Early Clinical Studies with CB 3717 (N-(4-(N-((2-Amino-4-Hydroxy-6-Quinazolinyl)Methyl)Prop-2-Ynylamino)Benzoyl)-L-Glutamic Acid) at the Royal Marsden Hospital
The folate analogue CB 3717, a potent inhibitor of thymidylate synthetase, was used to treat 77 patients with a wide variety of tumours at the Royal Marsden Hospital. The starting dose of 100mg/m2 was escalated to 500mg/m2 and was given by a 1 hour infusion every 3 weeks. Transient reversible rises in serum liver transaminase levels associated with malaise occurred in 50% of patients. Other toxicities observed included occasional skin rashes and, rarely, myelosuppression. None of these side effects showed a dose relationship and the severity of malaise and rashes was ameliorated by administering prednisolone for 1 week after treatment. Renal toxicity was not evident at doses up to 450mg/m2 and pharmacokinetic studies showed the 24 hour renal excretion of CB 3717 to be fairly constant at 25%. At higher doses, the renal excretion was considerably reduced. Out of 21 heavily pretreated patients with ovarian carcinoma, 1 complete, 1 partial and 3 minor responses were seen, while out of 11 breast carcinoma patients, 3 partial and 1 minor responses occurred. In addition 1 out of 2 patients with mesothelioma had a partial response. We believe that this is the first clinical evaluation of a cytotoxic agent whose antitumour locus is exclusively thymidylate synthetase (Jackman et al, Brit. J. Cancer 46:505, 1982; Jackman et al, In “Advances in Tumour Prevention, Detection and Characterisation”, Volume 7, 1982). The antitumour responses observed suggest that further evaluation of the therapeutic effects of this biochemical lesion is justified.