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Twenty-four patients with epidermoid carcinoma of the esophagus have been treated, in a phase II trial, with methyl-GAG using a weekly schedule. Eighteen patients had received prior chemotherapy with cisplatin-containing combinations. Of 23 evaluable patients, four (17%) had partial remissions, each lasting 2 months. All patients had received prior chemotherapy. Toxic effects were manageable and included mild nausea and vomiting, mucositis, and fatigue. Using this schedule, methyl-GAG had modest activity in esophageal cancer, with acceptable toxicity. Its role in combination chemotherapy remains to be defined.

Methyl-GAG, a polyamine synthesis inhibitor, was prospectively evaluated in the treatment of advanced renal adenocarcinoma. Twenty-five patients with measurable disease received methyl-GAG weekly at a starting dose of 500 mg/m2 iv, with dose escalation by 50 mg/m2/week (maximum dose, 825). All 25 patients are evaluable for response. Four of these patients (16%) achieved responses including three partial responses and one complete response, with a median duration of 9 weeks (range, 4--15). Nine patients (36%) remained stable and 12 (48%) had progressive disease. In the four responders, regression of disease occurred within the first 4 weeks of therapy. Toxic effects were generally mild and included nausea or vomiting (68%), myalgia (44%), mucositis (40%), neuralgia (40%), weight loss (32%), diarrhea (24%), skin rash (8%), leukopenia (8%), and genital ulcers (4%). We conclude that methyl-GAG has clear, albeit limited, activity against renal adenocarcinoma.

Methyl-GAG was given to 71 patients with advanced malignancies as a weekly brief infusion (30-120 minutes) or as a biweekly 24- or 120-hour infusion. Mucositis (stomatitis, pharyngitis, esophagitis, and, rarely, inflammation of other mucous membranes) was dose-limiting in all three schedules. Generalized fatigue, malaise, myalgia, dysesthesias, nausea, and vomiting were more frequent in the brief-infusion schedule. Myelosuppression was mild and not dose-related. Fever, ventricular arrhythmias, skin rash, tender swelling of the palms, neuropathy, and paralytic ileus were rare. Toxicity was increased in patients with renal insufficiency or "third-space" fluid but was not increased by hepatic dysfunction. Cumulative and overlapping toxicity was evident only in the weekly schedule. Higher doses of methyl-GAG were tolerated when the duration of infusion was increased. The recommended doses for phase II trials are 700 mg/m2 weekly as a 1-2 hour infusion, 850 mg/m2/24 hours biweekly, and 1500 mg/m2/120 hours biweekly. Therapeutic effects were seen in all schedules and included objective responses in colon carcinoma (one of 13 patients), renal cell carcinoma (one of nine), and Hodgkin's lymphoma (one of two) and objective improvements in esophageal carcinoma (one of three), endometrial carcinoma (two of two), and leiomyosarcoma (one of three).

Twenty-nine patients with metastatic breast cancer were treated with methyl-GAG at an initial starting dose of 500 mg/m2 iv weekly and then escalated by 50 mg/m2/week to tolerance. There were two partial responders among the 26 evaluable patients. Gastrointestinal and cutaneous reactions were the limiting toxic effects of methyl-GAG. Myelosuppression was mild and infrequent.

Sixteen patients with primary malignant brain tumors, recurrent or progressive after surgery and radiation therapy, were treated with mitoguazone. Starting dose was 500 mg/m2 iv on a weekly schedule. In 15 evaluable patients no tumor regressions were observed. Four patients had stabilization of disease.

Eighteen patients with measurable or evaluable lesions from squamous cancer of the esophagus received a regimen combining four active agents on an outpatient basis. Nine of 14 evaluable patients (64%, or 50% of 18 patients entered) responded: four of five with previously untreated regional disease and five of nine with recurrent or metastatic disease. Median duration of response in the latter group was 5 months (longest response, 13). Treatment was well-tolerated in all patients but one, who developed signs of severe methotrexate toxicity and died of sepsis.

Eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and mitoguazone (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were evaluated in a phase I-II study for patients with primary recurrent malignant brain tumors. All patients had failed prior radiation therapy and most had also failed prior chemotherapy. Two dose schedules were used, with the second schedule (Group II) a modification of the first schedule (Group I). The Group II schedule, with different dose levels, was better tolerated than the Group I schedule. Gastrointestinal and myelotoxicity were dose-limiting in most patients, and tinnitus was dose-limiting in two patients. Nineteen of 33 evaluable patients had anaplastic gliomas, in whom response was observed in 21%, stable disease in 53%, and immediate progression after one course of therapy in 26%. Of six patients with glioblastoma multiforme, two had brief stabilization of disease. An additional patient with brainstem glioma and ependymoma also had disease stabilization. Four patients with medulloblastoma, a spinal cord mixed glioma, and one with oligodendroglioma failed DFMO-MGBG. Based on this study, we believe that a combination of DFMO and MGBG is well-tolerated and deserves further evaluation for patients with anaplastic gliomas, particularly those that appear to be biologically slow growing.

We used mitoguazone (500 mg/m2 iv weekly, with 50-mg/m2 escalations weekly as tolerated) to treat 22 patients with squamous cell carcinoma of the head and neck which recurred after initial therapy. Nine of 22 (11%) patients responded: two had complete responses and seven had partial responses. Gastrointestinal toxicity and anemia were commonly seen. We conclude that mitoguazone is active in squamous cell carcinoma of the head and neck and should be incorporated into phase III trials.