Lapatinib and Topotecan in Treating Patients With Ovarian Epithelial Cancer or Primary Peritoneal Cancer That Did Not Respond to Cisplatin or Carboplatin

Study Overview
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Brief Summary
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RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving lapatinib together with topotecan may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving lapatinib together with topotecan works in treating patients with ovarian epithelial cancer or primary peritoneal cancer that did not respond to cisplatin or carboplatin.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of lapatinib ditosylate and topotecan hydrochloride, in terms of response, in patients with platinum-resistant or refractory ovarian epithelial or primary peritoneal cavity carcinoma. Secondary Determine the overall survival time in patients treated with this regimen. Determine the time to progression in patients treated with this regimen. Assess the toxicity profile of this regimen in these patients. Translational Determine the expression patterns of epidermal growth factor receptor, HER2/neu, hypoxia-induced factor 1 alpha, CD31, breast cancer resistance protein, and topoisomerase I by immunohistochemistry using tumor tissue from primary debulking surgery. Determine the feasibility of monitoring circulating tumor cells with specific biological markers to determine or follow response in these patients. OUTLINE: This is a multicenter study. Patients receive oral lapatinib ditosylate once daily on days 1-28 and topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and on day 8 of course 1 (immediately after the topotecan infusion) and are evaluated for pharmacological studies. Tumor tissue samples obtained at debulking surgery are examined by immunohistochemistry for epidermal growth factor receptor, HER1, ErbB1, HER2/neu, ErbB2, hypoxia-induced factor 1 alpha, CD31, platelet endothelial cell adhesion molecule 1, topoisomerase I, and breast cancer resistance protein. After the completion of study treatment, patients are followed periodically for 2 years. PROJECTED ACCRUAL: A total of 39 patients will be accrued for this study.

Official Title
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A Phase II Trial of Lapatinib in Combination With Weekly Topotecan in Patients With Platinum-Refractory/Resistant Ovarian and Primary Peritoneal Carcinoma

Conditions
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Ovarian Cancer, Peritoneal Cavity Cancer

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Topotecan


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed ovarian epithelial or primary peritoneal carcinoma Must have one of the following: Measurable disease Evaluable disease AND a CA-125 value that has increased ≥ 2 times the nadir value established after debulking surgery and first-line chemotherapy, confirmed by a second measurement within the past 21 days If a second measurement has not been done, it can be done ≥ 7 days but < 21 days prior to study treatment Platinum-refractory and/or -resistant disease after first-line chemotherapy Patients retreated with platinum agents (i.e., second relapse) are not eligible Patients treated with first-line triplet therapy (e.g., on clinical trial GOG-182) are eligible Must have had debulking surgery Tissue blocks from this surgery must be available No CNS metastases PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 12 weeks Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST ≤ 3 times ULN (5 times ULN if there is liver involvement) Creatinine ≤ 1.5 times ULN Hemoglobin ≥ 9.0 g/dL No uncontrolled infection No New York Heart Association class III or IV heart failure Left Ventricular Ejection Fraction (LVEF) ≥ 50% by echocardiogram No seizure disorder No other prior or concurrent malignancy in the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior topotecan hydrochloride More than 4 weeks since prior surgery or procedure involving the peritoneum or pleura CA125 measurements used as basis for enrollment must be made outside of this 4-week window More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered More than 4 weeks since prior immunotherapy More than 4 weeks since prior biologic therapy More than 4 weeks since prior radiotherapy No prior radiotherapy to > 25 % of bone marrow No prior therapy with an anti-epidermal growth factor receptor or anti-HER2 tyrosine kinase inhibitors No prior agents targeting topoisomerase I No prior or concurrent human anti-mouse antibodies (HAMA) in patients with non-measurable disease At least 14 days since prior and no concurrent herbal or dietary supplements Vitamin supplements are allowed unless they include herbal additives At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following: Rifampin Rifabutin Rifapentine Phenytoin Carbamazepine Phenobarbital Efavirenz Nevirapine Cortisone (> 50 mg) Hydrocortisone (> 40 mg) Prednisone (> 10 mg) Methylprednisolone (> 8 mg) Dexamethasone (> 1.5 mg) Oral doses of ≤ 1.6 mg of dexamethasone allowed Modafinil Hypericum perforatum (St. John's wort) At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following: Clarithromycin Erythromycin Troleandomycin Itraconazole Ketoconazole Fluconazole (> 150 mg daily) Voriconazole Delaviridine Nelfinavir Amprenavir Ritonavir Indinavir Saquinavir Lopinavir Verapamil Diltiazem Nefazodone Fluvoxamine Cimetidine Aprepitant Grapefruit or grapefruit juice At least 6 months since prior and no concurrent amiodarone No concurrent participation in another study involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, gene therapy) for symptom control or therapeutic intent

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib + Topotecan<br>Assess biological effects of topotecan and lapatinib in patients with epithelial ovarian cancer and primary peritoneal carcinoma. | Drug: Lapatinib<br>* 1250 mg orally days 1 -28.<br>* Other names: Tykerb;Drug: Topotecan<br>* 3.2 mg/m2 IV over 30 min in 100mL D5W (5% dextrose in water) or 0.9% NS at days 1, 8 & 15.<br>* Other names: Hycamptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete Response (CR) or Partial Response (PR)) | Measurable disease patients: measureable disease is defined as at least one lesion whose longest diameter >= 2cm with conventional techniques or >=1cm with spiral CT Confirmed tumor response (complete and partial) as measured by RECIST(Response Evaluation Criteria In Solid Tumors) criteria on 2 consecutive evaluations at least 4 weeks apart. Confirmed tumor response is at least a 30% decrease in the sum of the longest diameter of target lesions and no new lesions. Non-measurable disease patients: Decrement in CA125 by > 50% Improvement in other evaluable disease | Two consecutive evaluations at least 4 weeks apart | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression was defined as the number of months from registration to the date of disease progression, with patients who are progression free being censored on the date of their last evaluation. | Time from registration to progression (up to 2 years) | 
| Adverse Event Profile | Number of patients that experienced adverse events (grade 3 or more) as measured by NCI CTCAE (Common Terminology Criteria for Adverse Events) v3.0 | Every 4 weeks | 
| Overall Survival | Overall survival time was defined as the number of months from registration to the date of death or last follow-up | Time from Registration to Death or last follow-up (up to 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent ovarian epithelial cancer, peritoneal cavity cancer