Safety and Efficacy Study of GC1008 to Treat Renal Cell Carcinoma or Malignant Melanoma
March 17, 2014 updated by: Genzyme, a Sanofi Company
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
The purpose of this study is to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of GC1008, a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in previously treated patients with locally advanced or metastatic renal cell carcinoma or malignant melanoma.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
- Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ ) Monoclonal Antibody
Detailed Description
Transforming growth factor-beta (TGFβ) is a cytokine which is often over-expressed and over-produced by malignancies and has been implicated as an important factor in promoting the growth, progression, and metastatic potential of advanced cancers. In preclinical studies, TGFβ can act to promote tumor cell migration/invasiveness, influence tumor stroma (by increasing extracellular matrix production, cytokine secretion, and angiogenesis), and suppress anti-tumor immunity. The purpose of this study is to investigate the clinical use of GC1008, a human monoclonal antibody capable of binding and neutralizing all isoforms of TGFβ.
This is a Phase 1 multi-center, open-label, dose-escalation study designed to characterize the safety, tolerability, pharmacokinetic, pharmacodynamic, and potential anti-tumor activity of GC1008, in patients with histologically confirmed, locally advanced and surgically inoperable or metastatic renal cell carcinoma (RCC) or malignant melanoma. Patients with RCC must have failed at least 1 prior therapy and patients with renal cell carcinoma must have failed either sorafenib or sunitinib. Other qualifying prior therapies includes any medical, surgical, radiation or investigational approaches used for potential therapeutic benefit (but not for diagnostic purposes) in patients with advanced disease. Patients may receive up to 4 intravenous infusions of GC1008, and patients with stable disease, with an objective tumor response or with clinical benefit may be eligible to receive extended therapy. For part 2 of the study, only patients with malignant melanoma will be enrolled.
Study Type
Interventional
Enrollment (Actual)
29
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Maryland
-
Bethesda, Maryland, United States, 20892
- National Cancer Institute (NCI)
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States, 02115
- Dana Farber/Harvard Cancer Center, Dana Farber Cancer Institute
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Cambridge, Massachusetts, United States, 02114
- Massachusetts General Hospital
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New Jersey
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New Brunswick, New Jersey, United States, 08901
- Cancer Institute Of New Jersey
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Ohio
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Columbus, Ohio, United States, 43210
- Ohio State University
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- In Part 1, Dose Escalation: Patients with histologically confirmed, locally advanced & surgically inoperable or metastatic renal cell carcinoma or malignant melanoma are eligible.
- In Part 2, Patient Expansion: Patients with histologically confirmed, locally advanced and surgically inoperable or metastatic malignant melanoma are eligible.
- In both part 1 and 2: All patients must have failed ≥ 1 prior therapy and potential patients may not be eligible for curative intent treatment (e.g., potentially curative surgical resection or chemotherapy). Other qualifying therapies include any medical, surgical, radiation, or investigational approach used for potential therapeutic benefit (but not for diagnostic purposes) in patients with advanced disease.In addition, In Part 1, Patients with renal cell carcinoma must have failed temsirolimus and either sorafenib or sunitinib as part of their prior therapies.
- Expected survival ≥5 months
- Eastern cooperative oncology Group (ECOG) Performance Status 0 to 2.
- Measurable disease as defined by RECIST
- Laboratory: a. Serum albumin > or = 3.0 g/dL. b. Marrow: Hemoglobin > or =10.0 g/dL, absolute neutrophil count (ANC) > or = 1,500/mm3, and platelets > or = 100,000/mm3. c. Hepatic: Serum total bilirubin < or = 1.5 x upper limit of normal (ULN) (Patients with Gilbert's Disease may be included if their total bilirubin is < or = 3.0 mg/dL.), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) < or = 2.5 x ULN. If the patient has known liver metastases, an ALT and/or AST < or =5 x ULN are allowed. d. Renal: If negative proteinuria on urine dipstick, serum creatinine (sCr) < 2 mg/dL or urine creatinine clearance > or = 60 mL/min. If urine is 1+ positive (30 mg/dL), urine protein must be < or =1 g/24 hours and measured creatinine clearance > or = 60 mL/min. e. Prothrombin time (PT) and partial thromboplastin time (PTT) within normal ranges. f. Negative tests (antibody and/or antigen) for hepatitis viruses B and C and HIV
- At the time of enrollment, patients must be >4 wks since major surgery, radiotherapy, chemotherapy (> or =6 wks if they were treated with a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab), immunotherapy, or biotherapy/targeted therapies and recovered from the toxicity of prior treatment to< or = Grade 1, exclusive of alopecia. Concurrent cancer therapy is not permitted. (In patients who received long acting agents, a treatment-free interval of 2 half-lives should be considered.)
- Patients must be able to give written informed consent to participate. Patients may not be consented by a durable power of attorney.
- Male and female patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment. Female patients of child-producing potential must have a negative serum pregnancy test confirmed within 7 days of receiving the initial dose of GC1008 therapy.
- Documentation of flu vaccination if enrolled during flu season (as defined by the availability of vaccine). Otherwise, patient should receive the current flu vaccine > or = 1 wk before beginning GC1008 therapy.
- Pre-treatment tumor samples, such as paraffin blocks or unstained slides, must be available for analyses.
Exclusion Criteria:
- Central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (e.g., unstable vertebral metastases).
- History of ascites or pleural effusions, unless successfully treated, completely resolved, and the patient has not been treated for these conditions for >4 months.
- Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or use of anti-coagulation therapy (including anti-platelet agents). Patients with a history of deep venous thrombosis may participate if successfully treated, completely resolved, and no treatment has been given for >4 months.
- Hypercalcemia: Calcium >11.0 mg/dL (2.75 mmol/L) unresponsive or uncontrolled in response to standard therapy (e.g., bisphosphonates).
