Dose Escalation Study MORAb-066 Targeting TF-expressing Malignancies Including Breast, Pancreatic, Colorectal, NSCLC

Primary Objective

-To evaluate the safety and tolerability of weekly intravenous (IV) infusions of MORAb-066.

Secondary Objectives

- To identify the dose-limiting toxicities (DLT) and to determine the maximum tolerated
dose (MTD) of MORAb-066.

- To characterize the pharmacokinetic (PK) properties of MORAb-066.

- To identify, on the basis of safety, PK, and pharmacodynamics (PDx) data, a recommended
Phase II dose and schedule for MORAb-066.

- To make a preliminary assessment of the antitumor activity of MORAb-066.

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- To detect any antibody response (i.e., human antihuman antibodies [HAHA]) to multiple
IV infusions to MORAb-066.

Exploratory Objectives

- To evaluate the presence of tissue factor (TF) substrates such as protease activated
receptor 2 when applicable.

- To evaluate the archived tumor tissue for TF overexpression by immunohistochemistry.

- To evaluate whether there are potential biomarkers that correlate responses to
MORAb-066.

Inclusion Criteria:

Patients must meet the following criteria in order to be included in this clinical trial:

1. Histologically or cytologically confirmed diagnosis of breast, colorectal, pancreas,
or NSCLC (adenocarcinoma) that is metastatic or unresectable for which there is no
effective therapy.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see
Appendix A).

3. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
v1.1.

4. Subject has recovered (to Grade less than or equal to 1) from all clinically
significant toxicities related to prior antineoplastic therapies with the exception
of alopecia and bone marrow and organ functions (described separately below).

5. Adequate organ system function less than or equal to 2 weeks prior to Day1, defined
as follows:

- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L

- Platelets greater than or equal to 100 x 10^9/L

- Hemoglobin greater than or equal to 9 g/dL

- Prothrombin time/partial thromboplastin time (PT/PTT) within institutional
limits of normal

- Serum total bilirubin less than or equal to 1.5 times the upper limit of normal
(ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or
equal to 3.0 x ULN if no liver involvement or less than or equal to 5 x ULN with
liver involvement.

- Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine
clearance greater than or equal to 50 mL/min as calculated by the
Cockcroft-Gault method, OR 24-hour measured urine creatinine clearance greater
than or equal to 50 mL/min.

6. Life expectancy of greater than or equal to 12 weeks.

7. Female patients of child-bearing potential (see Appendix C), and all male patients
must consent to use a medically acceptable method of contraception throughout the
study period and for 30 days after their last MORAb-066 administration. A barrier
method of contraception must be included.

8. Patients must be greater than or equal to 18 years of age.

9. Patients entering this study will be asked to provide archival tissue from a previous
tumor biopsy (if available) for correlative testing. If tissue is not available, the
subject will still be eligible for enrollment into the study.

10. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from trial entry:

1. Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor
embolization).

2. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of MORAb-066. For investigational drugs for which 5
half-lives is less than 21 days, a minimum of 10 days between termination of the
investigational drug and administration of MORAb-066 is required.

3. Any major surgery, chemotherapy, radiotherapy, or immunotherapy within the last 21
days (limited palliative radiation is allowed greater than or equal to 2 weeks).

4. Subject has received wide field radiotherapy (including therapeutic radioisotopes
such as strontium 89) less than or equal to 28 days or limited field radiation for
palliation less than or equal to 14 days prior to starting study drug or has not
recovered from side effects of such therapy.

5. Known intracranial involvement, leptomeningeal metastases or spinal cord compression
due to disease.

6. Known allergy or hypersensitivity to monoclonal antibodies.

7. Known bleeding diathesis, such as factor deficiency, factor inhibitor, platelet
disorder, or who are on active anticoagulation, or any dose of aspirin within 5 days
prior to first dose of MORAb-066.

8. Known prior significant bleeding history.

9. Patients with ureteral stents or 3+ blood in the urine at baseline.

10. Patients who are receiving chronic systemic anticoagulation therapy (warfarin sodium
or heparin, etc.).

11. Patients who received a previous mAb therapy and have evidence of an immune or
allergic reaction or previously documented HAHA reaction.

12. A serious non-healing wound, active ulcer, or untreated bone fracture. An abdominal
fistula or gastrointestinal perforation less than 6 months prior to treatment.

13. History of hematemesis or hemoptysis (defined as having bright red blood of 1/2
teaspoon or more per episode) less than or equal to 1 month prior to study
enrollment.

14. Subject has cardiac dysfunction including any of the following:

- Myocardial infarction within the last 6 months, documented by persistent
elevated cardiac enzymes or persistent regional wall abnormalities on assessment
of left ventricular ejection fraction function

- QTcF greater than 470 msec

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV [see Appendix B])

- Angina not well-controlled by medication

15. A serious active infection (bacterial or fungal) at the time of treatment, or another
serious underlying medical condition that would impair the ability of the subject to
receive protocol treatment.

16. Chronic inflammatory disorder(e.g., inflammatory bowel disease, active vasculitis).

17. Herbal preparations/medications must be discontinued 7 days prior to first dose of
study drug (see Section 5.3.1).

18. Known diagnosis of human immunodeficiency virus, Hepatitis B or Hepatitis C.

19. Women who are pregnant or lactating.

20. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

21. Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol.

22. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.