Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Human Anti-TGF-Beta Monoclonal Antibody GC1008 in Treating Patients With Unresectable Locally Advanced or Metastatic Kidney Cancer or Malignant Melanoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Temporarily closed 18 and over NCI, Pharmaceutical / Industry NCI-06-C-0200 NCI-P6962, GENZ-GC100800305, NCT00356460

Special Category: NCI Web site featured trial

Objectives

Primary

1. Assess the maximum tolerated dose, dose-limiting toxicity, and safety of human anti-TGF-beta monoclonal antibody GC1008 in patients with unresectable locally advanced or metastatic renal cell carcinoma or malignant melanoma.

Secondary

1. Obtain the pharmacokinetic and pharmacodynamic profile of human anti-TGF-beta monoclonal antibody GC1008.
2. Determine, preliminarily, the tumor response to human anti-TGF-beta monoclonal antibody GC1008 in these patients.
3. Assess possible surrogate markers that may predict clinical efficacy using tumor and blood samples for exploratory biomarker analyses.

Entry Criteria

Disease Characteristics:

• Histologically confirmed renal cell carcinoma (RCC) or malignant melanoma meeting 1 of the following criteria:
  • Locally advanced and surgically inoperable disease
  • Metastatic disease



• Measurable disease by RECIST criteria



• Failed ≥ 1 prior therapy
  • RCC patients must have failed either sorafenib tosylate or sunitinib malate as 1 of their prior therapies



• Not eligible for curative intent therapy (e.g., potentially curative surgical resection or chemotherapy)



• No CNS metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (e.g., unstable vertebral metastases)



• No history of ascites or pleural effusions unless successfully treated, completely resolved, and > 4 months since treatment

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
• Prior flu vaccine required (≥ 1 week before beginning study therapy)
• More than 4 weeks since prior major surgery
• More than 4 weeks since prior radiotherapy or chemotherapy
• No investigational agents within the past 4 weeks (6 weeks for long-acting agents, such as a monoclonal antibody)
• No prior organ transplant, including allogeneic bone marrow transplantation
• No immunotherapy or biologic/targeted therapy within the past 4 weeks (6 weeks for monoclonal antibodies [e.g., bevacizumab])
• No antibiotic therapy within the past week
• No other concurrent cancer therapy
• No concurrent anticoagulation therapy (including antiplatelet agents [e.g., acetylsalicylic acid (aspirin), clopidogrel, ticlopidine, dipyridamole])
  • Heparin flush of a central line allowed
  • Transient ibuprofen allowed
• No concurrent immunosuppressive therapy, including the following:
  • Systemic corticosteroid therapy, including replacement therapy for hypoadrenalism
    • Inhaled or topical corticosteroids allowed
  • Cyclosporine
  • Tacrolimus
  • Sirolimus
• No concurrent cytotoxic therapy, interferon, or investigational therapy

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy ≥ 5 months
• Albumin ≥ 3.0 g/dL
• Hemoglobin > 10.0 g/dL
• Absolute neutrophil count > 1,500/mm³
• Platelet count > 100,000/mm³
• Serum bilirubin > 1.5 times upper limit of normal (ULN)
  • Patients with Gilbert's disease allowed if bilirubin ≤ 3.0 mg/dL
• ALT and AST ≤ 2.5 times ULN (5 times ULN in the presence of liver metastases)
• Creatinine < 2 mg/dL OR creatinine clearance ≥ 60 mL/min
• Urine protein ≤ 1 g/24 hours for 1+ positive (30 mg/dL) proteinuria
• PT and PTT normal
• Not nursing or pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• Hepatitis B and C negative
• HIV negative
• No active thrombophlebitis, thromboembolism, hypercoagulability states, or bleeding
  • History of deep venous thrombosis allowed if successfully treated, completely resolved, and required no treatment for > 4 months
• Calcium ≤ 11 mg/dL (responsive and controlled hypercalcemia allowed)
• No other malignancy unless disease free for ≥ 5 years after curative intent treatment and probability of recurrence is < 5%
  • Patients with curatively treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are allowed
• No significant or uncontrolled illness including, but not limited to, the following:
  • Congestive heart failure
  • Myocardial infarction
  • Symptomatic coronary artery disease
  • Significant ventricular arrhythmias within the past 6 months
  • Significant pulmonary dysfunction
• No active infection, including unexplained fever (temperature > 38.1 °C) within the past week
• No systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid arthritis)
• No know allergy to any component of GC1008
• No significant medical or psychosocial problems including, but not limited to, the following:
  • Other serious nonmalignancy-associated medical conditions that limit life expectancy to < 2 years (e.g., liver cirrhosis) or increase the risk of adverse events
  • Any social or psychological condition that would limit study compliance (e.g., untreated schizophrenia or other significant cognitive impairment)
  • Concurrent drug or alcohol abuse
  • High risk for poor compliance

Expected Enrollment

A total of 36 patients will be accrued for this study.

Outcomes

Maximum tolerated dose of human anti-TGF-beta monoclonal antibody GC1008
Safety

Pharmacokinetic profile
Pharmacodynamic profile
Tumor response by RECIST criteria
Surrogate markers for biomarker analyses
Duration of response
Progression-free survival by Kaplan-Meier method

Outline

This is a multicenter, open-label, dose-escalation study.

Patients receive human anti-TGF-beta monoclonal antibody GC1008 IV over 30-180 minutes on day 0 and then on days 14, 28, and 42 in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of human anti-TGF-beta monoclonal antibody GC1008 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Blood is collected periodically for pharmacokinetic, pharmacodynamic, and biomarker studies. Involved and uninvolved skin samples are collected and analyzed for histology, biomarker and genetic analysis.

After completion of study treatment, patients are followed every 3 months for up to 2 years.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

John Morris, MD, Principal investigator		Ph: 301-402-2912 Email: jmorris@mail.nih.gov

Related Information

Featured trial article
Web site for additional information

Registry Information
Official Title		A Phase 1 Study of the Safety and Efficacy of GC1008: A Human Anti Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Renal Cell Carcinoma or Malignant Melanoma
Trial Start Date		2006-06-01
Trial Completion Date		2010-07-01 (estimated)
Registered in ClinicalTrials.gov		NCT00356460
Date Submitted to PDQ		2006-07-14
Information Last Verified		2008-12-21

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