SJG-136 in Treating Patients With Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer That Did Not Respond to Previous Treatment With Cisplatin or Carboplatin

Study Overview
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Brief Summary
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This phase II trial is studying how well SJG-126 works in treating patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer that did not respond to previous treatment with cisplatin or carboplatin. Drugs used in chemotherapy, such as SJG-136, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the overall response rate to SJG-136 in patients with persistent or recurrent platinum-refractory epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. II. To assess the nature and degree of toxicity of this regimen in these patients. III. To determine other parameters of response, including progression-free survival, overall survival, and time to progression in patients treated with this regimen. Correlative Endpoints: I. To correlate response rates with the degree of DNA adduct formation in peripheral blood mononuclear cells (PBMCs) and tumor cells as measured by the single-cell gel electrophoresis (Comet) assay and γ-H2AX assay. II. To assess whether the rate of DNA adduct formation in PBMCs correlates with the rate of DNA adduct formation in tumor cells. III. To evaluate BRCA1 protein expression in archival tissue specimens from the patient's primary tumor reductive surgery. IV. To determine the ability of BRCA1 protein in repairing/removing DNA-adducts in PBMCs and tumor tissue. VI. To evaluate the effect of BRCA1 protein expression on the overall response rate to SJG-136. OUTLINE: This is a multicenter study. Patients receive SJG-136 IV over 20 minutes on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection at baseline and periodically during study for correlative studies. Tumor tissue samples may also be collected. After completion of study therapy, patients are followed up for 30 days and then annually thereafter.

Official Title
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A Phase II Evaluation of SJG-136 in Women With Cisplatin-Refractory or Resistant Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Carcinoma

Conditions
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Recurrent Fallopian Tube Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Primary Peritoneal Cavity Cancer

Intervention / Treatment
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* Drug: SJG-136
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma, with histologic confirmation of the original primary tumor. Must have had at least one prior platinum-based (cisplatin or carboplatin) chemotherapy regimen for the management of their primary disease. This would include intraperitoneal chemotherapy. Must be considered platinum refractory or resistant, defined as patients with progression of disease during platinum-based chemotherapy, patients having persistent disease at the completion of platinum-based chemotherapy, or patients having a disease free interval following prior platinum therapy of less than six months. May have had no more than three prior treatment regimens for their epithelial ovarian, primary peritoneal or fallopian tube carcinoma. Consolidation or maintenance therapy initiated within six weeks of the completion of primary therapy will not be counted as an additional regimen. Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Time interval from last chemotherapy, radiotherapy, or surgery of at least four weeks and the patient must have recovered from any significant adverse effects of prior treatment. Patients must be at least six weeks from having received nitrosoureas or mitomycin C. Life expectancy greater than three months. Must have adequate bone marrow and organ function: Leukocyte count > 3 x 10^9/L Absolute neutrophil count (ANC) > 1.5 x 10^9/L Platelet count > 100 x 10^9/L Total bilirubin Within normal institutional limits Aspartate aminotransferase (AST)/alanine transaminase (ALT) < 2.5 x institutional upper limits of normal Creatinine < 1.5 mg/dL or calculated creatinine clearance (ClCr) > 60 ml/min by Cockcroft Gault method, as below. ClCr = weight (kg) x (140-age) x 0.85 72 x serum creatinine (mg/dL) Participants must have signed an approved informed consent. Participants of childbearing potential must have a negative serum pregnancy test prior to study entry and must use an effective form of contraception. Must have archival tissue available from their original tumor debulking surgery for assessment of BRCA1 protein expression. Exclusion Criteria: Patients with borderline ovarian tumors, ovarian germ cell tumors, ovarian sex-cord stromal tumors, or other non-epithelial ovarian tumors are not eligible. Patients receiving any other investigational agents. Patients who have received radiation therapy to more than 25% of the bone marrow. Patients who have previously received SJG-136 or related compounds. Uncontrolled intercurrent illness including, but not limited to, ongoing active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with the study requirements. Prior malignancy (other than cervical carcinoma in situ, ductal carcinoma in situ of the breast, or non-melanoma skin cancer) unless treated with curative intent and without evidence of disease for three years. With the exception of alopecia (or other situations in which the organ dysfunction or symptoms are considered clinically insignificant or irrelevant to the study), patients may not have baseline organ dysfunction or symptoms that qualify as grade 2 or higher by the CTEP Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0. Particular attention should be paid to assessment of pre-existing edema, since vascular leak syndrome was the dose limiting toxicity of this agent in the phase I trial.

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 (SJG-136)<br>Patients receive SJG-136 IV over 20 minutes on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: SJG-136<br>* Given IV<br>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 |
| --- | --- | --- |
| Overall Response (OR) | Number of patients in each response category, per RECIST v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), >=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD. Confirmation of CR or PR is required to deem either one the best overall response. | On-treatment date to date of disease progression (assessed up to 12 months) | 
| Number of Patients With Each Worst-grade Toxicity | Count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death. | On-study date to 30 days following final dose of study | 
| Progression-free Survival (PFS) | Estimated probable duration of life without disease progression, from on-study date to earlier of progression date or date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >=20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions. | On-study date to lesser of date of progression or date of (assessed up to 12 months) | 
| Overall Survival (OS) | Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details). | On-study date to date of death from any cause (assessed up to 12 months) | 
| Time to Progression (TTP) | Estimated probable duration from on-study date to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >=20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions. | On-study date to date of progression (assessed up to 12 months) |