Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
GDC-0449 · 4 trials · 4 indications
Percent change = (\[trough concentration on Day 15 minus trough concentration on Day 57\] divided by trough concentration on Day 15) multiplied by 100.
Ratio = trough concentration on Day 57 divided by trough concentration on Day 15. If the ratio of total and unbound trough GDC-0449 concentration between Day 57 to Day 15 is less than 1, then it indicates reduction in total and unbound trough GDC-0449 concentration between Day 15 to Day 57.
Plasma GDC-0449 concentrations were reported in nanogram per milliliter (ng/mL) units and converted to micromolar (mcM) units using the molecular weight (421.30 grams per mole \[g/mol\]) prior to PK analysis. Css was calculated for Days 28 to 56.
Plasma GDC-0449 concentrations were reported in ng/mL units and converted to mcM units using the molecular weight (421.30 g/mol) prior to PK analysis.
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). Below the limit of quantitation (BLQ) values at pre-dose were considered as zero for PK analysis.
AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). BLQ values at pre-dose were considered as zero for PK analysis.
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.
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.
Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
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 was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
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.
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| A | ACTIVE_COMPARATOR | - |
| B | ACTIVE_COMPARATOR | - |
| C | EXPERIMENTAL | - |
| D | EXPERIMENTAL | On Days 1-6, subjects received a single oral dose of non-labeled GDC-0449. On Day 7, subjects received a single oral dose of 14C-GDC-0449. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Name | Type | Description |
|---|---|---|
| GDC-0449 | DRUG | Oral repeating dose |
| moxifloxacin | DRUG | Oral single dose |
| placebo | DRUG | Oral repeating dose |
| GDC-0449 oral capsules (non-labeled) | DRUG | 150 mg oral capsule |
| GDC-0449 IV injection (labeled) | DRUG | 10 mcg (in 2 mL) IV dose of 14C-GDC-0449 |
| CDC-0449 oral suspension (labeled) | DRUG | 30-mL oral suspension containing 6.5 mcg 14CGDC-0449 and 150 mg GDC-0449 |
Inclusion Criteria: * Female, over 45 years of age * In good health, as determined by the absence of clinically significant findings from the screening visit * Body mass index between 18 and 32 kg/m\^2 inclusive, with a body weight \> 45 kg * Of non-childbearing potential Exclusion Criteria: * Hi...
GDC-0449 is an investigational small molecule being studied in Phase 1 clinical trials for the treatment of locally advanced or metastatic solid tumors that are refractory to standard therapy or for which no standard therapy exists. It has also been studied in healthy volunteers for safety and tolerability assessments.
GDC-0449 is being developed by Roche Holding AG, which trades under the ticker RHHBY. The drug is currently in Phase 1 clinical development.
GDC-0449 is in Phase 1 clinical development. It is an investigational drug and has not been approved by regulatory authorities. All four clinical trials listed for GDC-0449 are Phase 1 studies that have been completed.
GDC-0449 has been studied in four completed Phase 1 trials: NCT00607724 in patients with advanced solid tumors, NCT00968981 in patients with refractory solid cancers, NCT00991718 in healthy female subjects, and NCT01173536 to evaluate its effect on QT/QTc interval in healthy female volunteers.
GDC-0449 is also known as vismodegib, a hedgehog pathway inhibitor. It has been studied under the name GDC-0449 in clinical trials for solid tumors and in healthy volunteers.