Study WCMC IST/VOS/MDS evaluates the safety and tolerability of escalating doses of vosaroxin in adult patients with pathologically confirmed Myelodysplastic Syndrome, or MDS, (< 20% blasts in bone marrow, peripheral blood, or both) by World Health Organization (WHO) classification with an intermediate 2 (INT-2) or high-risk score (ie, ≥ 1.5) as assessed by the International Scoring System (IPSS) after failure of hypomethylating agent-based therapy. Based on 3 completed studies and xenograft models, Vosaroxin is hypothesized to be safe and will effective in this patient population.

This is a phase 1-2, dose escalation study of the safety and clinical activity of vosaroxin in subjects with INT-2 or high risk MDS who have failed prior hypomethylating agent based therapy. The study will utilize a standard 3+3 design to estimate the MTD [maximum tolerated dose] for vosaroxin administered to subjects with MDS. MTD will be defined as the highest dose level at which no more than 33% of the subjects observed at a given dose level experience a DLT [dose limiting toxicity]. Subjects will be assessed for safety and DLT in the first cycle of vosaroxin. Subjects will be enrolled into the study in cohorts of 3. Three eligible subjects will be enrolled in sequential cohorts at increasing dose levels until at least 1 DLT is observed during the first cycle of vosaroxin therapy. Subjects who receive both doses of vosaroxin will be evaluated for the MTD, DLTs, and safety profile during the first cycle of therapy. Once the MTD has been determined, an expanded evaluation of safety and hematologic response or improvement rate at this dose level will be conducted in additional subjects so that the total number of subjects exposed to this dose level is up to 15 subjects, inclusive of those treated at this dose level in the dose-escalation phase. The exposure of additional subjects at the MTD will provide a better estimate of the toxicity rate. Subjects with a documented response of Complete Response, Partial Response, or hematologic improvement at the end of Cycle 2 may continue to receive vosaroxin for additional cycles at the discretion of the treating investigator and after discussion with the medical staff at Sunesis Pharmaceuticals. There will be a 30-day follow-up period following the termination of study drug treatment.

Inclusion Criteria:

• Able to understand and to provide written informed consent

• At least 18 years of age with pathologically confirmed MDS (< 20% blasts in bone marrow, peripheral blood, or both) by WHO classification with an intermediate 2 or high-risk score assessed by IPSS (score ≥ 1.5)

• Must have received at least 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy and are either refractory to, relapsed after, or are intolerant of prior therapy with either agent.

  1. Primary failure/refractory: Stable or worsening disease after a minimum of 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy
  2. Secondary failure/relapse: Bone marrow blast count increase or loss of hematologic response after initial treatment response with hypomethylating agent-based therapy
  3. Intolerance: Intolerance of hypomethylating agent-based therapy regardless of number of cycles completed and clinical response

• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2

• Must have a life expectancy of at least 2 months

• Must demonstrate adequate clinical laboratory values (based on local laboratory results) as follows:

  1. Serum creatinine 1.5 ≤ x the upper limit of normal (ULN) or calculated creatinine clearance (CLCR) of ≥ 50 mL/min
  2. Total bilirubin ≤ 1.5 x ULN, higher levels are acceptable if these can be attributed to active hemolysis (as indicated by positive Coomb's test, decreased haptoglobin, Gilbert's disease, elevated indirect bilirubin, and/or lactate dehydrogenase) or ineffective erythropoiesis (as indicated by bone marrow findings).
  3. Aspartate aminotransferase (AST) ≤ 2.5 x ULN
  4. Alanine aminotransferase (ALT) ≤ 2.5 x ULN
  5. Must show adequate cardiac function defined as a left ventricular ejection fraction (LVEF)

• 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

• Must have acceptable recovery from clinically significant non-hematologic toxicity after prior therapy

• Must be infertile or agree to use an effective contraceptive method for the duration of the study and for 30 days after the last dose (for men and women of child-producing potential).

Exclusion Criteria:

• Patients meeting any of the following criteria are excluded:
• Presence of AML (≥ 20% blasts in bone marrow, peripheral blood, or both)
• Presence of serious illness, medical condition, or other medical history, involving the heart, kidney, liver or other organ system, including abnormal laboratory parameters, which, in the opinion of the Investigator, would be likely to interfere with a subject's participation in the study or with the interpretation of the results.
• Have known active central nervous system disease or active, uncontrolled, clinically significant infection(s).
• Have other active malignancies (including other hematologic malignancies) or other malignancies within 12 months before enrollment, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
• Have experienced CTCAE Grade 2 or greater oral mucositis within the last 14 days
• Are receiving any other investigational therapy or protocol-prohibited therapy
• Have received previous treatment with vosaroxin
• Pregnant or breastfeeding females
• Known allergy to D-sorbitol or methanesulfonic acid (excipients used in vosaroxin)
• Treatment with any anticancer therapy (including radiation) within the previous 14 days prior to the first dose of study drug or less than full recovery (CTCAE grade 1) from the clinically significant toxic effects of that treatment.
• Treatment with any investigational drugs within the previous 14 days prior to Cycle 1, Day 1 or ongoing adverse events from previous cancer treatment with investigational drugs, regardless of the time period.
• Have any other medical, psychological, or social condition that, in the opinion of the PI, would contraindicate the patient's participation in the clinical study due to safety or compliance with clinical study procedures

Adverse events were collected over a period of 15 months.

The adverse events and SAEs were assessed and graded by the principal investigator throughout the study.