Safety and Efficacy Study of Glufosfamide in Ovarian Cancer

Primary Objectives:

* To evaluate the effect of glufosfamide on the serum concentrations of CA125 in subjects with ovarian cancer
* To evaluate the safety of weekly glufosfamide dosing in subjects with ovarian cancer as compared with every 21-day dosing

Secondary objectives:

* To evaluate the efficacy of glufosfamide in subjects with ovarian cancer as measured by objective response rate, duration of response, progression-free survival, and overall survival
* To evaluate the pharmacokinetics of glufosfamide and isophosphoramide mustard during and after treatment

Exploratory objective:

* To correlate efficacy endpoints with expression of tumor-associated glucose transporter proteins

Open-label, multicenter, Phase 2 dose escalation study. Subjects will be randomized to receive either once every three weeks dosing regimen or the weekly dosing regimen. Randomization will utilize a 2:1 ratio with two-thirds of the subjects randomized to the weekly dosing regimen.

In the weekly dosing schedule, treatment with glufosfamide 2,500 mg/m2 will be initiated only after the 1,660 mg/m2 treatment cohort has been enrolled and there is evidence that the dose of 1,660 mg/m2 has been well tolerated (See below Section on Pharmacokinetic/Statistical Analyses).

Eligibility Criteria:
Inclusion Criteria:

* At least 18 years of age
* Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee
* Pathologically confirmed epithelial ovarian cancer, peritoneal serous cancer, or carcinoma of the fallopian tube
* Prior treatment with at least one platinum-based chemotherapy
* Evidence of resistance to most recent platinum-containing regimen (relapsed during or within 6 months after completing chemotherapy)
* Evidence of CA 125 progression after most recent chemotherapy defined as either:

  * CA 125 at least 40 U/mL for patients with elevated CA 125 that decreased to \<20 U/mL on therapy; or
  * CA 125 at least 40 U/mL and at least a 50% increase over the nadir value for patients with elevated CA 125 that did not decrease to \<20 U/mL on therapy.

CA 125 must meet criteria on two occasions not less than one week apart if the CA 125 has increased by at least 100% (i.e., doubled). There must be 3 consecutive increasing measurements over a period of at least two weeks if the CA 125 has increased by at least 50% but less than 100%.

* Elevated serum CA125 (≥40 U/mL) within 2 weeks prior to starting treatment
* At least one target or nontarget lesion by RECIST
* A minimum of 21 days between prior chemotherapy, radiation therapy, immunotherapy, or other anti-tumor therapy and study entry
* Recovered from reversible toxicities of prior therapy
* ECOG score of 0 or 1
* ANC ≥ 1,500/µL, platelets ≥ 100,000/µL, hemoglobin ≥9 g/dL
* Total bilirubin ≤ 1.5-fold ULN, AST/ALT ≤ 2.5-fold ULN (≤ 5-fold ULN if liver metastases)
* Creatinine clearance ≥ 60 mL/min (calculated by Cockcroft-Gault formula)
* All women of childbearing potential must have a negative serum pregnancy test and must agree to use effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) from entry into the study through 6 months after the last dose

Exclusion Criteria:

* Concomitant or planned hormonal therapy, radiation therapy, biologic therapy, chemotherapy or other systemic antitumor therapy for ovarian cancer other than protocol therapy
* Symptomatic brain metastases
* Active clinically significant infection requiring antibiotics
* Known HIV positive or active hepatitis B or C
* Recent (one year) history or symptoms of cardiovascular disease (NYHA Class 2, 3, or 4), particularly coronary artery disease, arrhythmias or conduction defects with risk of cardiovascular instability, uncontrolled hypertension, clinically significant pericardial effusion, congestive heart failure or stroke
* Other active malignancies (other than treated non-melanoma skin cancer or treated in situ cancer) within the past 5 years
* Major surgery within 3 weeks of the start of study treatment, without complete recovery
* Females who are pregnant or breast-feeding
* Participation in an investigational drug or device study within 28 days of the first day of dosing on this study
* Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
* Unwillingness or inability to comply with the study protocol for any other reason