Trial of Pemetrexed and Carboplatin in Patients With Recurrent Ovarian or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine efficacy of the combination therapy of pemetrexed and carboplatin as treatment for patients with platinum-sensitive ovarian cancer. This study also includes patients with primary peritoneal cancer.

Official Title
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A Phase 1 and 2 Clinical Trial of ALIMTA® (Pemetrexed) in Combination With Carboplatin in Patients With Recurrent Ovarian or Primary Peritoneal Cancer

Conditions
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Ovarian Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: Pemetrexed - Phase 1
* Drug: Carboplatin - Phase 1
* Drug: Pemetrexed - Phase 2
* Drug: Carboplatin - Phase 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ovarian or primary peritoneal cancer confirmed by pathology Patients must have recurrent ovarian cancer which is sensitive to platinum therapy Prior radiation therapy is allowed Measurable disease as defined by the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines, or non-measurable but cancer antigen 125 (CA-125) greater than or equal to 2X upper limit. Exclusion Criteria: More than 2 lines of therapy for ovarian or primary peritoneal cancer. Pregnant or breast feeding. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.

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: Pemetrexed/Carboplatin Phase 1<br>Pemetrexed was administered intravenously over approximately 10 minutes on Day 1 of a 21-day cycle. Carboplatin was administered intravenously over approximately 30 minutes on Day 1 of a 21-day cycle, beginning approximately 30 minutes after the end of the pemetrexed infusion. | Drug: Pemetrexed - Phase 1<br>* 500, 600, 700, 800, or 900 milligrams per square meter (mg/m^2), administered intravenously (IV), every 21 days x 6 cycles, dose escalate to Maximum Tolerated Dose (MTD)<br>* Other names: Alimta;Drug: Carboplatin - Phase 1<br>* area under the concentration time curve (AUC) 5 or 6 mg/mL*min, administered intravenously (IV), every 21 days x 6 cycles, dose escalation to Maximum Tolerated Dose (MTD)<br>|
| Experimental: Pemetrexed/Carboplatin Phase 2<br>Pemetrexed was administered intravenously over approximately 10 minutes on Day 1 of a 21-day cycle. Carboplatin was administered intravenously over approximately 30 minutes on Day 1 of a 21-day cycle, beginning approximately 30 minutes after the end of the pemetrexed infusion. | Drug: Pemetrexed - Phase 2<br>* Dose determined from Phase 1: 500 mg/m^2, administered IV, every 21 days x 6 cycles<br>* Other names: Alimta;Drug: Carboplatin - Phase 2<br>* Dose determined from Phase 1: AUC 6 mg/mL*min, administered IV, every 21 days x 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - Maximum Tolerated Dose (MTD) of Pemetrexed in Combination With Carboplatin | MTD was to be determined by increasing doses of pemetrexed up to 900 mg/m^2 and carboplatin Area Under the Concentration-Time Curve (AUC) up to 6 mg/mL*min based on observed pattern of dose limiting toxicity (DLT). See Outcome #3 for DLT. If none of 3 initial participants at a given level experienced a DLT in Cycle 1, enrollment proceeded to the next dose level. If at least 2 participants experienced a DLT in Cycle 1 at a dose level, that dose level was considered the MTD. However, based on results from a different Phase 2 Study (NCT00109096), further dose escalations were not explored. | First treatment to toxicity (up to 18 months) | 
| Phase 2 - Percentage of Participants With Overall Tumor Response (Response Rate) | Response is defined as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumor (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions. Response rate (%) = (number of patients with CR+PR/number of patients in Phase 2)*100 | baseline to measured progressive disease (PD) (up to 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - Number of Dose-Limiting Toxicities (DLTs) | The following toxicities were considered DLT: CTCAE Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 10^9/L lasting ≥7 days. Febrile neutropenia (ANC <1.0 × 10^9/L, fever 38.5°C, and no documented infection). CTCAE Grade 4 thrombocytopenia (platelets <25.0 × 10^9/L). Any hemorrhage with CTCAE Grade ≥3 thrombocytopenia (50.0 × 10^9/L). CTCAE Grade ≥3 nonhematologic toxicity (excluding nausea, vomiting, or CTCAE Grade 3 alanine transaminase (ALT) or aspartate aminotransferase (AST) that returned to baseline prior to next treatment). Treatment delay more than 1 week due to toxicity. | baseline through end of Phase 1 (up to 18 months) | 
| Phase 1 - Number of Participants With Adverse Events (Toxicity) | A listing of adverse events is located in the Reported Adverse Event module. | baseline measured to progressive disease (up to 18 months) | 
