Dose Escalation of Lapatinib With Paclitaxel in Ovarian Cancer

Study Overview
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Brief Summary
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This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.

Detailed Description
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While ABCB1 (P-glycoprotein 1) upregulation after paclitaxel administration is well known, there is currently no clinically available method for preventing or overcoming it. To develop a therapy able to prevent ABCB1 upregulation and paclitaxel resistance, several ABCB1 inhibitors have been evaluated in combination with paclitaxel in preclinical model systems. Pulsed-dose lapatinib and paclitaxel are synergistic and inhibition of ABCB1 by lapatinib increases sensitivity to paclitaxel. Lapatinib is FDA approved, orally available, and previously studied in combination with weekly paclitaxel for breast cancer at doses of 1000mg to 1250mg daily (7000-8250mg per week). This trial will use twice-daily dosing of lapatinib at a starting dose of 750 mg for 2 days (1500mg a day and 3000mg weekly dose), which is less than half of the continuous dose and has been shown to achieve plasma concentrations at 48 hours that are associated with synergy. Therefore, these findings can be translated into a novel, well-tolerated, and convenient combination regimen with significant potential for clinical activity. This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.

Official Title
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A Phase I Dose-Escalation Study on the Safety of Lapatinib With Dose-Dense Paclitaxel in Patients With Platinum-Resistant Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Lapatinib and Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically or cytologically confirmed ovarian cancer who recur within 12 months of platinum-based chemotherapy ECOG performance status less than or equal to 2 Adequate organ and marrow function at baseline ability to sign a written informed consent document Exclusion Criteria: hypersensitivity to lapatinib or paclitaxel uncontrolled intercurrent illness receiving medications that inhibit or induce CYP3A4 malabsorption syndrome congestive heart failure receiving any other anti-cancer investigational agents baseline neuropathy greater than Grade 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib - Group 1<br>Patients in this group will receive Lapatinib (500mg PO BID) and Paclitaxel (80mg/m2). | Drug: Lapatinib and Paclitaxel<br>* Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.<br>|
| Experimental: Lapatinib - Group 2<br>Patients in this group will receive Lapatinib (750mg PO BID) and Paclitaxel (80mg/m2). | Drug: Lapatinib and Paclitaxel<br>* Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.<br>|
| Experimental: Lapatinib - Group 3<br>Patients in this group will receive Lapatinib (1500mg PO BID) and Paclitaxel (80mg/m2). | Drug: Lapatinib and Paclitaxel<br>* Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.<br>|
| Experimental: Lapatinib - Group 4<br>Patients in this group will receive Lapatinib (2000mg PO BID) and Paclitaxel (80mg/m2). | Drug: Lapatinib and Paclitaxel<br>* Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival. | Proportion of patients with progression-free survival at one year. | One year | 
| Dose-limiting toxicity | Dose limiting toxicity (DLT) is calculated as the total number of patients experiencing DLTs divided by the total number treated. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma concentration of lapatinib. | Plasma concentrations of lapatinib will be measured on days 1, 8 and 15. | 15 days (on day 1, 8 and 15) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platinum-resistant