A Study of Hedgehog Pathway Inhibitor GDC-0449 in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists
- Registration Number
- NCT00968981
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
This is a two stage, Phase Ib study designed to describe the pharmacokinetics of GDC-0449 in patients with advanced solid tumors that are refractory to treatment or for whom no standard therapy exists.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 67
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description A GDC-0449 - B GDC-0449 - C GDC-0449 -
- Primary Outcome Measures
Name Time Method Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57 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.
Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57 Percent change = (\[trough concentration on Day 15 minus trough concentration on Day 57\] divided by trough concentration on Day 15) multiplied by 100.
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57 Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 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.
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1, 15 and 57 post-dose 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.
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57 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.
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57 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.
Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Disease Progression or Death Screening, Day 57, and every 8 weeks thereafter up to 52 weeks Disease progression (assessed by Response Evaluation Criteria in Solid Tumors \[RECIST\]) was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing non target lesions.
Percentage of Participants With a Response by Best Overall Response (BOR) Screening Day 57, and every 8 weeks thereafter up to 52 weeks BOR was defined as the best overall response observed during the treatment period according to RECIST. 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. Progressive disease (PD): at least a 20% increase in the sum of diameters of TLs, taking as a reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase in 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Stable disease (SD) was defined as neither sufficient shrinkages to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Progression-Free Survival (PFS) Time Screening Day 57, and every 8 weeks thereafter up to 52 weeks PFS defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by the investigator review of tumor assessments using RECIST, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).
Duration of Response (DR) Screening Day 57, and every 8 weeks thereafter up to 52 weeks DR during first line therapy is defined as the time from when response (complete response \[CR\] or partial response \[PR\]) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only be 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. 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. PR: at least a 30% decrease in the sum of diameters of TLs, with reference to baseline sum diameters. DR was not calculated as only 1 responding participant reached their response at the last scheduled response assessment, hence follow-up data are not available.