Erlotinib Plus Carboplatin and Paclitaxel in Ovarian Carcinoma

Study Overview
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Brief Summary
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This phase II trial is studying the side effects of giving erlotinib together with carboplatin and paclitaxel and to see how well it works in treating patients with stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer. Biological therapies such as erlotinib may interfere with the growth of tumor cells and slow the growth of the tumor. Drugs used in chemotherapy such as carboplatin and paclitaxel use different ways to stop tumor cells from dividing so they stop growing or die.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish whether the addition of OSI-774 (Tarceva) to the combination of paclitaxel and carboplatin encourages pathologic complete response (pCR) rates in patients with Stage III optimally cytoreduced (stratum 1) and Stage III suboptimally cytoreduced or Stage IV (stratum 2) ovarian, primary peritoneal or fallopian tube carcinomas when used as front line therapy. II. To determine the degree and type of toxicity associated with this combined regimen. SECONDARY OBJECTIVES: I. To establish baseline epidermal growth factor receptor (EGFR), truncated EGFR (EGFRvIII), phosphorylated EGFR (pEGFR) and related signal transduction pathway protein expression levels (such as the mitogen activated protein kinase p-ERK, AKT phosphorylation and Her2/neu) in tumor samples obtained pretreatment, and to correlate these with achieving pCR. II. To describe changes in EGFR, EGFRvIII, pEGFR expression levels and other related signal transduction pathway expression occurring during treatment with OSI-774 in combination with chemotherapy. III. To determine the effect of the addition of OSI-774 (Tarceva) to the combination of paclitaxel and carboplatin on progression-free interval in patients with Stage III optimally cytoreduced (stratum 1) and Stage III suboptimally cytoreduced or Stage IV (stratum 2) ovarian or primary peritoneal carcinomas when used as front line therapy. IV. To determine the tolerability of twelve months of maintenance treatment with OSI-774 for patients achieving pCR, and to measure the progression-free interval for this population. V. To document cutaneous effects of OSI 774 prospectively, and to correlate the degree of skin rash with clinical and translational endpoints. OUTLINE: This is a non-randomized study. Patients are stratified according to disease stage (stage III with optimal residual disease vs stage III with suboptimal residual disease or stage IV). Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Patients also receive oral erlotinib daily. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve a pathologic complete response, those initially suboptimally debulked with a response, and patients who elect not to undergo surgical reassessment but who achieve a complete clinical response receive maintenance erlotinib for an additional 12 months.

Official Title
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Phase II Study of Erlotinib Plus Carboplatin and Paclitaxel in Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

Conditions
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Brenner Tumor, Fallopian Tube Cancer, Ovarian Clear Cell Cystadenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Cystadenocarcinoma, Ovarian Serous Cystadenocarcinoma, Ovarian Undifferentiated Adenocarcinoma, Stage III Ovarian Epithelial Cancer, Stage IV Ovarian Epithelial Cancer

Intervention / Treatment
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* Drug: paclitaxel
* Drug: carboplatin
* Drug: erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a histologic diagnosis of primary peritoneal carcinoma, fallopian tube epithelial ovarian carcinoma, Stage III with either greater than 1 cm (suboptimal) residual disease following initial surgery, or Stage IV; all patients must either have had appropriate surgery for ovarian, fallopian tube or peritoneal carcinoma with appropriate tissue available for histologic evaluation to confirm diagnosis and stage or must be unresectable at time of diagnosis (to be determined by gynecological oncologist); cytology alone is not adequate Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified (NOS) Patients must begin chemotherapy on this study no more than twelve weeks postoperatively Patients must not have received chemotherapy within five years prior to enrollment ECOG performance status =< 2 (Karnofsky >= 60%) Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< 1.5 x institutional upper limit of normal AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Neuropathy (sensory and motor) =< CTC grade 1 No medical contraindications to planned regimen Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had courses of chemotherapy within the five years prior to entering the study Patients may not be receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition OSI-774 or other agents used in the study Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because OSI-774 has the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with OSI-774, breastfeeding should be discontinued if the mother is treated with OSI-774; these potential risks may also apply to other agents used in this study Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with OSI-774 or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

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: Paclitaxel, carboplatin, erlotinib<br>Carboplatin and paclitaxel IV every 21 days x 6 cycles plus oral erlotinib | Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: erlotinib<br>* Given PO<br>* Other names: OSI-774;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rates | Pathologic complete response was defined as having no pathologic or cytologic evidence of disease following surgical reassessment. | Up to 7 years | 
| The Percentage of Participants Experiencing Toxicty (Grade 2 and Grade 3/4) Associated With the Combined Regimen | Adverse event assessment | For the duration of the study up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Measure EGFR Gene Amplification in Tumor Specimens |  | The duration of the study for up to 7 years | 
| To Determine Progession Free Survival With the Addition of OSI-774 (Tarceva) to the Combination of Paclitaxel and Carboplatin |  | The duration of the study | 
| To Determine the Tolerability of Twelve Months of Maintenance Treatment |  | Twelve months of maintenance |