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CompletedNCT00607724Updated Oct 8, 2015Results posted

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

A Phase 1 interventional study of GDC-0449 in Unspecified Adult Solid Tumor, Protocol Specific, sponsored by Genentech, Inc.. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-10-08.

Sponsored by Genentech, Inc. · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
68
Allocation
Non-randomized
Ages
18 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Unspecified Adult Solid Tumor, Protocol Specific

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Keywords

  • unspecified adult solid tumor, protocol specific
03

In context

Neoplasms

9,365 studies on the registry are indexed under Neoplasms; 2,489 are open to participants now.

This study's enrollment of 68 is above the median of 50 across 7,253 interventional studies indexed under Neoplasms.

Browse Neoplasms studies →

Lead sponsor

Genentech, Inc. is the lead sponsor of 507 studies on the registry; 23 are open to participants now.

Of its 90 completed or terminated interventional studies of FDA-regulated products, 50 (56%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

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
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
68 participants (actual)

Study arms

  • Experimental
    Stage 1: GDC-0449 (150 mg)

    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

  • Experimental
    Stage 1: GDC-0449 (270 mg)

    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

  • Experimental
    Stage 1: GDC-0449 (540 mg)

    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

  • Experimental
    Stage 2: BCC [GDC-0449 (150 mg)]

    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

  • Experimental
    Stage 2: BCC [GDC-0449 (270 mg)]

    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

  • Experimental
    Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]

    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

  • Experimental
    Stage 2: New Formulation [GDC-0449 (150 mg )]

    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

Interventions

  • DrugGDC-0449

    Also known as: Hedgehog Pathway Inhibitor

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: Up to Week 6

  2. 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.

    Time frame: -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

  3. 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.

    Time frame: -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

  4. 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.

    Time frame: -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

  5. 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.

    Time frame: -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

  6. 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.

    Time frame: -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

  7. 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.

    Time frame: -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

  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.

    Time frame: -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

  9. 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.

    Time frame: -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 outcomes

  1. 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.

    Time frame: Baseline up to Day 29

  2. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

  3. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

  4. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

  5. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

  6. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

  7. 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.

    Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

07

Results

Posted Oct 8, 2015

Participant flow

Stage 1: Dose Escalation
Participant flow — Stage 1: Dose Escalation
MilestoneStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]
Started7940000
Completed0100000
Not completed7840000
Withdrew: Tumour progression-clinical/radiographic7840000
Stage 2: Expanded Cohort
Participant flow — Stage 2: Expanded Cohort
MilestoneStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]
Started0006141216
Completed0001505
Not completed000591211
Withdrew: Adverse event0000001
Withdrew: Tumour progression-clinical/radiographic000481110
Withdrew: Physician decision0000110
Withdrew: Withdrawal by subject0001000

Outcome measures

PrimaryPercentage 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.

Time frame:
Up to Week 6
Reported as:
Number · percentage of participants
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
percentage of participantsStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg])Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg])Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg])Stage 2: New Formulation (GDC-0449 [150 mg])
Percentage of Participants With Dose-Limiting Toxicities (DLTs)0000000
PrimaryMaximum 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.

Time frame:
-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
Reported as:
Mean · micromolar (mcM)
Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449
micromolar (mcM)Stage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: New Formulation (GDC-0449 [150 mg])
Phase I3.58 ± 1.346.34 ± 3.406.81 ± 2.69NA ± NA
Phase IINA ± NANA ± NANA ± NA7.2 ± 3.38
PrimaryCmax 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.

Time frame:
-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

No measurements were reported for this outcome.

PrimaryTime 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.

Time frame:
-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
Reported as:
Median · days
Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449
daysStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: New Formulation (GDC-0449 [150 mg])
Phase I2 (0.0417 to 7)2 (1 to 3)2.5 (0.167 to 3)NA (NA to NA)
Phase IINA (NA to NA)NA (NA to NA)NA (NA to NA)1 (0.0833 to 1)
PrimaryTmax 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.

Time frame:
-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

No measurements were reported for this outcome.

PrimaryAverage 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.

Time frame:
-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
Reported as:
Mean · mcM
Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449
mcMStage 1+Stage 2: GDC-0449 (150 mg)Stage 1+Stage 2: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: New Formulation (GDC-0449 [150 mg])
Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-044923.1 ± 10.619.8 ± 9.5122.2 ± 8.3824.5 ± 6.85
PrimaryArea 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.

Time frame:
-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
Reported as:
Mean · mcM*day
Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449
mcM*dayStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: New Formulation (GDC-0449 [150 mg])
Phase I2.22 ± 0.9664.24 ± 1.954.79 ± 2.22NA ± NA
Phase IINA ± NANA ± NANA ± NA5.2 ± 2.79
PrimaryAUC0-24 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.

Time frame:
-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

No measurements were reported for this outcome.

PrimaryAccumulation 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.

Time frame:
-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

No measurements were reported for this outcome.

SecondaryPercentage 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.