| Phase 1 - Recommended Dose of Pemetrexed for Phase 2 | MTD was to be used as Phase 2 recommended dose. MTD was to be determined by increasing doses of pemetrexed up to 900 mg/m^2 based on observed pattern of dose limiting toxicity (DLT: See Outcome #3). If none of 3 initial participants at a given level had a DLT in Cycle 1, enrollment proceeded to next dose level. If at least 2 participants had a DLT in Cycle 1 at a dose level, that dose level was considered the MTD. However, based on results from another Phase 2 Study (NCT00109096), further dose escalations were not explored and dose was selected based on results of that Phase 2 Study. | baseline measured to progressive disease (up to 18 months) | 
| Phase 1 - Recommended Area Under the Curve (AUC) Dose of Carboplatin for Phase 2 | MTD was to be used as Phase 2 recommended dose. MTD determined by increasing doses up to AUC 6 mg/mL*min based on pattern of DLT (Outcome #3). If none of 3 initial participants at given level had DLT in Cycle 1, enrollment proceeded to next dose level. If at least 2 participants had DLT in Cycle 1 at dose level, that dose level was considered MTD. However, based on results from Phase 2 Study (NCT00109096), further dose escalations were not explored: carboplatin dose was selected based on standard dose employed in control arm of first-line therapy for epithelial ovarian cancer (Bookman 2006). | baseline measured to progressive disease (up to 18 months) | 
| Phase 1 - Number of Participants With Tumor Response | Patients were analyzed by Cancer Antigen-125 (CA-125) response criteria and RECIST guidelines. Possible evaluations include: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions. Progressive Disease (PD): At least a 20% increase in the size of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | baseline measured to progressive disease (up to 18 months) | 
| Phase 2 - Time to Response (TTR) | Response is defined as CR (Complete Response) or PR (Partial Response) per RECIST criteria. Possible evaluations include: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions. Progressive Disease (PD): At least a 20% increase in the size of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | First treatment to response (up to 31 months) | 
| Phase 2 - Duration of Response (DOR) | Duration of response is defined as the time from first observation of Complete Response or Partial Response to the first observation of Progressive Disease or death from any cause. For patients who are still alive at the time of analysis, and who do not have Progressive Disease, duration of response will be censored at the date of the last objective progression-free disease assessment. | time of response to progressive disease (up to 31 months) | 
| Phase 2 - Time to Disease Progression | Time to objective progressive disease (TTPD) is defined as the time from the date of study enrollment to the date of objectively determined Progressive Disease (PD). For patients who die without objective PD (including death from study disease), TTPD will be censored at the date of the last objective progression-free disease assessment. For patients who are still alive at the time of analysis, and who do not have PD, TTPD will be censored at the date of the last objective progression-free disease assessment. | baseline to measured progressive disease (up to 31 months) | 
| Phase 2 - Time to Treatment Failure | Time to treatment failure (TTTF) is defined as the time from the date of study enrollment to the date of the first observation of disease progression, death from any cause, or early discontinuation of treatment (any reason). For patients who are alive, progression-free, and have not discontinued early at the time of analysis, TTTF will be censored at the date of the last objective progression-free disease assessment. | First treatment to discontinuation of study drug, progressive disease, or death (up to 31 months) | 
| Phase 2 - Overall Survival | Overall survival is defined as the time from the date of study enrollment to the date of death from any cause. This analysis was not done due to the high number of censored patients. | baseline to date of death from any cause (up to 31 months) | 
| Phase 2 - Number of Participants With Adverse Events (Toxicity) | A listing of adverse events is located in the Reported Adverse Event module. | baseline through end of Phase 2 (up to 31 months) | 
| Phase 2 - Progression-Free Survival | Progression-free survival (PFS) is defined as the time from the date of study enrollment to the date of objectively determined PD or death from any cause, whichever comes first. For patients who are still alive at the time of analysis, and who do not have PD, PFS will be censored at the date of the last objective progression-free disease assessment. | baseline to measured progressive disease (up to 31 months) |