trial is studying the side effects and best dose of GDC-0449 in treating patients with locally advanced or metastatic solid tumors.

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Keywords

unspecified adult solid tumor, protocol specific

Outcome Measures

Primary Outcomes (9)

• Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  A DLT was defined as any Grade 3 or 4 hematologic or major organ toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) that occurred during the first 35 days after the initiation of study drug (Days 1-35) and was attributable to GDC-0449.

  Up to Week 6

• Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449

  Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

  -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

• Cmax After Multiple Doses of GDC-0449

  Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

  -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

• Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449

  Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

  -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

• Tmax After Multiple Doses of GDC-0449

  Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

  -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

• Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449

  Steady state GDC-0449 plasma concentrations (Css) were calculated as an average of plasma concentrations from Study Day 21 (Stage 2) or Study Day 28 (Stage 1) onward.

  -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

• Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449

  AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

  -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

• AUC0-24 After Multiple Doses of GDC-0449

  AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

  -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

• Accumulation Index (AI) After Multiple Doses of GDC-0449

  AI was calculated using the formula \[AI = AUC(0-24) on Day 15/AUC(0-24) on Day 1\]. AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AI was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

  -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

Secondary Outcomes (7)

• Percentage of Participants With a Greater Than (>) 2-Fold Down-Modulation of GLI1 Expression in Skin Biopsy-Derived or Hair Follicle-Derived Messenger Ribonucleic Acid (mRNA)

  Baseline up to Day 29

• Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants

  Screening, at Week 8 thereafter every 8 weeks, up to Week 116

• Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma

  Screening, at Week 8 thereafter every 8 weeks, up to Week 116

• Duration of Objective Response: All Participants

  Screening, at Week 8 thereafter every 8 weeks, up to Week 116

• Duration of Objective Response: Participants With BCC

  Screening, at Week 8 thereafter every 8 weeks, up to Week 116

Study Arms (7)

Stage 1: GDC-0449 (150 mg)

EXPERIMENTAL

Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability.

Drug: GDC-0449

Stage 1: GDC-0449 (270 mg)

EXPERIMENTAL

Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Stage 1: GDC-0449 (540 mg)

EXPERIMENTAL

Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Stage 2: BCC [GDC-0449 (150 mg)]

EXPERIMENTAL

Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Stage 2: BCC [GDC-0449 (270 mg)]

EXPERIMENTAL

Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]

EXPERIMENTAL

Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Stage 2: New Formulation [GDC-0449 (150 mg )]

EXPERIMENTAL

Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

Drug: GDC-0449

Interventions

GDC-0449 DRUG

Also known as: Hedgehog Pathway Inhibitor

Stage 1: GDC-0449 (150 mg); Stage 1: GDC-0449 (270 mg); Stage 1: GDC-0449 (540 mg); Stage 2: BCC [GDC-0449 (150 mg)]; Stage 2: BCC [GDC-0449 (270 mg)]; Stage 2: New Formulation [GDC-0449 (150 mg )]; Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]

Eligibility Criteria

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

DISEASE CHARACTERISTICS: * Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists * Progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit) * Must receive standard second-line therapy if second-line therapy has been shown to provide clinical benefit * Evaluable disease by physical examination, imaging, and/or one of the following: * Two rising prostate-specific antigen (PSA) levels ≥ 2 weeks apart, with one obtained during screening (for patients with prostate cancer) * Two rising CA-125 levels ≥ 2 weeks apart, with one obtained during screening (for patients with ovarian cancer) * No CNS cancer, either primary lesions or metastatic disease, as the current malignancy * No pleural effusions, ascites, or leptomeningeal disease as the only manifestation of the current malignancy PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Granulocyte count ≥ 1,500/μL * Platelet count ≥ 100,000/μL * Hemoglobin ≥ 9 g/dL * Serum bilirubin normal * Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN) (≤ 4 times ULN for patients with liver or bone metastases) * AST and ALT ≤ 1.5 times ULN (≤ 5 times the ULN for patients with liver metastases) * Serum creatinine ≤ 1.5 mg/dL * INR \< 1.3 * aPTT ≤ 1.5 times ULN * Fasting total serum cholesterol ≤ 220 mg/dL (without cholesterol-lowering drugs) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Able and willing to swallow pills * No malabsorption syndrome or other condition that would interfere with enteral absorption * No history of significant atherosclerotic disease, including the following: * Coronary artery disease (i.e., myocardial infarction within the past year or unstable angina) * Documented carotid atheromas * No history of congestive heart failure or ventricular arrhythmia requiring medication * No congenital long QT syndrome * No baseline QTc intervals \> 0.47 seconds on two of three baseline 12-lead ECGs recorded during the screening period * No active infection requiring intravenous antibiotics * No known HIV infection * No uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia, defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation * No history of clinically important liver disease, including cirrhosis or viral or other hepatitis * No current alcohol abuse * No significant traumatic injury within the past 3 weeks * No other disease, 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 or that may affect the interpretation of the study results or renders the patient at high risk from treatment complications PRIOR CONCURRENT THERAPY: * At least 4 weeks since prior chemotherapy, investigational therapy, radiotherapy, or major surgical procedure and recovered * No concurrent medications with narrow therapeutic indices that are cytochrome P450 substrates (warfarin sodium \[Coumadin®\]) * No concurrent medications known to prolong the QT interval, including any of the following: * Quinidine or other anti-arrhythmic agents * Haloperidol, fluoxetine, paroxetine, or sertraline * Pentamidine, fluoroquinolone, or macrolide antibiotics * No concurrent medications that may interfere with the metabolism of GDC-0449 (e.g., ketoconazole) * No concurrent grapefruit juice

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Genentech, Inc.: lead
• National Cancer Institute (NCI): collaborator
• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: collaborator

Related Publications (2)

• Thacker CA, Weiss GJ, Tibes R, Blaydorn L, Downhour M, White E, Baldwin J, Hoff DD, Korn RL. 18-FDG PET/CT assessment of basal cell carcinoma with vismodegib. Cancer Med. 2012 Oct;1(2):230-6. doi: 10.1002/cam4.33. Epub 2012 Sep 17.

  PMID: 23342272 DERIVED

• Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2.

  PMID: 19726763 DERIVED

MeSH Terms

Interventions

HhAntag691

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-LaRoche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  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: January 31, 2008
• First Posted: February 6, 2008
• Study Start: April 1, 2007
• Primary Completion: November 1, 2009
• Study Completion: November 1, 2009
• Last Updated: October 8, 2015
• Results First Posted: October 8, 2015

Record last verified: 2015-09