Time frame:
Baseline up to Day 29
Reported as:
Number · percentage of participants
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)
percentage of participantsAll Participants
Skin biopsy (n = 34)73.5
Hair follicle (n = 20)30.0
SecondaryPercentage 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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Number · percentage of participants
Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants
percentage of participantsStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg])Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg])Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg])Stage 2: New Formulation (GDC-0449 [150 mg])
Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants14.311.10.066.742.90.037.5
SecondaryPercentage 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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Number · percentage of participants
Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma
percentage of participantsStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg])Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg])Stage 2: New Formulation (GDC-0449 [150 mg])
Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma100.0100.00.066.742.960.0
SecondaryDuration 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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Median · months
Duration of Objective Response: All Participants
monthsStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg])Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg])Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg])Stage 2: New Formulation (GDC-0449 [150 mg])
Duration of Objective Response: All Participants9.2 (NA to NA)NA (NA to NA)—6.1 (3.71 to NA)NA (5.72 to NA)—8.3 (3.71 to NA)
SecondaryDuration 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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Median · months
Duration of Objective Response: Participants With BCC
monthsStage 1+Stage 2: GDC-0449 (150 mg)Stage 1+Stage 2: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)
Duration of Objective Response: Participants With BCC8.3 (3.71 to NA)NA (5.72 to NA)—
SecondaryProgression-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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Median · months
Progression-Free Survival (PFS): All Participants
monthsStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg])Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg])Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg])Stage 2: New Formulation (GDC-0449 [150 mg])
Progression-Free Survival (PFS): All Participants2.0 (0.99 to 14.85)1.6 (0.85 to 5.88)2.1 (1.25 to 3.02)9.6 (5.75 to NA)12.7 (6.70 to NA)1.8 (0.76 to 2.10)7.1 (0.99 to NA)
SecondaryPFS: 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.

Time frame:
Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Reported as:
Median · months
PFS: Participants With BCC
monthsStage 1+Stage 2: GDC-0449 (150 mg)Stage 1+Stage 2: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)
PFS: Participants With BCC10.8 (6.67 to NA)12.7 (6.70 to NA)1.2 (NA to NA)

Adverse events

Collected over From Screening up to 28 days after the last dose of GDC-0449 (Week 116).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Stage 1: GDC-0449 (150 mg)—3/7 (42.9%)7/7 (100%)
Stage 1: GDC-0449 (270 mg)—2/9 (22.2%)9/9 (100%)
Stage 1: GDC-0449 (540 mg)—1/4 (25%)4/4 (100%)
Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]—2/6 (33.3%)6/6 (100%)
Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]—4/14 (28.6%)14/14 (100%)
Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]—4/12 (33.3%)12/12 (100%)
Stage 2: New Formulation [GDC-0449 (150 mg )]—4/16 (25%)16/16 (100%)
Most frequent serious events
Showing 10 of 24
Most frequent serious events
EventStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]
PneumoniaInfections and infestations0/70/91/40/60/140/120/16
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/70/91/40/60/140/120/16
Atrial fibrillationCardiac disorders0/70/90/41/60/140/120/16
Abdominal painGastrointestinal disorders1/70/90/40/60/142/120/16
HyponatraemiaMetabolism and nutrition disorders0/70/90/41/60/141/120/16
DyspnoeaRespiratory, thoracic and mediastinal disorders0/70/90/41/60/140/120/16
HyperkalaemiaMetabolism and nutrition disorders1/70/90/40/60/140/120/16
DehydrationMetabolism and nutrition disorders1/70/90/40/60/140/120/16
Pancreatic carcinoma metastaticNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/71/90/40/60/140/120/16
Pancreatic carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/70/90/40/60/140/120/16
Most frequent other events
Showing 10 of 310
Most frequent other events
EventStage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]
Muscle spasmsMusculoskeletal and connective tissue disorders2/72/91/44/612/140/1211/16
DysgeusiaNervous system disorders1/73/91/45/68/142/128/16
HypoaesthesiaNervous system disorders0/70/93/41/60/141/122/16
AlopeciaSkin and subcutaneous tissue disorders0/71/90/43/610/141/129/16
FatigueGeneral disorders1/74/90/44/68/146/125/16
NauseaGastrointestinal disorders1/75/91/42/65/144/125/16
DiarrhoeaGastrointestinal disorders1/72/91/43/64/141/126/16
ConstipationGastrointestinal disorders1/71/91/43/62/142/122/16
Decreased appetiteMetabolism and nutrition disorders0/74/92/41/64/145/123/16
Urinary hesitationRenal and urinary disorders0/70/92/42/60/140/120/16

Baseline characteristics

Safety-evaluable population included all participants who received any amount of GDC-0449.

Age, Continuous
Age, Continuous(years)Stage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]Total
Mean57.6 ± 10.559.9 ± 12.642.3 ± 15.354.2 ± 15.354.7 ± 11.255.3 ± 14.854.6 ± 11.055.0 ± 12.6
Sex: Female, Male
Sex: Female, Male(Participants)Stage 1: GDC-0449 (150 mg)Stage 1: GDC-0449 (270 mg)Stage 1: GDC-0449 (540 mg)Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]Stage 2: New Formulation [GDC-0449 (150 mg )]Total
Female251145624
Male54351071044
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Study locations

No study locations are listed for this record.

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References and documents

Publications

  • Thacker CA, Weiss GJ, Tibes R, Blaydorn L, Downhour M, White E, Baldwin J, Hoff DD, Korn RL. 18-FDG PET/CT assessment of basal cell carcinoma with vismodegib. Cancer Med. 2012 Oct;1(2):230-6. doi: 10.1002/cam4.33. Epub 2012 Sep 17. PubMed 23342272 ↗
  • Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2. PubMed 19726763 ↗
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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Oct 8, 2015, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT00607724
Lead sponsor
Genentech, Inc.
Collaborators
National Cancer Institute (NCI), Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Responsible party
Sponsor
First posted
Feb 6, 2008
Start date
Apr 2007
Primary completion
Nov 2009
Completion
Nov 2009
Results posted
Oct 8, 2015
Last update
Oct 8, 2015

Study contacts

Clinical Trials
study director · Hoffmann-La Roche
View the source record on ClinicalTrials.gov ↗

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