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

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary To evaluate the safety and tolerability of escalating doses of systemic Hedgehog antagonist GDC-0449 in patients with locally advanced or metastatic solid tumors. To estimate the maximum tolerated dose of GDC-0449 in these patients. To define the dose-limiting toxicities of GDC-0449 in these patients. To characterize the pharmacokinetic properties of GDC-0449 following a single dose and multiple doses. To determine the recommended phase II dose and schedule of GDC-0449 for efficacy testing based on achievement of the target exposure with an acceptable safety profile. Secondary To determine whether inhibition of Hedgehog (Hh) signaling by GDC-0449 can be reliably measured in human hair follicles and to define the relationship between this pharmacodynamic (PD) effect in surrogate tissue and GDC-0449 dose and exposure. To make a preliminary assessment of tumor response in patients treated with this drug. Tertiary To examine modulation of Hh target genes (other than GLI1) by GDC-0449 in hair follicles and/or tumor tissue. OUTLINE: This is a multicenter study. Patients receive oral systemic Hedgehog antagonist GDC-0449 once on day 1 and then once or twice daily beginning on day 8 and continuing for up to 49 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo plasma, urine, and hair sample collection and skin punch biopsies periodically for pharmacokinetic and pharmacodynamic analyses. The plasma and urine samples are analyzed separately using liquid chromatography/tandem mass spectrometry-based methods. Ex vivo plasma protein binding of GDC-0449 is assayed using an equilibrium dialysis approach. Expression levels of Gli1 and other Hedgehog target genes in hair follicle samples and/or tumor tissue are measured at the RNA level using qRT-PCR. After completion of study therapy, patients are followed at 21 days.

Official Title
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An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: GDC-0449


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: GDC-0449 (150 mg)<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 1: GDC-0449 (270 mg)<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 1: GDC-0449 (540 mg)<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 2: BCC [GDC-0449 (150 mg)]<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 2: BCC [GDC-0449 (270 mg)]<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|
| Experimental: Stage 2: New Formulation [GDC-0449 (150 mg )]<br>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<br> <br> * Other names: Hedgehog Pathway Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Ribonucleic acid (RNA) was extracted from biopsy specimens of noninvolved skin or hair follicles at baseline and at 7 and 21 days after the start of daily drug therapy. Control mRNA was obtained from formalin-fixed, paraffin-embedded samples of normal skin and hair follicles from participants who were not enrolled in the study. | Baseline up to Day 29 | 
| Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants | BOR was defined as the best objective response (complete or partial response determined by two consecutive investigator assessments which were at least 28 days apart) observed during the treatment period according to RECIST v1.0. CR: disappearance of all target lesions (TLs), with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 millimeters (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of TLs, taking as reference the baseline (BL) sum diameters. | 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 | BOR was defined as the best objective response observed during the treatment period according to RECIST v1.0. CR: disappearance of all TLs, with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in the sum of diameters of TLs, taking as reference the BL sum diameters. | Screening, at Week 8 thereafter every 8 weeks, up to Week 116 | 
| Duration of Objective Response: All Participants | Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy. | Screening, at Week 8 thereafter every 8 weeks, up to Week 116 | 
| Duration of Objective Response: Participants With BCC | Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy. | Screening, at Week 8 thereafter every 8 weeks, up to Week 116 | 
| Progression-Free Survival (PFS): All Participants | PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first. | Screening, at Week 8 thereafter every 8 weeks, up to Week 116 | 
| PFS: Participants With BCC | PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first. | Screening, at Week 8 thereafter every 8 weeks, up to Week 116 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific