A6 in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well A6 works in treating patients with persistent or recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer. A6 may stop the growth of tumor cells by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the activity of A6, as measured by the 6-month progression-free survival (PFS) rate and objective tumor response (complete or partial) rate, in patients with persistent or recurrent ovarian epithelial, fallopian tube, or primary peritoneal carcinoma. II. To determine the frequency and severity of adverse events as assessed by CTCAE v3.0. SECONDARY OBJECTIVES: I. To characterize the duration of PFS and overall survival. II. To identify biomarkers of drug effect on peripheral blood mononuclear cells (PBMCs). TERTIARY OBJECTIVES: I. To explore whether genes identified as being up- or down-regulated by exposure of human PBMCs to A6 in vitro are also up- or down-regulated following treatment of patients with A6 in vivo. II. To explore whether there is an association between the expression of candidate A6 receptors in the tumor prior to treatment with A6 (as determined by IHC) and response and PFS. III. To explore whether there is an association between change in expression of candidate biomarkers in PBMCs between 0-24 hours following the first dose of A6 and response and PFS. IV. To explore whether there is an association between change in expression of candidate biomarkers in PBMCs over the course of the first one month cycle (course 1) and response and PFS. V. To determine whether there is an association between plasma A6 levels measured on days 2 (24 hours after the first dose and 4 hours after the second dose) and 8 (prior to injection of A6) of course 1 and levels of expression of candidate biomarkers in PBMCs collected on the same days. VI. To explore whether there is an association between plasma A6 levels measured on days 2 (24 hours after the first dose and 4 hours after the second dose) and 8 (prior to injection of A6) of course 1 and response and PFS. VII. To explore whether there is an association between candidate serum biomarkers and response and PFS over the course of A6 treatment. OUTLINE: This is a multicenter study. Patients receive A6 subcutaneously once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Phase II Evaluation of a Urokinase-Derived Peptide (A6) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

Conditions
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Fallopian Tube Carcinoma, Malignant Ovarian Mixed Epithelial Tumor, Ovarian Brenner Tumor, Ovarian Clear Cell Cystadenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Cystadenocarcinoma, Ovarian Serous Cystadenocarcinoma, Primary Peritoneal Carcinoma, Recurrent Ovarian Carcinoma, Undifferentiated Ovarian Carcinoma

Intervention / Treatment
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* Biological: Urokinase-Derived Peptide A6
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed persistent or recurrent ovarian epithelial, fallopian tube, or primary peritoneal carcinoma, including any of the following epithelial cell types: Serous adenocarcinoma Endometrioid adenocarcinoma Mucinous adenocarcinoma Undifferentiated carcinoma Clear cell adenocarcinoma Mixed epithelial carcinoma Transitional cell carcinoma Malignant Brenner tumor Adenocarcinoma not otherwise specified Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension as ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan Must have ≥ 1 target lesion to assess response as defined by RECIST criteria Tumors within a previously irradiated field are designated as non-target lesions unless progression is documented or a biopsy is obtained to confirm persistence of disease ≥ 90 days following completion of radiotherapy Must not be eligible for a higher priority GOG clinical trial, if one exists (i.e., any active GOG Phase III clinical trial for the same patient population) Must have received 1 prior platinum-based chemotherapeutic regimen containing carboplatin, cisplatin, or another organoplatinum compound for management of primary disease Initial treatment may have included high-dose therapy, consolidation therapy, non-cytotoxic therapy, or extended therapy administered after surgical or non-surgical assessment One additional cytotoxic regimen for management of recurrent or persistent disease allowed Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease) must have a platinum-free interval of < 12 months, have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy GOG performance status 0-2 (for patients who received 1 prior regimen) OR 0-1 (for patients who received 2 prior regimens) ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN SGOT ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able and willing to self-administer daily subcutaneous (SC) injections or has a caregiver who is willing and able to administer daily SC injections No active infection requiring antibiotics, except uncomplicated urinary tract infection No neuropathy (sensory and motor) > grade 2, according to CTCAE v3.0 No other invasive malignancies within the past 5 years, except for non-melanoma skin cancer No history of sensitivity to A6 No active gastrointestinal bleeding within the past month No other disease that, in the opinion of the investigator, could jeopardize patient safety or interfere with study objectives No concurrent amifostine or other protective reagents Recovered from prior surgery, radiotherapy, or chemotherapy No prior non-cytotoxic therapy for management of recurrent or persistent disease Prior biologic (non-cytotoxic) therapy as part of primary treatment regimen allowed At least 1 week since prior hormonal therapy directed at the malignant tumor At least 3 weeks since any other prior therapy directed at the malignant tumor, including immunological agents More than 2 weeks since prior major surgical procedure More than 5 years since prior radiotherapy to any portion of the abdominal cavity or pelvis other than for the treatment of ovarian, fallopian tube, or primary peritoneal cancer More than 3 years since prior radiotherapy for localized cancer of the breast, head and neck, or skin AND remains free of recurrent or metastatic disease Patients with ductal breast carcinoma in situ may have undergone localized radiotherapy within the past 3 years More than 5 years since prior chemotherapy for any abdominal or pelvic tumor other than for the treatment of ovarian, fallopian tube, or primary peritoneal cancer More than 3 years since prior adjuvant chemotherapy for localized breast cancer AND remains free of recurrent or metastatic disease More than 30 days since prior investigational drugs No prior A6 No prior radiotherapy to > 25% of marrow-bearing areas No prior cancer treatment that would contraindicate study therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (urokinase-derived peptide A6)<br>Patients receive A6 subcutaneously once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Urokinase-Derived Peptide A6<br>* Given SC<br>* Other names: uPA-derived Peptide A6;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 6 Months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since study entry, or unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. CT scan or MRI is used to follow lesion for measurable disease every other cycle for the first 6 months; every three months thereafter; and at any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tumor marker levels. Responses must be confirmed by repeat imaging 4 weeks following documentation of response. | Scans to assess progression were done every other cycle for the first 6 months. | 
| Tumor Response | Complete and Partial Tumor Response by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Per RECIST v1.0 for target lesions and assessed by MRI or CT scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. CT scan or MRI is used to follow lesion for measurable disease every other cycle for the first 6 months; every three months thereafter; and at any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tumor marker levels. Responses must be confirmed by repeat imaging 4 weeks following documentation of response. | Scans to assess response were done every other cycle for the first 6 months; every three months thereafter; and at any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tumor marker levels. | 
| Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 |  | Every cycle during treatment (average collection time = 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since study entry, or unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. CT scan or MRI is used to follow lesion for measurable disease every other cycle for the first 6 months; every three months thereafter; and at any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tumor marker levels. Responses must be confirmed by repeat imaging 4 weeks following documentation of response. | scans to assess response were done every other cycle for the first 6 months; every three months thereafter; and at any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or rising serum tumor marker levels. | 
| Overall Survival |  | Every other cycle, up to 5 years | 
| Biomarkers of Drug Effect on Peripheral Blood Mononuclear Cells (PBMCs) | Note: due to the limited activity of this agent, it was decided not to expend resources assaying the PBMCs. Data was not collected. | Day 1 prior to dosing; Day 2 prior to dosing and 4-hour post dosing; Day 8 prior to dosing. |