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

Genentech, Inc.68 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Interventions

GDC-0449DRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

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

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

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

Data from ClinicalTrials.gov

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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)

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

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.