A Study of ALT-836 in Combination With Gemcitabine for Locally Advanced or Metastatic Solid Tumors

Tissue Factor (TF) is over-expressed in most cancer types. Results from many recent studies have suggested a key role for TF in the development of cancer-associated thrombosis, tumor growth, tumor angiogenesis, and tumor metastasis. ALT-836, a recombinant human-chimeric monoclonal antibody, is designed as a direct TF antagonist to block TF displayed by cancers and to inhibit cancer-associated venous thromboembolism, tumor growth, tumor angiogenesis and tumor metastasis. In numerous pre-clinical studies in laboratory animals, including non-human primates, ALT-836 exhibits potent anti-tumor, anti-thrombotic and anti-inflammatory activities with a remarkable safety profile. In humans, ALT-836, administered as a single bolus and monotherapy in patients with coronary artery disease (CAD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS), is safe and exhibits anti-coagulant and anti-inflammatory effects. A Phase II study using a multi-dose regimen of ALT-836 is being conducted in patients with ALI/ARDS. In the dose-escalation study described in this protocol, the investigators will assess the safety and determine the maximum tolerated dose (MTD) of ALT-836 in combination with gemcitabine in patients with advanced malignancies known to overexpress TF and in which venous thromboembolism is a major complication.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed
• Locally advanced or metastatic non-hematologic malignancies
• Measureable
• Refractory to standard therapies or single agent gemcitabine is indicated as a standard treatment option

PRIOR/CONCURRENT THERAPY:

• No concurrent radiotherapy, chemotherapy, immunotherapy or other investigational agents
• Must have recovered from side effects of prior therapies

PATIENT CHARACTERISTICS:

Life expectancy

• > 12 weeks

Performance Status

• ECOG 0 or 1

Bone Marrow Reserve

• Absolute Neutrophil count (AGC/ANC) ≥ 1,500/uL
• Platelets ≥ 100,000/uL
• Hemoglobin > 9 g/dL

Renal Function

• Calculated Glomerular filtration rate (GFR) > 59mL/min/1.73M^2

Hepatic Function

• Total bilirubin ≤ 1.5 X ULN
• AST, ALT, and ALP ≤ 3 X ULN or ≤ 5.0 x ULN, if liver metastasis exists
• PT INR ≤ 1.5 X ULN

Cardiovascular

• No history of clinically significant vascular disease
• No New York Heart Association (NYHA) Class > II heart failure

Hematologic

• No history of bleeding disorders
• No evidence of bleeding diathesis or coagulopathy
• No presence of clinically significant hemoptysis or hematuria, presence of serious non-healing wound or ulceration, or signs of other bleeding
• No evidence of a tumor invasion of any major blood vessel
• No trauma with increased risk of life-threatening bleeding or history of severe head trauma or intracranial surgery within two months of study entry

Surgery/Procedures

• No major surgery or open biopsy within 28 days before drug infusion or evidence of active bleeding postoperatively
• No plan for any major surgery during treatment period
• No presence or requirement of an epidural catheter or lumbar puncture within 48 hours prior to each dose of study treatment
• No anticipation of receiving an epidural catheter or a lumbar puncture within 48 hours after each dose of study treatment

Excluded Medications or Treatment Regimens

• Unfractionated heparin of > 15,000 units/day within 8 hours prior to each dose of study treatment
• Low-molecular weight heparin at a higher dose than recommended for prophylactic used or required within 20 hours prior to each dose of study treatment
• Warfarin used or required within 48 hours prior to each dose of study treatment and the prothrombin time (INR) exceeded the upper limit of normal range
• Direct thrombin inhibitors or Xa inhibitors
• Acetylsalicylic acid used or required within 72 hours prior to each dose of study treatment
• Clopidogrel bisulfate used or required within 48 hours prior to each dose of study treatment
• Anticipated requirement for anti-platelet or anti-coagulant agents excluding non-aspirin NSAID within 48 hours following study treatment infusion

Other

• No active systemic infection requiring parenteral antibiotic therapy
• No history of or presence of a CNS disease
• No history of allergic reactions to compounds of similar chemical or biologic composition
• Not HIV positive
• No women who are pregnant or nursing
• A negative serum pregnancy test if female
• Patients, both females and males, with reproductive potential must agree to use effective contraceptive measures for the duration of the study
• No history of significant renal, endocrinologic, metabolic, immunologic or hepatic disease
• No evidence of psychiatric illness/social situations
• Other illness that in the opinion of the investigator would exclude the patient from participating
• Must provide informed consent and HIPAA authorization and comply with protocol-specified procedures and follow-up evaluations