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

Study Overview
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Brief Summary
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This is a Phase I, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-836 in combination with standard of care gemcitabine in participants who have locally advanced or metastatic solid tumors. The purpose of this study is to determine the maximum tolerated dose (MTD), and to assess the safety and pharmacokinetic profile of ALT-836 given with gemcitabine. The clinical benefit, progression-free survival and overall survival of study participants will also be assessed.

Detailed Description
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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.

Official Title
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A Phase I, Open-Label, Multi-center, Competitive Enrollment and Dose-escalation Study of ALT-836 in Combination With Gemcitabine for Locally Advanced or Metastatic Solid Tumors

Conditions
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Locally Advanced Malignant Neoplasm, Malignant Solid Tumour

Intervention / Treatment
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* Biological: ALT-836 in combination with gemcitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: ALT-836 in combination with gemcitabine|Study participants will receive up to four courses of a 28-day biochemotherapy with the study drug (ALT-836) and gemcitabine. Each treatment course consists of five doses of ALT-836 (on Day 1, 4, 8, 15 and 22) and three doses of gemcitabine (Day 1, 8 and 15). Participants with persistent responses will receive additional two cycles, three doses each, of standard of care gemcitabine therapy.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of ALT-836 in combination with gemcitabine |  | 18 months | 
| Safety Profile | Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment | 18 months | 
| Clinical Benefit | Number of participants with complete response, partial response or stable disease | 18 months | 
| Progression Free Survival | Number of participants with 9-month, 12-month, 18-month, 24-month, 30-month or 36-month progression-free survival | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Number of participants with 9-month, 12-month, 18-month, 24-month, 30-month or 36-month overall survival | 36 months | 
| Pharmacokinetics | Area under the plasma concentration-time curve from time zero to infinity (AUC) and the half-life of ALT-836 | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, tissue factor, solid tumor, ovarian cancer, breast cancer, non-small cell lung cancer, colon cancer, pancreatic cancer, head and neck cancer, prostate cancer, soft-tissue sarcoma, metastatic, gemcitabine, anti-tumor, venous thromboembolism