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

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.

Time frame: First treatment to toxicity (up to 18 months)

Population: MTD was not determined in this study, so zero participants were analyzed.

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

Time frame: baseline to measured progressive disease (PD) (up to 18 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined by RECIST.

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.

Time frame: baseline through end of Phase 1 (up to 18 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

A listing of adverse events is located in the Reported Adverse Event module.

Time frame: baseline measured to progressive disease (up to 18 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

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.

Time frame: baseline measured to progressive disease (up to 18 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

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).

Time frame: baseline measured to progressive disease (up to 18 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

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.

Time frame: baseline measured to progressive disease (up to 18 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

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 frame: time of response to progressive disease (up to 31 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined by RECIST.

A listing of adverse events is located in the Reported Adverse Event module.

Time frame: baseline through end of Phase 2 (up to 31 months)

Population: Intention to Treat (ITT) population - all patients that consented and were successfully screened (note patient may or may not have received treatment; patients that were screen failures were not included in this population).

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.

Time frame: baseline to date of death from any cause (up to 31 months)

Population: Protocol Qualified (PQ) population. This analysis was not done due to the high number of censored patients.

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.

Time frame: baseline to measured progressive disease (up to 31 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined by RECIST.

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.

Time frame: baseline to measured progressive disease (up to 31 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined using RECIST.

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.

Time frame: First treatment to response (up to 31 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined by RECIST.

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.

Time frame: First treatment to discontinuation of study drug, progressive disease, or death (up to 31 months)

Population: Protocol Qualified (PQ) population. This population includes all patients in the Phase 2 study who met the following requirements:~Histologic diagnosis of ovarian or primary peritoneal cancer, no concurrent chemotherapy, treatment with at least 1 dose of pemetrexed or 1 dose of carboplatin, presence of measurable disease as defined by RECIST.