Solid Cancers
Conditions
Keywords
Hedgehog, BCC, basal cell carcinoma
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.
Interventions
DRUGGDC-0449
Daily oral repeating dose
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented, incurable, locally advanced or metastatic solid malignancy that has progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit); patients with basal cell carcinoma will be excluded from this study unless they do not qualify for another open GDC-0449 clinical trial * For patients with disease that is evaluable by physical examination only, diagnosis must also include biomarker confirmation * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Documented negative pregnancy test for women of childbearing potential and agreement to use an effective form of contraception for the duration of the study * Adequate hematopoietic capacity * Adequate hepatic function * Adequate renal function * At least 3 weeks since last chemotherapy, investigational agent, radiation therapy, or major surgical procedure and recovery to pre-treatment baseline or stabilization of all treatment-related toxicities
Exclusion criteria
* Known, untreated central nervous system (CNS) malignancies or treated brain metastases that are not radiographically stable for ≥ 3 months * Active infection requiring intravenous (IV) antibiotics * Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis * Any medical condition or diagnosis that would likely impair absorption of an orally administered drug (e.g., gastrectomy, ileal bypass, chronic diarrhea, gastroparesis) * Any other diseases, 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 results or renders the patient at high risk from treatment complications * Pregnant or lactating * Treatment with excluded medications, including strong CYP450 inhibitors and inducers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 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 | — |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GDC-0449 150 mg QD Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose). | 23 |
| GDC-0449 150 mg TIW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose). | 22 |
| GDC-0449 150 mg QW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose). | 22 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Disease Progression | 14 | 16 | 13 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Physician Decision | 5 | 3 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 3 |
Baseline characteristics
| Characteristic | GDC-0449 150 mg QD | GDC-0449 150 mg TIW | GDC-0449 150 mg QW | Total |
|---|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 10.4 | 64.0 years STANDARD_DEVIATION 12.3 | 62.9 years STANDARD_DEVIATION 10.3 | 63.0 years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 10 Participants | 9 Participants | 10 Participants | 29 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 12 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 20 | 19 / 21 | 20 / 22 |
| serious Total, serious adverse events | 6 / 20 | 8 / 21 | 8 / 22 |
Outcome results
Primary
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449
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.
Time frame: 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
Population: PK Evaluable Population. n = number of participants with data available at specified timepoint in each group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Single Dose (n=20,21,22) | 130.88 mcM*hour | Standard Deviation 73.69 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 29 (n=14,17,18) | 696 mcM*hour | Standard Deviation 258 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 50 (n=11,13,9) | 729 mcM*hour | Standard Deviation 251 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.38 mcM*hour | Standard Deviation 0.31 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 29 (n=14,17,17) | 4.06 mcM*hour | Standard Deviation 1.13 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 50 (n=11,13,9) | 4.8 mcM*hour | Standard Deviation 1.75 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 50 (n=11,13,9) | 2.44 mcM*hour | Standard Deviation 1.19 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Single Dose (n=20,21,22) | 129.44 mcM*hour | Standard Deviation 71.66 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.30 mcM*hour | Standard Deviation 0.27 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 29 (n=14,17,17) | 2.39 mcM*hour | Standard Deviation 1.29 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 29 (n=14,17,18) | 595 mcM*hour | Standard Deviation 241 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 50 (n=11,13,9) | 587 mcM*hour | Standard Deviation 274 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 29 (n=14,17,18) | 455 mcM*hour | Standard Deviation 116 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Day 50 (n=11,13,9) | 387 mcM*hour | Standard Deviation 86 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 50 (n=11,13,9) | 1.51 mcM*hour | Standard Deviation 0.615 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.32 mcM*hour | Standard Deviation 0.2 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Total GDC-0449: Single Dose (n=20,21,22) | 126.05 mcM*hour | Standard Deviation 61.73 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 | AUC0-24,Unbound GDC-0449:Day 29 (n=14,17,17) | 1.81 mcM*hour | Standard Deviation 0.958 |
Primary
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449
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 frame: 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
Population: PK Evaluable Population. n = number of participants with data available at specified time point in each group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Single Dose (n=20,21,22) | 431.20 mcM*hour | Standard Deviation 201.18 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 28-35 (n=14,14,18) | 4834.06 mcM*hour | Standard Deviation 1708.27 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 49-56 (n=9,13,9) | 5235.09 mcM*hour | Standard Deviation 2010.93 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449: Single Dose (n=20,21,22) | 1.19 mcM*hour | Standard Deviation 0.73 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 28-35 (n=14,17,17) | 28.32 mcM*hour | Standard Deviation 8.37 |
| GDC-0449 150 mg QD | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 49-56 (n=8,13,9) | 33.40 mcM*hour | Standard Deviation 11.91 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 49-56 (n=8,13,9) | 15.57 mcM*hour | Standard Deviation 6.52 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Single Dose (n=20,21,22) | 478.38 mcM*hour | Standard Deviation 212.88 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449: Single Dose (n=20,21,22) | 1.08 mcM*hour | Standard Deviation 0.82 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 28-35 (n=14,17,17) | 15.69 mcM*hour | Standard Deviation 7.79 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 28-35 (n=14,14,18) | 4302.84 mcM*hour | Standard Deviation 1691.87 |
| GDC-0449 150 mg TIW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 49-56 (n=9,13,9) | 4074.88 mcM*hour | Standard Deviation 1779.33 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 28-35 (n=14,14,18) | 2935.33 mcM*hour | Standard Deviation 926.74 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Day 49-56 (n=9,13,9) | 2656.65 mcM*hour | Standard Deviation 666.09 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 49-56 (n=8,13,9) | 8.76 mcM*hour | Standard Deviation 3.23 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449: Single Dose (n=20,21,22) | 1.09 mcM*hour | Standard Deviation 0.65 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Total GDC-0449: Single Dose (n=20,21,22) | 453.14 mcM*hour | Standard Deviation 209.48 |
| GDC-0449 150 mg QW | Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 | AUClast,Unbound GDC-0449:Day 28-35 (n=14,17,17) | 10.50 mcM*hour | Standard Deviation 6.08 |
Primary
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449
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.
