A Dose Escalation Study of OMP-52M51 in Subjects With Solid Tumors

Inclusion criteria

Subjects must meet all of the following criteria to be eligible for the study:

• Age >18 years
• ECOG performance status <2 (see Appendix B)
• Solid tumor malignancy for which there is no remaining standard therapy or either refuse or are not considered to be candidates for any remaining standard therapy.
• Must have a tumor that is measurable or evaluable per RECIST v1.1 in the dose escalation phase. In the expansion cohort(s), subjects must have measurable disease.
• Subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tissue available either archived or fresh core or punch needle biopsied at study entry (two fresh cores/punches preferred whenever possible) for determination of Notch1 pathway activation status.
• Must have received their last chemotherapy, biologic, radiotherapy, or investigational therapy at least 4 weeks prior to enrollment; 6 weeks if the last regimen included BCNU or mitomycin C.
• Subjects must have normal organ and marrow function as defined below:

• Absolute neutrophil count >1500/mL without growth factor support in the past 7 days
• Platelets >100,000/mL without transfusions in the past 7 days
• 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 but cannot be associated with elevated bilirubin)
• 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
• Normal Ejection Fraction (>50%) on ECHO scan or MUGA
• 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 their malignancy including other investigational agents
• Prior treatment with gamma secretase inhibitors or other Notch 1 inhibitors
• Uncontrolled seizure disorder, active neurologic disease, or active CNS involvement except for individuals who have previously-treated CNS metastases, are asymptomatic, and have no requirement for higher doses of corticosteroids (> prednisone 10mg orally per day) or anti-seizure medication for at least 4 weeks prior to first dose of study drug.
• 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 malignancies included in this trial. Patients with history of known squamous cell 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
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
• Hemoptysis in excess of 2.5 mL(or one-half teaspoon) within 8 weeks of first dose of study drug.
• 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 (see Appendix D)
• Subjects with poorly controlled blood pressure (defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥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.

NOTE: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry.

• Subjects with ECG 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
• active peptic ulcer disease
• known intraluminal metastatic lesion(s) with risk of bleeding
• history of abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
• Subjects with diarrhea at time of enrollment or have an ongoing requirement for anti diarrheal therapy