GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors
- Conditions
- Unspecified Adult Solid Tumor, Protocol Specific
- Interventions
- Registration Number
- NCT00607724
- Lead Sponsor
- Genentech, Inc.
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 68
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stage 1: GDC-0449 (270 mg) GDC-0449 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. Stage 1: GDC-0449 (150 mg) GDC-0449 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. Stage 1: GDC-0449 (540 mg) GDC-0449 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. Stage 2: BCC [GDC-0449 (150 mg)] GDC-0449 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. Stage 2: BCC [GDC-0449 (270 mg)] GDC-0449 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. Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] GDC-0449 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. Stage 2: New Formulation [GDC-0449 (150 mg )] GDC-0449 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.
- Primary Outcome Measures
Name Time Method Cmax After Multiple Doses of GDC-0449 -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 Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Percentage of Participants With Dose-Limiting Toxicities (DLTs) Up to Week 6 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.
Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449 -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 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.
Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449 -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 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.
Tmax After Multiple Doses of GDC-0449 -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 Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449 -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 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.
Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449 -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 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.
AUC0-24 After Multiple Doses of GDC-0449 -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 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.
Accumulation Index (AI) After Multiple Doses of GDC-0449 -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 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.
- Secondary Outcome Measures
Name Time Method 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 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.
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 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.
Duration of Objective Response: All Participants Screening, at Week 8 thereafter every 8 weeks, up to Week 116 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.
Duration of Objective Response: Participants With BCC Screening, at Week 8 thereafter every 8 weeks, up to Week 116 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.
Progression-Free Survival (PFS): All Participants Screening, at Week 8 thereafter every 8 weeks, up to Week 116 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.
PFS: Participants With BCC Screening, at Week 8 thereafter every 8 weeks, up to Week 116 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.
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 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.
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