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Safety and Efficacy Study of GC1008 to Treat Renal Cell Carcinoma or Malignant Melanoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00356460
First received: July 24, 2006
Last updated: March 17, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Carcinoma, Renal Cell
Melanoma
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ ) Monoclonal Antibody
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Part 1 & 2: To obtain pharmacokinetic (PK) and pharmacodynamic (PD) data on GC1008. [ Time Frame: up to 2.5 years ] [ Designated as safety issue: No ]
  • Part 1 & 2: To evaluate tumor response as a preliminary assessment of clinical activity. [ Time Frame: up to 2.5 years ] [ Designated as safety issue: No ]
  • Part 2: To evaluate the relationship between GC1008 exposure, clinical response, and the development of skin lesions. [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 29
Study Start Date: September 2006
Study Completion Date: May 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)
Experimental: 2 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)
Experimental: 3 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)
Experimental: 4 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)
Experimental: 5 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)
Experimental: 6 - Part 1
Dose Group
Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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: 1 (Part 2) Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ ) Monoclonal Antibody
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) Biological: GC1008 Human Anti Transforming Growth Factor _Beta (TGFβ) Monoclonal Antibody
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)

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00356460

Locations
United States, Maryland
National Cancer Institute (NCI)
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber/Harvard Cancer Center, Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital
Cambridge, Massachusetts, United States, 02114
United States, New Jersey
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08901
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

Additional Information:
No publications provided by Sanofi

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00356460     History of Changes
Obsolete Identifiers: NCT00381745
Other Study ID Numbers: GC100800305
Study First Received: July 24, 2006
Last Updated: March 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Melanoma
Adenocarcinoma
Kidney Diseases
Kidney Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Antibodies
Antibodies, Monoclonal
Immunoglobulins
Mitogens
Immunologic Factors
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 20, 2014