Phase II trial of topotecan in malignant melanoma.

Topotecan (S-9-dimethyl-10-hydroxycamptothecin hydrochloride SKF 104864-A) is a semisynthetic analog of the alkaloid camptothecin and, similar to the parent compound, a potent inhibitor of topoisomerase I. The cytotoxicity induced by topotecan appears due to interference with the normal breakage reunion reaction of topoisomerase I leading to DNA damage and cell death. Since preclinical studies of topotecan suggested antitumor activity against refractory solid tumors, a phase II trial of the drug was initiated in melanoma patients with recurrent and/or metastatic disease. Topotecan 1.5 mg/m2 was given as a daily 30-min infusion for 5 days and repeated every 21-28 days. Seventeen patients were entered into the treatment program with all evaluable for toxicity but I patient, inevaluable for response. There were no objective responses. Toxicity was predominantly severe myelosuppression, which occurred in 12 of 17 (70%) patients. Topotecan in this dose and schedule is inactive in malignant melanoma.

Clinical and immunological effects of a synthetic Beta-human chorionic-gonadotropin vaccine.

We treated 23 patients with non-trophoblastic cancers with escalating doses of a synthetic vaccine consisting of the carboxy-terminal peptide of beta human chorionic gonadotropin conjugated to diphtheria toroid (CTP37), a muramyl dipeptide as an adjuvant, and squalene/mannide monooleate as a vehicle. Toxicity consisted of pain and sterile abscess formation at the injection site and of constitutional symptoms. Diphtheria toxoid hypersensitivity developed in one patient. Immunizations elicited anti-beta hCG IgG antibody which persisted for more than 10 months. Disappearance of circulating hCG present pre-immunization and tumor regressions were observed. Active specific immunotherapy with CTP37 vaccine is well-tolerated and has biological activity in patients with cancer.

Immunosuppressive effects of pentostatin.

The immune function of patients with hairy cell leukemia (HCL) and solid tumors was evaluated before and after treatment with the investigational drug 2'-deoxycoformycin (pentostatin; dCF). Thirteen HCL patients received doses of dCF of 2 to 4 mg/m2 intravenously at 2- to 6-week intervals for up to 15 courses. After completion of treatment, 12 of 13 patients had resolution of severe monocytopenia and five of nine had normal monocyte antibody dependent cellular cytotoxicity. There was statistically significant depression of total lymphocytes, T cells, and B cells. Evaluation of T subsets showed a decrease in CD4+ cells. Immunoglobulin G (IgG) in sera were decreased from baseline, while IgM and IgA were unaffected. There was no significant effect on skin-test reactivity or large granular lymphocyte numbers. Lymphoblastic transformation was variably affected. Natural-killer (NK) cell function was improved or unchanged after dCF treatment. Reevaluation of seven patients at 21 to 119 weeks after receiving dCF demonstrated that recovery to normal T- and B-cell numbers and subsets does occur. Five solid tumor patients were given dCF at 4 mg/m2 intravenously at 1- to 2-week intervals for up to five courses. There was significant reduction in T cells, B cells, CD4+, and CD8+ cells with no statistically significant effect on the other immune parameters. We conclude that low doses of dCF can cause persistent immunosuppression though recovery may occur after the drug is stopped. In patients followed after completion of dCF, there was no associated increase in second malignancies or unusual infections.

Phase II trial of MVE-II in metastatic malignant melanoma.

MVE-II, a low molecular weight fraction of pyran copolymer was utilized in a Phase II trial in patients with metastatic malignant melanoma. A total of 15 patients were investigated and no clinical responses or immunologic responses were observed. We concluded that MVE-II is not an active agent in malignant melanoma.

A comparison of mitoxantrone and doxorubicin in breast cancer.

Ninety patients with breast cancer refractory to cyclophosphamide/fluorouracil/methotrexate (CMF) have been randomized in their treatment, receiving either doxorubicin or mitoxantrone. Seventy-nine have received two full courses of therapy. Twelve of the 40 (30%) who initially received doxorubicin responded, whereas eight of the 47 (17%) who received mitoxantrone responded. These rates are not statistically different. The degree of myelosuppression was equivalent. Patients who received mitoxantrone had less nausea, vomiting, alopecia, and fatigue. Controllable clinical congestive heart failure developed in seven patients, and four others had a deterioration of noninvasive measures of cardiac function without clinical failure. One patient with clinical heart failure developing received only doxorubicin and one, only mitoxantrone, whereas the others received both agents. The duration of remission and time lapsed before disease progression were almost identical for the two regimens. This study included a crossover design. Two of 22 (10%) patients receiving doxorubicin and five of 24 (21%) receiving mitoxantrone as secondary therapy responded. This suggests that there is not absolute cross-resistance between these agents. We conclude that the efficacy of these two drugs is comparable in patients refractory to CMF, though the nonhematologic side effects of mitoxantrone are less.

A comparative trial of mitoxantrone and doxorubicin in patients with minimally pretreated breast cancer.

A randomized trial began in 1980 comparing the efficacy and toxicity of mitoxantrone and doxorubicin. Patients with metastatic breast cancer unresponsive to cyclophosphamide-methotrexate-5-fluorouracil with or without tamoxifen were randomized to either mitoxantrone, 12 mg/m2, or doxorubicin, 60 mg/m2, every 3 weeks. Patients were crossed over to the alternative treatment if they progressed after two courses or fail to respond after four courses. Fifty-nine patients have been randomized at the present time, and most of these have a performance status near to normal. During initial therapy, partial responses were obtained in 10 of 25 patients receiving doxorubicin, and a further 12 showed stable disease; 3 showed progressive disease. Of the 26 patients who received mitoxantrone as initial therapy, 7 achieved a partial response, 14 had stable disease, and 5 progressive disease. Twenty-seven patients received doxorubicin or mitoxantrone as secondary therapy; two patients each responded to these drugs, suggesting a lack of cross-resistance. The median time to response was 48 days for doxorubicin and 57 days for mitoxantrone. The duration of partial responses measured from the onset of response was similar for both drugs, being 84 days for doxorubicin and 96 days for mitoxantrone. Hematologic toxicity, vomiting, alopecia, and fatigue tended to be less frequent and less severe with mitoxantrone than with doxorubicin. Mitoxantrone appears to be an effective and well-tolerated agent for breast cancer. Definitive comparisons will be available at the completion of this study.

A randomized trial of metoclopramide and a combination of dexamethasone and lorazepam for prevention of chemotherapy-induced vomiting.

In a randomized, crossover design the antiemetic activity of one of the most active single agents, metoclopramide was compared with a combination of dexamethasone and lorazepam. Both regimens were effective, but dexamethasone-lorazepam was significantly better than metoclopramide in preventing (26% versus 13%) or limiting (44% versus 23%) vomiting. Although side effects were more frequent with lorazepam-dexamethasone, the patients generally judged them desirable and overall patient preference was strong (70% versus 12%) for the lorazepam-dexamethasone combination. Patients required supervision and assistance due to lorazepam-induced drowsiness.