Clinical trial NCT00607724: GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: National Cancer Institute (NCI)
name: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
First posted: 2008-02-06
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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

Primary outcomes:
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Up to Week 6
measure: Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449
timeFrame: -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
measure: Cmax After Multiple Doses of GDC-0449
timeFrame: -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
measure: Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449
timeFrame: -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
measure: Tmax After Multiple Doses of GDC-0449
timeFrame: -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
measure: Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449
timeFrame: -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
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449
timeFrame: -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
measure: AUC0-24 After Multiple Doses of GDC-0449
timeFrame: -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
measure: Accumulation Index (AI) After Multiple Doses of GDC-0449
timeFrame: -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:
measure: 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)
timeFrame: Baseline up to Day 29
measure: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
measure: Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
measure: Duration of Objective Response: All Participants
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
measure: Duration of Objective Response: Participants With BCC
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
measure: Progression-Free Survival (PFS): All Participants
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
measure: PFS: Participants With BCC
timeFrame: Screening, at Week 8 thereafter every 8 weeks, up to Week 116
Other outcomes:
Locations:
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.