A Dose Escalation Study of OMP-52M51 in Subjects With Lymphoid Malignancies

Inclusion criteria

• Lymphoid malignancy that has relapsed or is refractory after two or more treatments that are FDA approved or are commonly used clinically.
• Subjects must have progressive disease requiring therapy. Subjects who are candidates for observation only are not eligible.
• Subjects are either not currently considered to be candidates or refuse potentially curative therapies including peripheral stem cell or bone marrow transplant
• Subjects must have measurable disease as per disease specific criteria
• Must have received their last chemotherapy, biologic, radiotherapy, or investigational therapy at least 4 weeks prior to enrollment; 12 weeks from their last radioimmunotherapy; 3 months if the last therapy was bone marrow/ peripheral stem cell transplant.
• Age >18 years
• ECOG performance status <2
• Normal Ejection Fraction on ECHO scan
• Subjects must have normal organ and marrow function as defined below:

Absolute neutrophil count >1000/mL Platelets >75,000/mL For subjects with known marrow infiltration, ANC ≥500 and platelets ≥30,000 Total bilirubin <1.5 X institutional upper limit of normal (ULN) (<2X ULN for subjects with Gilbert's syndrome) AST (SGOT) and ALT (SGPT) <3 X institutional ULN (for subjects with hepatic involvement <5 X institutional ULN) PT/INR and aPTT within 1.5 X institutional ULN Creatinine <1.5 X institutional ULN OR Creatinine clearance >60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal

• Women of childbearing potential must have had a prior hysterectomy or have a negative serum pregnancy test and be using adequate contraception prior to study entry and must agree to use adequate contraception from study entry through at least 6 months after discontinuation of study drug. Men must also agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and from study entry through at least 6 months after discontinuation of study drug. Should a woman enrolled in the study or a female partner of a man enrolled in the study become pregnant or suspect she is pregnant while participating in this study or within 6 months after discontinuation of study, she should inform the Investigator immediately.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

Subjects who meet any of the following criteria will not be eligible for participation in the study:

• Currently receiving any therapeutic treatment for lymphoid malignancies including other investigational agents
• Prior treatment with gamma secretase inhibitors or other Notch 1 inhibitors
• Active CNS involvement, uncontrolled seizure disorder, or active neurologic disease
• History of a Grade 4 allergic reaction attributed to humanized or human monoclonal antibody therapy
• Significant intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women or nursing women
• Ongoing malignancies or malignancies in remission <3 years other than the lymphoid malignancies included in this trial. Patients with history of known skin cancers including non-melanotic skin cancers within the past 3 years will not be included in this trial. The following prior malignancies are allowable irrespective of when they occurred: in situ carcinoma of the cervix, in situ ductal breast cancer, and low-grade local bladder cancer.
• Subjects with known HIV infection
• Known bleeding disorder or coagulopathy
• Subjects receiving heparin, warfarin, or other similar anticoagulants, except for subjects on low molecular weight heparin for DVT/PE prophylaxis. Note: Subjects may be receiving low-dose aspirin and/or non-steroidal anti-inflammatory agents.
• New York Heart Association Classification II, III, or IV
• Subjects with a blood pressure of >140/90 mmHg that is not responsive to medical therapy. Subjects taking antihypertensive medications must be taking ≤2 medications to obtain this level of blood pressure control.
• Subjects with EKG evidence of ischemia or ≥Grade 2 ventricular arrhythmia, subjects who have a history of acute myocardial infarction within 6 months, or subjects with unstable angina.
• Subjects with known clinically significant gastrointestinal disease including, but not limited to, inflammatory bowel disease
• Subjects with diarrhea at time of enrollment or have an ongoing requirement for anti diarrheal therapy