A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer (REPROVe)

Inclusion Criteria:

1. Patient must willingly provide written consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. (Human protection committee approval of this protocol and consent form is required).
2. Must be ≥18 years old.
3. Histologically-confirmed initial diagnosis of adenocarcinoma of the ovary (AO), excluding clear cell, low grade serous, mucinous adenocarcinoma or carcinosarcoma.
4. Subjects must have completed and failed a minimum of 2 previous lines of platinum-containing therapy (e.g., carboplatin, oxaliplatin, or cisplatin).
5. Subjects may have failed up to 2 additional cytotoxic regimens that may have included platinum.
6. Subjects must have had no more than 4 lines of prior drug therapy.
7. If treated with bevazicumab, subjects should have completed and failed treatment.
8. Subjects with BRCA mutation (positive) should have completed and failed treatment with a PARP inhibitor, or have been ineligible for treatment with a PARP inhibitor.
9. Patient must have had documented best response, disease recurrence, and date of progression based on RECIST v1.1 or CGIG criteria within 6 months from the start of last prior platinum-based therapy.
10. Formalin fixed, paraffin-embedded archival tumor available from the primary or recurrent cancer required.
11. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 and have been stable during wash-out period from prior therapy.
12. Adequate recovery from all recent surgery is required; at least 1 week must have elapsed from the time of a minor surgery; at least 21 days must have elapsed from the time of a major surgery. Must have recovered from all surgery-related toxicities to Grade 1 or less.
13. A minimum of 28 days between termination of the investigational drug and administration of VAL 083.
14. Must have recovered from all prior treatment-related toxicities to Grade 1 or less.

15. Laboratory values as follows at screening and within 3 days of planned first dose of therapy:

    1. Absolute neutrophil count (ANC) ≥ 1500/μL
    2. Hemoglobin (HgB) ≥ 9 g/dL
    3. Platelets ≥ 100,000/μL ( > 150,000/μL if prior nitrosureas)
    4. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance > 60 mL/min (measured or calculated by the Cockcroft-Gault formula) (Cockcroft & Gault, 1976)
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 2 × ULN unless liver metastases are present, in which case they must be ≤ 5 × ULN.
    6. Total bilirubin < 1.5 × the institutional ULN, unless the patient has documented conjugated bilirubin disorder such as Gilbert's syndrome. Subjects with known Gilbert's disease who have serum bilirubin ≤ 3 × ULN (NCI CTCAE v4.03 Grade 2) may be enrolled.
    7. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
16. Heart-rate corrected QT interval (QTc) < 450 msec on screening EKG.
17. No clinically significant cardiac conduction disorder on screening.
18. Subjects must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and be accessible for follow-up.

Exclusion Criteria:

1. Subjects with clear cell, low grade serous or mucinous adenocarcinoma, or carcinosarcoma.
2. Current history of neoplasm other than the entry diagnosis. Subjects with previous cancers treated and cured with local therapy alone may be considered with approval of the Medical Monitor.
3. Persistent Grade ≥2 toxicity from prior cancer therapy.
4. Subjects with declining ECOG performance status, defined by 1 point over a 28-day period, will be excluded.
5. Concurrent severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements.

6. Any of the following cardiac conditions:

   1. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting up to 12 weeks before initiation of treatment with VAL-083
   2. Class III or IV heart failure as defined by the New York Heart Association functional classification system up to 6 months before initiation of treatment with VAL-083
7. Subjects with known active hepatic disease (i.e., hepatitis B or C).
8. Subjects known to be HIV positive and not on stable medication or have an AIDS-related illness.
9. Subjects with a known sensitivity to any of the products to be administered during treatment and assessments.