- Pregnant or nursing women, due to the unknown effects of GC1008 on the developing fetus or newborn infant.
- Patients diagnosed with another malignancy - unless following curative intent therapy, the patient has been disease free for at least 5 yrs and the probability of recurrence of the prior malignancy is <5%. Patients with curatively treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study.
- Patients with an organ transplant, including those that have received an allogeneic bone marrow transplant.
- Use of investigational agents within 4 wks prior to study enrollment (within 6 wks if the treatment was with a long-acting agent such as a monoclonal antibody).
- Patients on immunosuppressive therapy including: a. Systemic corticosteroid therapy for any reason, including replacement therapy for hypoadrenalism, pAtients receiving inhaled or topical corticosteroids may participate. b. Patients receiving cyclosporine A, tacrolimus, or sirolimus are not eligible for this study.
- Significant or uncontrolled medical illness, such as congestive heart failure (CHF), myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients with a remote history of asthma or active mild asthma may participate.
- Active infection, including unexplained fever (temperature >38.1 degrees C) or antibiotic therapy within 1 wk prior to enrollment.
- Systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid arthritis, etc.).
- A known allergy to any component of GC1008.
- Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems that warrant exclusion. Examples of significant problems include, but are not limited to: a. Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy to less than 2 years (e.g., liver cirrhosis) or significantly increase the risk of SAEs. b. Any condition psychiatric or otherwise, that would preclude informed consent, consistent follow-up, or compliance with any aspect of the study (e.g., untreated schizophrenia or other significant cognitive impairment). c. Patients currently abusing drugs or alcohol or, in the opinion of the investigator, at high risk for poor compliance.
- Part 2 only: Prior therapy with a TGFB antagonist, such as an antibody, receptor, or kinase inhibitor or anti-sense therapy.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: 1 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 2 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 3 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 4 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 5 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 6 - Part 1
Dose Group
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 1 (Part 2)
|
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
|
|
Experimental: 2 (part 2)
|
1 dose of 0.1 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.1 mg/kg IV (one dose every 14 days)
1 dose of 0.3 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 0.3 mg/kg IV (one dose every 14 days)
1 dose of 1.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 1.0 mg/kg IV (one dose every 14 days)
1 dose of 3.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 3.0 mg/kg IV (one dose every 14 days)
1 dose of 10.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 10.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 mg/kg IV followed by a 28 day observation period and then 3 additional doses of 15.0 mg/kg IV (one dose every 14 days)
1 dose of 15.0 or 10.0 mg/kg IV (based on safety profile of part 2, cohort 1) followed by a 28 day observation period and then 3 additional doses of 15.0 or 10.0 mg/kg IV (one dose every 14 days)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Part 1: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety of GC1008 in patients with locally advanced or metastatic renal cell carcinoma or malignant melanoma.
Time Frame: up to 2.5 years
|
up to 2.5 years
|
|
Part 1: To assess dose-limiting toxicity of GC1008 in patients with locally advanced metastatic renal cell carcinoma or malignant melanoma.
Time Frame: up to 2.5 years
|
up to 2.5 years
|
|
Part 1: To assess the safety of GC1008 in patients with locally advanced or metastatic renal cell carcinoma or malignant melanoma.
Time Frame: up to 2.5
|
up to 2.5
|
|
Part 2: To assess the safety of GC1008 following multiple doses at 15 mg/kg (or 10 mg/kg depending on the safety review of the first cohort of 6 patients at 15 mg/kg) in patients with locally advanced or metastatic malignant melanoma.
Time Frame: Up to 2 years
|
Up to 2 years
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Part 1 & 2: To assess possible surrogate markers that might predict clinical efficacy by obtaining skin (part 2), tumor and blood samples for exploratory biomarker analyses.
Time Frame: up to 2.5 years
|
up to 2.5 years
|
|
Part 1 & 2: To obtain pharmacokinetic (PK) and pharmacodynamic (PD) data on GC1008.
Time Frame: up to 2.5 years
|
up to 2.5 years
|
|
Part 1 & 2: To evaluate tumor response as a preliminary assessment of clinical activity.
Time Frame: up to 2.5 years
|
up to 2.5 years
|
|
Part 2: To evaluate the relationship between GC1008 exposure, clinical response, and the development of skin lesions.
Time Frame: Up to 2 years
|
Up to 2 years
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Berzofsky JA, Wood LV, Terabe M. Cancer vaccines: 21st century approaches to harnessing an ancient modality to fight cancer. Expert Rev Vaccines. 2013 Oct;12(10):1115-8. doi: 10.1586/14760584.2013.836906. No abstract available.
- Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, Hsu FJ, Berzofsky JA, Lawrence DP. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014 Mar 11;9(3):e90353. doi: 10.1371/journal.pone.0090353. eCollection 2014.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
September 1, 2006
Primary Completion (Actual)
May 1, 2009
Study Completion (Actual)
May 1, 2009
Study Registration Dates
First Submitted
July 24, 2006
First Submitted That Met QC Criteria
July 24, 2006
First Posted (Estimate)
July 26, 2006
Study Record Updates
Last Update Posted (Estimate)
March 19, 2014
Last Update Submitted That Met QC Criteria
March 17, 2014
Last Verified
March 1, 2014
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Urologic Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Kidney Diseases
- Urologic Diseases
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Kidney Neoplasms
- Neuroendocrine Tumors
- Nevi and Melanomas
- Carcinoma, Renal Cell
- Carcinoma
- Melanoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Immunologic Factors
- Mitosis Modulators
- Antibodies
- Immunoglobulins
- Antibodies, Monoclonal
- Antineoplastic Agents, Immunological
- Mitogens
Other Study ID Numbers
- GC100800305
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.