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In vitro tests of tumor cell drug sensitivity have been suggested as a means of selecting more appropriate clinical strategies against human cancer and improving preclinical drug development. The lack of biotransformation in these in vitro assays precludes the meaningful assessment of several major chemotherapeutic agents, including dacarbazine and cyclophosphamide. In vivo drug exposure of tumor cells in agar diffusion chambers placed in mice offers a possible solution to problems of drug biotransformation and pharmacokinetics. We have prospectively used this system as an assay for sensitivity of clonogenic human melanoma cells. Tumor cells were tested fresh, cryopreserved, and/or cultured in vitro before or after clinical use of dacarbazine, semustine, and mitolactol in 41 patient-drug combinations in which a clinical correlation could be made. Tumor cell drug sensitivity in the assay using fresh or cryopreserved tumor cells was highly correlated with clinical response and resistance with clinical nonresponse. Cultured melanoma cells exhibited enhanced plating efficiency in comparison to both fresh and cryopreserved cells of the same tumor. Cultured cells also showed increased drug sensitivity which did not correlate with drug sensitivity of the same fresh or cryopreserved tumor or with clinical response. Tumor cell drug sensitivity assays carried out in vivo provide a possible basis for preclinical evaluation of drugs which are unsuitable for in vitro testing.

Fifty-one patients (43 evaluable) with malignant melanoma were treated with mitolactol in an intermittent oral schedule. There were four objective tumor responses, all occurring in patients previously treated with dacarbazine.

Twenty-four patients were evaluated in a non-randomized study to assess the effectiveness of dibromodulcitol (DBD) in Stage IV melanoma. Patients received 100 mg/m2 of DBD orally for 35 days. The dose was escalated to 130 mg/m2 and then to 160 mg/m2 if no significant hematologic toxicity occurred. There were no objective responses, including six patients who had had no prior chemotherapy. Five patients (21%) remained stable. Median survival was 151 days. Survival favored females, nonvisceral involvement pretherapy, and patients with a disease-free interval (DFI) of greater than 1 year. None of these advantages was statistically significant. Toxicity was predominantly hematologic, but nausea, vomiting, shortness of breath, and diarrhea were also seen. Oral DBD, using this dose and schedule, does not appear efficacious in advanced disseminated melanoma.

Twenty-five patients with measurable metastatic melanoma refractory to DTIC and a nitrosourea were treated with dibromodulcitol (DBD). DBD was administered orally at bedtime at a dose of 100 mg/m2/day until hematologic toxicity (a greater than or equal to 50% decrease in the wbc or platelet count) was induced. Five patients experienced clinically useful objective remissions; responding lesions included both soft tissue metastases and visceral metastatic disease. It is concluded that DBD is useful in the treatment of patients with metastatic melanoma and thus joins DTIC and the nitrosoureas as single agents which are active against this malignancy.

In this Eastern Cooperative Oncology Group (ECOG) phase II study, dibromodulcitol (DBD) and a combination of actinomycin D, hydroxyurea, and cyclophosphamide (AHC) were compared with methyl-CCNU, the current ECOG standard, in patients who had received no prior chemotherapy for disseminated malignant melanoma. The response rates were 6% (3/50) for AHC, 9% (3/34) for DBD, and 14% (7/49) for methyl-CCNU. Median survival times were 4, 5, and 6 months, respectively. Neither regimen appears to offer any advantage over methyl-CCNU as front-line therapy for patients with disseminated melanoma.

The Central Pennsylvania Oncology Group conducted a phase II study of mitolactol in advanced metastatic melanoma to determine the overall survival rate and duration of response to this agent. The starting dose was 100 mg/m2/day orally. If no hematologic toxicity was noted on weekly blood cell counts, the dose was increased to 130 mg/m2/day on Day 35, and, if still tolerated, to 160 mg/m2/day on Day 70. Six of 25 evaluable patients (24%) had objective partial response. The median duration of response was 20 weeks, with a range of 10-66 weeks. Six of 25 patients (24%) had stable measurable disease, with a median duration of 9 weeks. The median survival from date of entry in this study was 21 weeks in responding or stable patients compared to 7 weeks in nonresponders. Hematologic toxicity was the dose-limiting factor. This study shows that mitolactol has moderate activity against advanced melanoma, and the drug deserves further study in combination with nonmyelotoxic drugs.