Disease	Brain cancer – primary
Disease	Lymphoma – non‐Hodgkins
Stage of Disease/Treatment	Primary
Prior Therapy	Two prior regimens
Type of Study − 1	Phase I, 3 + 3
Primary Endpoints	Maximum tolerated dose, tolerability, safety
Secondary Endpoints	Progression‐free survival, overall survival, overall response to treatment
Additional Details of Endpoints or Study Design
We conducted a multicenter, open‐label, single‐agent phase I study of pemetrexed. Patients were enrolled using a 3 + 3 dose‐escalating design. The MTD was defined as the dose level below which dose‐limiting toxicity (DLT) was encountered in one‐third of the patients. DLT was defined as any grade 4 toxicity (except grade 4 febrile neutropenia lasting less than 5 days) and any grade 3 nonhematologic, non‐neurologic toxicity (except grade 3 hepatic transaminase elevations and grade 3 fatigue or generalized weakness) within the first two cycles (28 days) of therapy or the 14‐day observation period between each dose level cohort. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to grade all the toxicities.
Pemetrexed was administered as an intravenous infusion over 10–20 minutes every 2 weeks. Three patients per dose‐level cohort were treated and evaluated for toxicity over a period of 28 days (two cycles of pemetrexed per dose). After the third patient in each dose‐level cohort completed the second administration of pemetrexed, there was a 14‐day observation period. If no DLT was observed in any of the three patients in the cohort, escalation to the next dose‐level cohort was performed. A starting dose at 600 mg/m2 was chosen. The dose was escalated in increments of 300 mg/m2 to a maximum of 1,200 mg/m2 of pemetrexed. If a drug‐related DLT occurred at any dose‐level cohort, an additional three patients were added to a total accrual of six patients at this dose‐level cohort.
Patients received dexamethasone (4 mg of oral or equivalent) twice daily, on the day before, the day of, and the day after each dose of pemetrexed, for prophylaxis of skin‐related adverse effects and rashes. To reduce potential side effects of pemetrexed, patients were also instructed to take folic acid 800 μg daily, starting 7 days before the first dose of pemetrexed and continuing for 3 weeks after the last dose. Vitamin B12 1,000 μg supplementation, as an intramuscular injection, was also administrated, starting 7–14 days prior to the first dose of pemetrexed, and was repeated every 9 weeks until 3 weeks after the last dose. Because of grade 4 neutropenia toxicity observed in the first treatment cohort, all patients were subsequently treated with granulocyte colony‐stimulating factor. Patients remained on treatment until complete response or cycle 8. Patients with complete response received up to two additional consolidation cycles.
In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study.
Investigator's Analysis	Correlative endpoints met but not powered to assess activity