Unspecified Adult Solid Tumor, Protocol SpecificPhase 1NCT00607724

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

A Phase 1 study testing GDC-0449 in people with Unspecified Adult Solid Tumor, Protocol Specific, run by Genentech, Inc..

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Unspecified Adult Solid Tumor, Protocol Specific
What is being tested?: GDC-0449
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 68 participants
Where: No sites listed yet
Study dates: Apr 2007to Nov 2009
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

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

About this study

Official title: 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.

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.

Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Being tested: GDC-0449
Keywords: unspecified adult solid tumor, protocol specific

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GDC-0449Drug
Also called Hedgehog Pathway Inhibitor

Study groups in NCT00607724
Study group	Role	What they receive
Stage 1: GDC-0449 (150 mg)	Experimental	Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 1: GDC-0449 (270 mg)	Experimental	Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 1: GDC-0449 (540 mg)	Experimental	Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 2: BCC [GDC-0449 (150 mg)]	Experimental	Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 2: BCC [GDC-0449 (270 mg)]	Experimental	Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]	Experimental	Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449
Stage 2: New Formulation [GDC-0449 (150 mg )]	Experimental	Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Receives: Drug: GDC-0449

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Up to Week 6
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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
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.
Measured: -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 (7)

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.
Measured: Baseline up to Day 29
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
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.
Measured: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Apr 2007Nov 2009

First posted6 Feb 2008 (estimated)
Study startApr 2007
Primary completionNov 2009
Study completionNov 2009

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Unspecified Adult Solid Tumor, Protocol SpecificStudies of the same condition, open and under way.
More trials run by Genentech, Inc.The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 68 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00607724
Sponsor's protocol ID: CDR0000585468
Other IDs: JHOC-J06131, GENETECH-SHH3925g
Status last verified: Sep 2015
First submitted: 31 Jan 2008
Last updated: 8 Oct 2015
Results posted: Yes, on ClinicalTrials.gov

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

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Study at a glance

From the registry record, last updated by the sponsor on 8 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT00607724
Acronym / sponsor ID: CDR0000585468
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 68 participants (actual)
Lead sponsor: Genentech, Inc.Industry (pharma, biotech, devices)
Collaborators: National Cancer Institute (NCI), Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study start: Apr 2007
Primary completion: Nov 2009 (actual)
Study completion: Nov 2009 (actual)
First posted: 6 Feb 2008 (estimated)
Results: Posted 8 Oct 2015

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

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.

After completion of study therapy, patients are followed at 21 days.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 7

Arm	Type	Receives
Stage 1: GDC-0449 (150 mg)	Experimental	Drug: GDC-0449Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability.
Stage 1: GDC-0449 (270 mg)	Experimental	Drug: GDC-0449Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
Stage 1: GDC-0449 (540 mg)	Experimental	Drug: GDC-0449Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
Stage 2: BCC [GDC-0449 (150 mg)]	Experimental	Drug: GDC-0449Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
Stage 2: BCC [GDC-0449 (270 mg)]	Experimental	Drug: GDC-0449Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]	Experimental	Drug: GDC-0449Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
Stage 2: New Formulation [GDC-0449 (150 mg )]	Experimental	Drug: GDC-0449Participants 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GDC-0449Also: Hedgehog Pathway Inhibitor	Drug	Stage 1: GDC-0449 (150 mg), Stage 1: GDC-0449 (270 mg), Stage 1: GDC-0449 (540 mg), Stage 2: BCC [GDC-0449 (150 mg)], Stage 2: BCC [GDC-0449 (270 mg)], Stage 2: New Formulation [GDC-0449 (150 mg )], Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]

Primary outcome

Percentage of Participants With Dose-Limiting Toxicities (DLTs)
Time frame: 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.
Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449
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
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
Cmax After Multiple Doses of GDC-0449
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
Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449
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
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
Tmax After Multiple Doses of GDC-0449
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
Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449
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
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.
Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449
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
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.
AUC0-24 After Multiple Doses of GDC-0449
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
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.
Accumulation Index (AI) After Multiple Doses of GDC-0449
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
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.

