PHASE-I STUDY OF (6R)-5,10-DIDEAZATETRAHYDROFOLATE - A FOLATE ANTIMETABOLITE INHIBITORY TO DE-NOVO PURINE SYNTHESIS

Background: Cancer chemotherapy with folate antimetabolites has been t raditionally targeted at the enzyme dihydrofolate reductase and is bas ed on the requirement of dividing tumor cells for a supply of thymidyl ate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has beco me available that prevents tumor cell growth by inhibiting the first o f the folate-dependent enzymes involved in de novo purine synthesis, g lycinamide ribonucleotide formyltransferase. Purpose: We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial. Methods: DDATHF was given at one of the following dose levels t o 33 patients (16 females and 17 males) with malignant solid tumors: 3 .0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Eac h drug cycle consisted of three weekly injections of DDATHF followed b y a 2-week rest prior to redosing in the next cycle. Results: Of 33 pa tients, 27 received at least one full cycle of DDATHF. Thrombocytopeni a was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during th e second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was gen erally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or gr eater thrombocytopenia and resulted in hematologic recovery within 1 w eek in all eight patients so treated. Without leucovorin, the thromboc ytopenia lasted from 7 to 49 days in three patients. A partial respons e was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with color ectal cancer achieved stable disease for greater than 3 months with im provement in carcinoembryonic antigen levels in one patient. Conclusio ns: DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than w ould be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeat ed cycles require careful monitoring because of cumulative toxic effec ts. Implications: Additional phase I studies of DDATHF that relate tox icity to folate intake and tissue folate pools appear warranted.