Platinum Resistant Ovarian Cancer Evaluation of Doxil and Vintafolide (MK-8109, EC145) Combination Therapy (8109-009, EC-FV-04)

Phase 2

Completed

Conditions: Ovarian Cancer

Interventions: Drug: Vintafolide
Drug: pegylated liposomal doxorubicin (PLD)
Other: EC20

Registration Number: NCT00722592

Lead Sponsor: Endocyte

Brief Summary: The objective of this study is to compare progression-free survival (PFS), based upon investigator assessment using Response Evaluation Criteria In Solid Tumors version 1.0 (RECIST 1.0) and clinical findings, in participants with platinum-resistant ovarian cancer who receive combination therapy with vintafolide and pegylated liposomal doxorubicin (PLD/Doxil®/Caelyx®) with that in subjects with platinum-resistant ovarian cancer who receive PLD alone.

Detailed Description: This is a Phase II clinical trial to evaluate the efficacy and safety of the combination of vintafolide and pegylated liposomal doxorubicin (PLD; available in the United States as Doxil® and outside the United States as Caelyx®) compared to PLD alone.

Vintafolide is a drug that is specifically designed to enter cancer cells via the folate vitamin receptor (FR). Experimental evidence shows that this target receptor is expressed on virtually all ovarian cancers. Early clinical evidence in a small number of Phase I subjects and in a subset of subjects in an on-going single-arm Phase II study suggests that vintafolide may have antitumor effect in women with advanced ovarian cancer and that it is generally well-tolerated. This evidence suggests that vintafolide may be useful as chemotherapy against advanced ovarian cancer.

Patients at centers with EC20 imaging capability will also undergo imaging with the folate receptor (FR-)targeting investigational diagnostic agent EC20 during the screening period to assess uptake of this agent into tumors. This non-invasive procedure will provide additional information on the utility of EC20 imaging to identify subjects with the FR molecular "target" before treatment with vintafolide therapy.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 162

Inclusion Criteria

To qualify for randomization and treatment the following criteria must be met:

Subjects must sign an approved informed consent form
Subjects must be ≥ 18 years of age
Subjects must have pathology-confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
Subjects must have platinum-resistant ovarian cancer, where platinum-resistant is defined as disease that responded to primary platinum therapy and then progressed within 6 months or disease that progressed during or within 6 months of completing secondary platinum therapy
Subjects must have at least a single (RECIST-defined) measurable lesion on a radiological evaluation that is conducted no more than four weeks prior to beginning study therapy (EC145 and/or PLD).
Subjects must have had prior debulking surgery
Subjects must have received prior platinum-based chemotherapy but must not have received more than 2 prior systemic cytotoxic regimens. Subjects are allowed to receive, but are not required to receive, one additional non-cytotoxic regimen for the management of recurrent or persistent disease. Non-cytotoxic (biologic or cytostatic) agents include, but are not limited to, monoclonal antibodies, cytokines, and small-molecule inhibitors of signal transduction.
Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Subjects must have recovered (to baseline/stabilization) from prior cytotoxic therapy-associated acute toxicities. Subjects who have recovered from non-cytotoxic therapy-associated toxicity or who have "controlled" non-cytotoxic therapy toxicity (e.g., vascular endothelial growth factor-related hypertension) can be entered into the trial after a drug wash-out period of 4 half lives
Subjects must have adequate organ function including:
1. Bone Marrow Reserve: Absolute neutrophil count(ANC)≥ 1.5x10^9/L prior to treatment. Subjects on maintenance doses of granulocyte colony stimulating factor (G-CSF) are eligible. Platelets ≥ 100x10^9/L and hemoglobin ≥ 9 g/dL.
2. Hepatic: Total bilirubin level < 1.5 x ULN and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase(GGT), and alkaline phosphatase levels < 2.5 x ULN.
3. Renal: Serum creatinine level ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73m^2 for subjects with serum creatinine levels above 1.5 x ULN.
4. Cardiac: Left ventricular ejection fraction (LVEF) equal to or greater than

the institutional lower limit of normal. LVEF must be elevated within 90 days prior to Cycle 1 Day 1

Subjects of childbearing potential must:
1. Have a negative serum pregnancy test prior to initiation of the therapeutic regimen
2. Practice an effective method of birth control (e.g., oral, transdermal or injectable contraceptives, intrauterine device, double-barrier contraception, such as diaphragm and spermicidal jelly) for the duration of their participation in the trial through 3 months following the last dose of study drug.

Exclusion Criteria

The presence of any of the following will exclude the subject from the study:

Diagnosis of tumor of low-malignant potential
Prior exposure to PLD or anthracycline therapy
Prior exposure to FR-targeted therapy (EC145, EC0225, farletuzumab, etc)
Prior therapy with mouse antibodies
Prior therapy with vinorelbine (Navelbine®) or vinca-containing compounds
Prior abdominal or pelvic radiation therapy, radiation therapy to > 10% of the bone marrow, or prior radiation therapy within the past 3 years to the breast/sternum, dermal lesions, head or neck
Recent (i.e., ≤ 6 weeks) history of abdominal surgery or peritonitis
Serious comorbidities (as determined by the investigator) such as, but not limited to, active congestive heart failure or recent myocardial infarction. Subjects who require antifolate therapy for the management of comorbid conditions (e.g., rheumatoid arthritis) will be excluded from the trial.
Pregnancy
Concurrent malignancy or history of other cancer (except noninvasive skin cancer) within the last 5 years
Symptomatic central nervous system metastasis
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation). Use of low dose corticosteroid therapy (for nausea prophylaxis, etc) is acceptable; however, concomitant tamoxifen therapy is not. Supportive care measures are allowed.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vintafolide + PLD	EC20	Participants receive vintafolide 2.5 mg intravenous (IV) bolus on Days 1, 3, 5, 15, 17, and 19 and Pegylated Liposomal Doxorubicin (PLD) weight-based dose, IV on Day 1 of each 4-week cycle.
Vintafolide + PLD	pegylated liposomal doxorubicin (PLD)	Participants receive vintafolide 2.5 mg intravenous (IV) bolus on Days 1, 3, 5, 15, 17, and 19 and Pegylated Liposomal Doxorubicin (PLD) weight-based dose, IV on Day 1 of each 4-week cycle.
PLD Alone	pegylated liposomal doxorubicin (PLD)	Participants receive PLD on Day 1 of each 4-week cycle.
PLD Alone	EC20	Participants receive PLD on Day 1 of each 4-week cycle.
Vintafolide + PLD	Vintafolide	Participants receive vintafolide 2.5 mg intravenous (IV) bolus on Days 1, 3, 5, 15, 17, and 19 and Pegylated Liposomal Doxorubicin (PLD) weight-based dose, IV on Day 1 of each 4-week cycle.

Primary Outcome Measures

Name	Time	Method
Progression-free survival based on investigator assessment using RECIST and clinical findings	Assessed within 12 months following completion of accrual

Secondary Outcome Measures

Name	Time	Method
Compare overall survival of subjects between the two treatment arms	Assessed within 18 months after initiation of PFS analysis
Evaluate the safety and tolerability of EC145 in combination with PLD	event driven
Compare objective response rate (ORR) and duration of response of EC145 in combination with PLD, versus PLD alone, based on investigator assessment when analyzed using RECIST.	event-driven
Explore the correlation between therapeutic response (e.g. PFS, radiologic response, etc) and 99mTc-EC20 levels	Assessed within 12 months following completion of accrual