- ICH GCP
- US Clinical Trials Registry
- Klinisk utprøving NCT00607724
GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors
An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists
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.
Studieoversikt
Status
Intervensjon / Behandling
Detaljert beskrivelse
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.
Studietype
Registrering (Faktiske)
Fase
- Fase 1
Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Beskrivelse
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
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Ikke-randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Eksperimentell: 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.
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Andre navn:
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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
---|---|---|
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
Tidsramme: Up to Week 6
|
A DLT was defined as any Grade 3 or 4 hematologic or major organ toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) that occurred during the first 35 days after the initiation of study drug (Days 1-35) and was attributable to GDC-0449.
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Up to Week 6
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Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449
Tidsramme: -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8
|
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2).
Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
|
-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
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Cmax After Multiple Doses of GDC-0449
Tidsramme: -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
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Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
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-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
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Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449
Tidsramme: -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8
|
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2).
Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
|
-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
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Tmax After Multiple Doses of GDC-0449
Tidsramme: -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
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Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
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-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
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Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449
Tidsramme: -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
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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.
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-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
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Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449
Tidsramme: -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
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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.
|
-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
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AUC0-24 After Multiple Doses of GDC-0449
Tidsramme: -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years
|
AUC is a measure of the serum concentration of the drug over time.
It is used to characterize drug absorption.
AUC was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
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-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
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Accumulation Index (AI) After Multiple Doses of GDC-0449
Tidsramme: -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
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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.
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-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
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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
---|---|---|
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)
Tidsramme: Baseline up to Day 29
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Ribonucleic acid (RNA) was extracted from biopsy specimens of noninvolved skin or hair follicles at baseline and at 7 and 21 days after the start of daily drug therapy.
Control mRNA was obtained from formalin-fixed, paraffin-embedded samples of normal skin and hair follicles from participants who were not enrolled in the study.
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Baseline up to Day 29
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Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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Duration of Objective Response: All Participants
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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Duration of Objective Response: Participants With BCC
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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Progression-Free Survival (PFS): All Participants
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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PFS: Participants With BCC
Tidsramme: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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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.
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Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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Samarbeidspartnere og etterforskere
Sponsor
Publikasjoner og nyttige lenker
Generelle publikasjoner
- 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.
- 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.
Studierekorddatoer
Studer hoveddatoer
Studiestart
Primær fullføring (Faktiske)
Studiet fullført (Faktiske)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Anslag)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Anslag)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
Sist bekreftet
Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- CDR0000585468
- JHOC-J06131
- GENETECH-SHH3925g
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