Time frame: 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1, 15 and 57 post-dose
Population: PK Evaluable Population. 'n' signifies number of participants with data available at specified timepoint in each group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 50-57 (n=11,13,10) | 0.247 mcM | Standard Deviation 0.0841 |
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 50-57 (n=11,13,10) | 33.9 mcM | Standard Deviation 12.2 |
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 29-36 (n=15,18,18) | 0.215 mcM | Standard Deviation 0.0797 |
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Single Dose (n=20,21,22) | 7.09 mcM | Standard Deviation 3.66 |
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.02 mcM | Standard Deviation 0.02 |
| GDC-0449 150 mg QD | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 29-36 (n=15,18,18) | 30.4 mcM | Standard Deviation 11.6 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.02 mcM | Standard Deviation 0.02 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 29-36 (n=15,18,18) | 0.122 mcM | Standard Deviation 0.0602 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 29-36 (n=15,18,18) | 29.5 mcM | Standard Deviation 12.6 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 50-57 (n=11,13,10) | 0.132 mcM | Standard Deviation 0.0717 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Single Dose (n=20,21,22) | 8.08 mcM | Standard Deviation 3.48 |
| GDC-0449 150 mg TIW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 50-57 (n=11,13,10) | 28.6 mcM | Standard Deviation 13.8 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 50-57 (n=11,13,10) | 18.2 mcM | Standard Deviation 4.23 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Single Dose (n=20,21,22) | 7.29 mcM | Standard Deviation 3.24 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Total GDC-0449: Day 29-36 (n=15,18,18) | 21.2 mcM | Standard Deviation 5.59 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 50-57 (n=11,13,10) | 0.0688 mcM | Standard Deviation 0.0312 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449: Single Dose (n=20,21,22) | 0.02 mcM | Standard Deviation 0.01 |
| GDC-0449 150 mg QW | Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 | Cmax,Unbound GDC-0449:Day 29-36 (n=15,18,18) | 0.0998 mcM | Standard Deviation 0.0516 |
Primary
Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough)
Percent change = (\[trough concentration on Day 15 minus trough concentration on Day 57\] divided by trough concentration on Day 15) multiplied by 100.
Time frame: 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
Population: PK Evaluable Population. Here number of participants analyzed (N) = participants with baseline and at least 1 post baseline assessment for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GDC-0449 150 mg QD | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Total GDC-0449 | 0 participants |
| GDC-0449 150 mg QD | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Unbound GDC-0449 | 0 participants |
| GDC-0449 150 mg TIW | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Total GDC-0449 | 1 participants |
| GDC-0449 150 mg TIW | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Unbound GDC-0449 | 6 participants |
| GDC-0449 150 mg QW | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Total GDC-0449 | 4 participants |
| GDC-0449 150 mg QW | Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) | Unbound GDC-0449 | 9 participants |
Primary
Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449
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.
Time frame: 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
Population: PK Evaluable Population. N = participants with baseline and post baseline data available for measurement of Css at steady state.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-0449 150 mg QD | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Total GDC-0449 | 28 mcM | Standard Deviation 11.4 |
| GDC-0449 150 mg QD | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Unbound GDC-0449 | 0.163 mcM | Standard Deviation 0.056 |
| GDC-0449 150 mg TIW | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Total GDC-0449 | 26.1 mcM | Standard Deviation 11.8 |
| GDC-0449 150 mg TIW | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Unbound GDC-0449 | 0.088 mcM | Standard Deviation 0.0408 |
| GDC-0449 150 mg QW | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Total GDC-0449 | 16.9 mcM | Standard Deviation 5.89 |
| GDC-0449 150 mg QW | Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 | Unbound GDC-0449 | 0.0489 mcM | Standard Deviation 0.0259 |
Primary
Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15
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.
