Part 2 of Phase 1 Study of GC1008 to Treat Advanced Melanoma (Part 2 Will Only Accept and Treat Patients With Advanced Malignant Melanoma)

Renal Cell Carcinoma Clinical Trial

Official title: A Phase 1 Study of the Safety and Efficacy of GC1008: A Human Anti-Transforming Growth Factor-Beta (TGFBeta) Monoclonal Antibody in Patients With Advanced Renal Cell Carcinoma or Malignant Melanoma

Status Completed

Clinical Trial Summary

Background:

• GC1008 is a genetically engineered antibody designed to block the activity of transforming growth factor-beta (TGF-beta). Although TGF-beta has some normal and beneficial effects in the body, it is often over-produced in malignant melanoma tumors, and it can help the melanoma grow and spread.

• Part 1 of this study enrolled 22 subjects with malignant melanoma or kidney cancer to determine the highest safe dose of GC1008, which was found to be 15 mg/kg.

• Three of 22 patients with malignant melanoma in Part 1 of the study developed skin problems, but it is not known if these problems were related to the administration of GC1008.

Objectives:

-To determine the frequency of adverse skin side effects of GC1008 in patients with malignant melanoma.

Eligibility:

-Patients 18 years of age and older with malignant melanoma for whom previous treatment was not successful.

Design:

• GC1008 is given intravenously (through a vein) at a dose of 15 mg/kg or 10 mg/kg for four doses on study days 0, 28, 42 and 56 (one treatment cycle). Patients whose cancer responds to GC1008 may receive one or two additional treatment cycles of four doses given every two weeks.

• Physical exam and vital signs on study days 1, 14, 28, 42, 56, 84 and 140.

• Vitals signs on study days 0, 14, 28, 42, 56, 84 and 140.

• Frequent blood sample collections for routine safety tests, measurement of blood levels of GC1008, analysis for antibodies against GC1008 and for research studies.

• CT or MRI scan, bone scan and PET CT scan before treatment and on study day 84 and 140.

• Biopsy of apparently normal skin before treatment and again on day 84.

• Review of medicines and well being on study days 0, 14, 28, 42, 56, 84, 112 and 140.

• Follow-up visits every 3 months for up 2 years for patients who have not received additional treatment for their cancer. Evaluations include physical exam, CT or MRI scan, PET CT scan, blood tests and possibly tumor biopsies.

Clinical Trial Description

BACKGROUND:

Transforming growth factor-beta (TGFBeta) is a member of a large family of evolutionarily conserved proteins with broad activity.

Paradoxically, TGFBeta is involved in both preventing malignant transformation of cells and promoting tumor progression by enhancing the proteolysis of extracellular matrix, stimulating tumor cell migration, tumor invasiveness, angiogenesis and inhibiting the immune response to tumor.

GC1008 is a human IgG4 monoclonal antibody that neutralizes all isoforms of TGFBeta.

GC1008 reduced metastatic burden and enhanced immune responses against cancers in preclinical studies.

OBJECTIVES:

To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety of GC1008 in patients with locally advanced of metastatic renal cell carcinoma or malignant melanoma.

To obtain pharmacokinetic (PK) and pharmacodynamic data on GC1008.

To evaluate tumor response as a preliminary assessment of clinical activity.

To assess possible surrogate markers that might predict clinical efficacy by obtaining tumors and blood samples for exploratory biomarker analysis.

ELIGIBILITY:

Adult patients with locally advanced, surgically inoperable metastatic renal cell carcinoma or malignant melanoma. The Part 2 cohort expansion will accrue only malignant melanoma patients.

Patients must have failed greater than or equal to 1 prior therapy.

Patients must have a hemoglobin greater than or equal to 10.0 gm/dL granulocyte count (ANC) of greater than or equal to 1500/miocroliter and platelets greater than or equal to 100,000/microliter; creatinine less than or equal to 2 mg/dL, serum bilirubin less than or equal to 1.5 x ULN, meet criteria for AST/ALT and have a normal PT/PTT.

Measurable disease by RECIST criteria.

Patients must test negative for hepatitis B virus, hepatitis C virus and human immune deficiency virus (HIV).

Patient must be greater than 4-weeks since major surgery, radiation therapy or chemotherapy.

DESIGN:

Part 1: Cohorts of 3-6 patients will be treated with a single intravenous dose of GC1008 at doses of 0.1 to 15 mg/kg as prescribed by the protocol (This part has been completed).

Part 2: A cohort expansion will treat an additional 6 subjects with GC1008 15 mg/kg to estimate the frequency of unacceptable skin adverse events (e.g., keratoacanthomas, etc). If an unacceptable frequency of skin adverse events are observed, an additional 6 subjects will be treated at the lower dose of 10 mg/kg to determine the phase II dose.

Patients will then be observed for adverse events and PK studies obtained for 4-weeks.

Patients will then receive three additional doses of GC1008 at same dose every 2-weeks. Responding patients and those with stable disease may receive additional treatments. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Melanoma
• Renal Cell Carcinoma

• NCT number: NCT00923169
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: July 9, 2006
• Completion date: January 20, 2010