Phase I clinical study of N-(Phosphonacetyl)-L-aspartic acid (PALA)

N-(Phosphonacetyl)-L-aspartic acid (PALA), a potent inhibitor of aspartate carbamoyltransferase (ACTase), was administered to 75 adult cancer patients to evaluate its toxicity, efficacy, and possible mechanism of action. PALA was administered at 2-week intervals as either a single or a multiple iv dose schedule. Fifty-eight patients received the single schedule at doses ranging between 0.8 and 15 g/m ². Seventeen patients received the multiple-dose schedule given as 1 g/m ²/day for 5, 8, and 10 days respectively. Dose-limiting toxic effects for both treatment schedules were skin rash and mucositis at total doses of >5 g/m ². These effects appeared slightly more common with the multiple-dose schedule. Myelosuppression was negligible. The in vivo effects of PALA on tumors were studied in 18 patients with biopsiable disease. Tumor ACTase activities were lower than those of the Lewis lung carcinoma, the most sensitive animal tumor to PALA. Therapy with PALA was followed by >80% inhibition of tumor ACTase activities and by approximately 40% inhibition of pyrimidine nucleotides. The effects of PALA on these parameters appeared to be directly related to the concentration of PALA within the tumor and inversely related to the time elapsing between the treatment and the tumor sampling. There was a partial remission in one patient with malignant melanoma and three less than partial remissions in one patient each with carcinoma of the colon and ovary and neurofibrosarcoma. Four additional patients had mixed responses and included one patient with malignant melanoma, two with colorectal cancer, and one with head and neck tumor. Antitumor activity did not seem to be schedule-dependent. We recommend that phase II studies of PALA be conducted at iv doses of 6 g/m ² (single-dose schedule) or 1 g/m ²/day x 5 (multiple-dose schedule), repeated every 2 weeks.