Phase II evaluation of N-(phosphonacetyl)-L-aspartic acid (PALA) in patients with advanced colorectal carcinoma

Twenty-one patients with metastatic colorectal carcinoma were treated with weekly injections of PALA. Rash and diarrhea were the most common and limiting side effects. The incidence of serious toxicity could not be predicted on the basis of liver function tests but was increased in patients with a creatinine level of ≥1.5 mg/100 ml. The neurologic toxicity observed in 21% of the patients was seen in one patient with intracerebral structural lesions and in other patients in whom no such lesions could be found. Similar results were seen in other phase II trials with PALA at MSKCC. It is possible that the structural lesions present in some of the patients facilitated entry of PALA into the brain with subsequent encephalopathy and lowering of the seizure threshold. Although abnormal EEGs were found in all patients who developed neurotoxicity, no EEG abnormality was predictive of subsequent neurologic symptoms. Minor responses were seen in two of 19 adequately treated patients. It should be emphasized that the majority of patients in this study were heavily pretreated, although a minor response of 7+ months was seen in a patient who had undergone three prior chemotherapy trials. With a predicted response rate of ≤15% (P=0.05). We conclude that PALA by this dose and schedule is not an effective single agent in previously treated patients with colorectal carcinoma.