Time frame: 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
Population: The PK Evaluable Population. N = participants who completed Day 57 of the study were included in this analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| GDC-0449 150 mg QD | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Total GDC-0449 | 1.23 ratio |
| GDC-0449 150 mg QD | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Unbound GDC-0449 | 1.34 ratio |
| GDC-0449 150 mg TIW | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Total GDC-0449 | 0.87 ratio |
| GDC-0449 150 mg TIW | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Unbound GDC-0449 | 0.58 ratio |
| GDC-0449 150 mg QW | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Total GDC-0449 | 0.54 ratio |
| GDC-0449 150 mg QW | Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 | Css,trough for Unbound GDC-0449 | 0.20 ratio |
Primary
Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449
Time frame: 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1
Population: PK Evaluable Population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GDC-0449 150 mg QD | Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449 | Total GDC-0449 | 48 hours |
| GDC-0449 150 mg QD | Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449 | Unbound GDC-0449 | 48 hours |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449
Time frame: 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
Population: The PK Evaluable Population. Number of participants analyzed (N) is equal to (=) participants with baseline and at least one post-baseline assessment for this outcome; n = participants evaluable at specified time-points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GDC-0449 150 mg QD | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 29-36 (n=15,18,18) | 24 hours |
| GDC-0449 150 mg QD | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 50-57 (n=11,13,10) | 74 hours |
| GDC-0449 150 mg QD | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound; Days 29-36 (n=15, 18, 18) | 24 hours |
| GDC-0449 150 mg QD | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound: Days 50-57 (n=11,13,10) | 104 hours |
| GDC-0449 150 mg TIW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound: Days 50-57 (n=11,13,10) | 94 hours |
| GDC-0449 150 mg TIW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 29-36 (n=15,18,18) | 72 hours |
| GDC-0449 150 mg TIW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound; Days 29-36 (n=15, 18, 18) | 6 hours |
| GDC-0449 150 mg TIW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 50-57 (n=11,13,10) | 74 hours |
| GDC-0449 150 mg QW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound: Days 50-57 (n=11,13,10) | 4 hours |
| GDC-0449 150 mg QW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 50-57 (n=11,13,10) | 24 hours |
| GDC-0449 150 mg QW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Unbound; Days 29-36 (n=15, 18, 18) | 6 hours |
| GDC-0449 150 mg QW | Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 | Total: Days 29-36 (n=15,18,18) | 15 hours |
Secondary
Duration of Response (DR)
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.
Time frame: Screening Day 57, and every 8 weeks thereafter up to 52 weeks
Secondary
Percentage of Participants With a Response by Best Overall Response (BOR)
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.
Time frame: Screening Day 57, and every 8 weeks thereafter up to 52 weeks
Population: Efficacy Evaluable Population; only participants with measurable disease at baseline were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GDC-0449 150 mg QD | Percentage of Participants With a Response by Best Overall Response (BOR) | Partial Response | 7.7 percentage of participants |
| GDC-0449 150 mg QD | Percentage of Participants With a Response by Best Overall Response (BOR) | Complete Response | 0.0 percentage of participants |
| GDC-0449 150 mg QD | Percentage of Participants With a Response by Best Overall Response (BOR) | Progressive Disease | 61.5 percentage of participants |
| GDC-0449 150 mg QD | Percentage of Participants With a Response by Best Overall Response (BOR) | Stable Disease | 30.8 percentage of participants |
| GDC-0449 150 mg QD | Percentage of Participants With a Response by Best Overall Response (BOR) | Unevaluable (UE) | 0.0 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With a Response by Best Overall Response (BOR) | Unevaluable (UE) | 0.0 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With a Response by Best Overall Response (BOR) | Complete Response | 0.0 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With a Response by Best Overall Response (BOR) | Partial Response | 0.0 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With a Response by Best Overall Response (BOR) | Stable Disease | 22.2 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With a Response by Best Overall Response (BOR) | Progressive Disease | 77.8 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With a Response by Best Overall Response (BOR) | Partial Response | 0.0 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With a Response by Best Overall Response (BOR) | Unevaluable (UE) | 6.7 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With a Response by Best Overall Response (BOR) | Progressive Disease | 40.0 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With a Response by Best Overall Response (BOR) | Complete Response | 0.0 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With a Response by Best Overall Response (BOR) | Stable Disease | 53.3 percentage of participants |
Secondary
Percentage of Participants With Disease Progression or Death
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.
Time frame: Screening, Day 57, and every 8 weeks thereafter up to 52 weeks
Population: Efficacy Evaluable Population: all participants who had measurable disease at baseline and either had at least one follow-up tumor assessment or discontinued the study due to disease progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GDC-0449 150 mg QD | Percentage of Participants With Disease Progression or Death | 52.9 percentage of participants |
| GDC-0449 150 mg TIW | Percentage of Participants With Disease Progression or Death | 75.0 percentage of participants |
| GDC-0449 150 mg QW | Percentage of Participants With Disease Progression or Death | 40.0 percentage of participants |
Secondary
Progression-Free Survival (PFS) Time
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).
Time frame: Screening Day 57, and every 8 weeks thereafter up to 52 weeks
Population: Efficacy Evaluable Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GDC-0449 150 mg QD | Progression-Free Survival (PFS) Time | 1.9 months |
| GDC-0449 150 mg TIW | Progression-Free Survival (PFS) Time | 1.9 months |
| GDC-0449 150 mg QW | Progression-Free Survival (PFS) Time | 2.2 months |