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

The basis of drug treatment for advanced-stage ovarian cancer in the first-line setting is platinum (cisplatin or carboplatin) plus taxane (paclitaxel or docetaxel), with or without bevacizumab. First line treatment regimens often result in high response rates, but most tumors will recur within 2 years and patients die within 3 to 4 years of diagnosis. If a patient progresses after 2 consecutive regimens without a response (refractory) or has recurrent ovarian cancer within 6 months from their last platinum-based regimen (platinum-resistant), prognosis is poor. The absence of an approved treatment or standard of care in the recurrent setting represents an unmet need. Early NCI studies in the 1970s and 1980s support VAL-083 activity in ovarian cancer. Interest in this agent for ovarian cancer has recently re-emerged. The unique functional groups and cytotoxic mechanisms are hoped to provide a viable novel treatment option in patients with recurrent ovarian cancer that was resistant to platinum chemotherapies. This is an open label, multi-center, Phase 1/2 clinical trial in subjects with recurrent adenocarcinoma of the ovary who have been previously treated with a minimum of two courses of platinum-based chemotherapy, and up to two additional cytotoxic regimens that may also have included platinum (no more than four total lines of prior therapy), with or without bevacizumab, whose cancer has recurred within six months of the most recent platinum-based chemotherapy. Study subjects will initially receive VAL-083 60 mg/m2 i.v. once weekly. If this regimen is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 67 mg/m2 i.v. If the 67 mg/m2 dose is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 75 mg/m2 i.v. once weekly for the remainder of the study. Dosing will continue once weekly for 16 weeks or until disease progression, development of other unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or Sponsor ending the study, whichever occurs first. The treatment plan is to enroll a minimum number of 20 subjects in Phase 1, followed by expansion of enrollment in Phase 2 using the optimal dosing regimen determined in Phase 1. Hematological safety assessments will be conducted at Screening and weekly before each treatment. Clinical evaluations for physical examination, vital signs, disease symptoms, quality of life measures (FOSI and opioid pain medication use), adverse events and concomitant medications will be completed while the subject remains on study treatment. Radiographic assessments (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) to obtain tumor measurements and CA-125 concentration will be conducted at Screening and every 8 weeks while on study treatment, independent of dose delays and/or dose interruptions, until progression of disease is suspected. Pharmacokinetics will be evaluated in each of the first 10 subjects who have plasma samples drawn on Day 1 of study treatment: pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of i.v. infusion with VAL-083. A post-treatment safety assessment is to be scheduled 28 ±7 days after the last dose of study treatment. Follow-up for subjects terminating from study for any reason other than withdrawal of consent will be done to allow an exploratory assessment of survival. All anti-tumor treatments received after discontinuing treatment with VAL-083 will be collected, if available, and survival status will also be reported to the Sponsor, on a monthly basis, when survival data are available. In addition to survival, this assessment includes outcomes for subsequent anticancer therapies including any new malignancy information. Date and cause of death will be recorded. The primary reason for study completion and discontinuation from monthly follow-up will be captured for each study subject.