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
- In Part 1, Dose Escalation: Patients with histologically confirmed, locally advanced
& surgically inoperable or metastatic renal cell carcinoma or malignant melanoma are
- 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
- 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.
- 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
- 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.