PH I SRC Kinase, Dasatinib Combo Paclitaxel & Carboplatin in Pts w Ovarian, Peritoneal, & Tubal Cancer

Study Overview
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Brief Summary
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Primary objective to determine the maximal tolerated (MTD) of dasatinib in combination with paclitaxel and carboplatin during the first cycle of treatment. Secondary objectives to describe the toxicity of this combination of therapy; to describe the pharmacokinetics and pharmacodynamics parameters related to this combination; to describe the clinical activity as defined as the response rate (complete and partial response rate) and progression-free survival > 6 month; to compare the SRC pathway microarray signature in pre and post-treatment cancer specimens; to evaluate SRC pathway downstream substrates, FAX, paxcillin, and CRK-L in pre and post-treatment cancer specimens.

Detailed Description
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This is a phase I multicenter study designed to determine the maximal tolerated dose (MTD) and toxicity of dasatinib in combination with paclitaxel and carboplatin during the first cycle of treatment in patients with advanced or recurrent ovarian, peritoneal, and tubal carcinoma. The MTD will be defined as the highest dose at which no more than 1 of 6 evaluable patient experiences a dose-limiting toxicity (DLT) due to the combination of dasatinib, paclitaxel,and carboplatin during the first cycle of treatment.

Official Title
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A Phase I Trial of A SRC Kinase Inhibitor, Dasatinib,in Combination With Paclitaxel and Carboplatin in Patients With Advanced or Recurrent Ovarian, Peritoneal, and Tubal Cancer

Conditions
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Ovarian Cancer, Peritoneal Cancer, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: Dasatinib, Paclitaxel, and Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pts must have histologic or cytologic evidence of ovarian, peritoneal, or tubal cancer All pts must have measurable disease > 18 yrs Expected survival of at least 3 months Pts must have GOG performance status pf 0, 1 or 2 Pts must have adequate:Bone marrow function, renal function, hepatic function, neurologic function No chemo, radiotherapy, biologic, hormonal, or investigational drug therapy within 28 days prior to study entry Pts may have had up to 3 prior cytotoxic chemo regimens including prior treatment w carboplatin & paclitaxel Capable of providing written informed consent Pts of childbearing potential must have negative serum pregnancy test prior to study entry & be practicing effective method of birth control during course of study, in manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential must be advised of importance of avoiding pregnancy during trial participation & potential risk factors for unintentional pregnancy Pts must have tissue block from their tumor available for evaluation for microarray & immunoblot analyses. Pretreatment tumor tissue may be obtained from either archival tissue or be obtained by guided by guided core needle or simple biopsy it must be performed within four weeks prior to enrollment on study. Pts must have tumor that is accessible to biopsy & consent to undergo post-treatment biopsy after cycle #2 of treatment as well Exclusion Criteria: Pts w epithelial ovarian tumors of low malignant potential (borderline tumor) Pts w history of other invasive malignancies, w exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within last 5 yrs Pts who have following cardiac conditions: uncontrolled angina or myocardial infarction within past 6 months; diagnosed or suspected congenital long QT syndrome; Any history of clinically significant ventricular arrhythmias; Prolonged QTc interval on pre-entry electrocardiogram on both Fridericia & Bazett's correction; uncontrolled hypertension History of significant bleeding disorder unrelated to cancer, including: diagnosed congenital bleeding disorders; diagnosed acquired bleeding disorder within 1 yr Pts currently taking drugs that are generally accepted to have risk of causing Torsades de Pointes including: quinidine, procainamide, disopyramide; amiodarone, sotalol, ibutilide, dofetilide; erythromycins, clarithromycin; chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide; cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine Serum creatinine > 1.5 times institutional upper limits of normal Pts taking certain concomitant medications, consider following prohibitions: medications that inhibit platelet function or anticoagulants Pts who have received radiation therapy to > 30 percent of bone marrow Pts w history of grade 3 hypersensitivity to paclitaxel or carboplatin Pts w septicemia, severe infection, acute hepatitis, other uncontrolled severe medical conditions

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: Dasatinib, paclitaxel,and carboplatin<br>Combination of dasatinib, paclitaxel,and carboplatin | Drug: Dasatinib, Paclitaxel, and Carboplatin<br>* Dasatinib will be administered as an oral dose (tablet) as per the dose escalation (50 mg everyday - 250 mg everyday)continuously on days 2-21 in the first cycle (3 weeks) therapy and continuously (days 1-21) throughout the remainder of therapy. Paclitaxel will be administered on a 21-day schedule. Paclitaxel (150-175 mg/m^2) IV infused over 3 hours on day #1 of each cycle. Carboplatin (AUC=5-6 mg/,l/min) will be infused over 30-60 minutes every cycle via IV on day 1 of every cycle following the paclitaxel administration. All patients will be followed until disease progression or study withdrawal. In addition, following disease progression, patients will be monitored for delayed toxicity and survival for a period of 5 years and data entered into eDC, unless is withdrawn.<br>* Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine maximal tolerated dose (MTD) of dasatinib in combination with paclitaxel and carboplatin during the first cycle of treatment |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To describe the toxicity of this combination of therapy |  | 6 months | 
| To describe the pharmacokinetics and pharmacodynamics parameters related to this combination |  | 6 months | 
| To describe the clinical activity as defined as the response rate (complete and partial response rate) and progression-free survival > 6 months |  | 6 months | 
| To compare the SRC pathway microarray signature in pre and post-treatment cancer specimens |  | 6 months | 
| To evaluate SRC pathway downstream substrates, FAX, paxcillin, and CRK-L in pre and post-treatment cancer specimens |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer, Peritoneal Cancer, Tubal Cancer, Fallopian Tube Cancer, Dasatinib, Sprycel, Paclitaxel, Taxol, Carboplatin, Paraplatin