7 secondary outcomes

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)
Time frame: Baseline up to Day 29
Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Duration of Objective Response: All Participants
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Duration of Objective Response: Participants With BCC
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Progression-Free Survival (PFS): All Participants
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
PFS: Participants With BCC
Time frame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116

Results and safety

Results posted to the registry on 8 Oct 2015, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Stage 1: GDC-0449 (150 mg)	7	0
Stage 1: GDC-0449 (270 mg)	9	1
Stage 1: GDC-0449 (540 mg)	4	0
Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]	0	0
Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]	0	0
Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]	0	0
Stage 2: New Formulation [GDC-0449 (150 mg )]	0	0

Primary outcome: Percentage of Participants With Dose-Limiting Toxicities (DLTs)

Time frame: Up to Week 6. Number. Unit: percentage of participants

Measure	Stage 1: GDC-0449 (150 mg) n = 7	Stage 1: GDC-0449 (270 mg) n = 9	Stage 1: GDC-0449 (540 mg) n = 4	Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) n = 6	Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) n = 14	Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg]) n = 12	Stage 2: New Formulation (GDC-0449 [150 mg]) n = 16
Value	0	0	0	0	0	0	0

Population analysed: Safety-evaluable population.

Primary outcome: Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449

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. Mean (Standard Deviation). Unit: micromolar (mcM)

Measure	Stage 1: GDC-0449 (150 mg) n = 7	Stage 1: GDC-0449 (270 mg) n = 9	Stage 1: GDC-0449 (540 mg) n = 4	Stage 2: New Formulation (GDC-0449 [150 mg]) n = 16
Phase I	3.58 (1.34)	6.34 (3.40)	6.81 (2.69)	NA (NA)
Phase II	NA (NA)	NA (NA)	NA (NA)	7.2 (3.38)

Population analysed: Pharmacokinetic (PK)-evaluable population included participants who had at least Day 1 PK samples available.

Primary outcome: Cmax After Multiple Doses of GDC-0449

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

Population analysed: Cmax was not reported as there were \<50% participants with extensive PK sampling and the PK profiles were flat over 24 hours at steady state which did not allow estimation of Cmax.

Primary outcome: Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449

Measure	Stage 1: GDC-0449 (150 mg) n = 7	Stage 1: GDC-0449 (270 mg) n = 9	Stage 1: GDC-0449 (540 mg) n = 4	Stage 2: New Formulation (GDC-0449 [150 mg]) n = 16
Phase I	2 (0.0417 to 7)	2 (1 to 3)	2.5 (0.167 to 3)	NA (NA to NA)
Phase II	NA (NA to NA)	NA (NA to NA)	NA (NA to NA)	1 (0.0833 to 1)

Population analysed: PK-evaluable population.

7 secondary outcomes are reported in the full results.

Adverse events

Time frame: From Screening up to 28 days after the last dose of GDC-0449 (Week 116).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Stage 1: GDC-0449 (150 mg)	3 of 7 (42.9%)	7 of 7 (100%)	Not reported
Stage 1: GDC-0449 (270 mg)	2 of 9 (22.2%)	9 of 9 (100%)	Not reported
Stage 1: GDC-0449 (540 mg)	1 of 4 (25%)	4 of 4 (100%)	Not reported
Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)]	2 of 6 (33.3%)	6 of 6 (100%)	Not reported
Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)]	4 of 14 (28.6%)	14 of 14 (100%)	Not reported
Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]	4 of 12 (33.3%)	12 of 12 (100%)	Not reported
Stage 2: New Formulation [GDC-0449 (150 mg )]	4 of 16 (25%)	16 of 16 (100%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2015.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 23342272Thacker 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.
Derived from this study: PubMed 19726763Von 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clinical Trials study director

Hoffmann-La Roche

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GDC-0449 in people with Unspecified Adult Solid Tumor, Protocol Specific, run by Genentech, Inc..

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Oct 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Dose-Limiting Toxicities (DLTs) (time frame: Up to Week 6). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00607724, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2015.