L-phenylalanine mustard-dianhydrogalactitol and hyponatremia.

The incidence of hyponatremia in 34 patients following administration of high-dose L-phenylalanine mustard (L-PAM) and dianhydrogalactitol (DAG) was determined. Two consecutive daily levels of 133 mEq/l or less were observed in 12 patients. These episodes coincided with the advent of diarrhea about 10-12 days after drug administration. The hyponatremia was not due to the syndrome of inappropriate antidiuretic hormone secretion.

Phase II evaluation of dianhydrogalactitol in the treatment of advanced non-squamous cervical carcinoma. A Gynecologic Oncology Group study.

In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix. The initial dosage was 60 mg/m2/wk with escalation to 75 mg/m2/wk if there were no adverse effects. Twenty-seven patients were evaluable for toxicity and response. There was one complete response and one partial response. Adverse effects were not infrequent but tolerable.

Phase II trial of galactitol 1,2:5,6-dianhydro (NSC 132313) in the treatment of advanced gynecologic malignancies: a Gynecologic Oncology Group study.

Dianhydrogalactitol was administered intravenously to patients with advanced or recurrent gynecologic malignancies on a weekly schedule. The initial dosage was 60 mg/m2 with escalation to 75 mg/m2 if there were no adverse effects. Forty-two patients with ovarian epithelial adenocarcinoma (OEA) and forty-one patients with squamous carcinoma of the cervix (SCC) were entered into this study. Of these, 39 patients with OEA and 36 with SCC were evaluable for toxicity and response. Seven patients (19.4%) with SCC had an objective response, while six patients (15.4%) with OEA had an objective response. Adverse effects were frequent but tolerable. There were no drug-related deaths, and only two patients suffered life-threatening hematologic toxicity. Myelosuppression was observed more frequently among the patients with OEA. A higher percentage of OEA patients had received prior chemotherapy. The level of activity and frequency of adverse effects observed at this dose schedule warrant further studies of this drug in these two tumors.

Phase II evaluation of galactitol in head and neck cancer: a Southwest Oncology Group Study.

A phase II evaluation of DAG in head and neck cancer patients produced one partial response and one patient with prolonged stable disease from nine fully evaluable patients with squamous carcinomas. One partial response was produced in a patient with anaplastic thyroid carcinoma. No drug deaths or life-threatening toxicity were reported. Further evaluation of DAG in thyroid tumors is warranted.

Dianhydrogalactitol and cisplatin in combination for advanced cancer of the uterine cervix.

Eighteen evaluable patients with squamous cancer of the uterine cervix recurrent after radiation therapy or with distant metastases were treated with dianhydrogalactitol (150 mg/m2) and cisplatin (DDP) (50 mg/m2), both given iv every 3 weeks. Only 39% of the patients responded, a result no better than that previously reported for DDP alone and only one-half as good as that previously reported by our group for a combination of this drug with mitomycin, vincristine, and bleomycin. Responses lasted a median of only 5 months. Hematologic toxicity was life-threatening in 22% of the patients and was severe in all but 11% of the remaining patients. We conclude that the addition of substantial and toxic doses of dianhydrogalactitol to DDP failed to substantially enhance the rate, quality, or duration of response compared to DDP alone.

Clinical and pharmacologic evaluation of split-dose intermittent therapy with dianhydrogalactitol.

Dianhydrogalactitol was administered as two 1-hr infusions separated by a 4-hr period once every 5 weeks to 21 patients with advanced solid tumors. Total doses ranged from 100 mg/m2 (50 mg/m2 twice on a single day) to 160 mg/m2 (80 mg/m2 twice on a single day). Peak concentrations of drug at the end of a 1-hr infusion ranged from 1.9 to 5.6 microgram/ml. Plasma elimination of dianhydrogalactitol was approximated best by a two-compartment open model. The alpha-half-life was 3.9 +/- 1.9 mins and the beta-half-life was 31.3 +/- 2.7 mins. Dose-limiting hematologic toxicity was encountered at a total dose of 160 mg/m2, with leukopenia occurring more frequently than thrombocytopenia. Other toxic effects included mild to moderate nausea in most patients and two instances of moderate alopecia. One patient with large cell cancer of the lung had a partial regression lasting 2 months and one patient with a carcinoid in the thymus had a partial regression lasting 7 1/2 months. A third patient with a mixed adenocarcinoma-squamous cell carcinoma of the lung had improvement (30% decrease) in his pulmonary tumor for greater than 2 months.

Clinical trials with the hexitol derivatives in the U.S.

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.

Phase II evaluation of dianhydrogalactitol in lung cancer: a Southwest Oncology Group Study.

A phase II study of dianhydrogalactitol in patients with advanced lung cancer yielded responses in three of 33 patients with adenocarcinoma and in one of 11 patients with large cell anaplastic carcinoma. Small cell and squamous cell carcinomas were unresponsive. Toxic effects were acceptable and were related to serum creatinine values.

Preliminary study of the combination, dianhydrogalactitol, cis-diaminedichloroplatinum (II), and VP-16-213 in patients with advanced cancer.

In a phase I study, a monthly regimen of dianhydrogalactitol 60 mg/m2 X 1 day, VP-16-213 60 mg/m2 X 3 days, and cis-platinum 20 mg/m2 X 3 days produced clinically acceptable toxicity. The program is suitable for outpatient administration and may have a role in the management of selected patients with advanced cancer.

Phase II evaluation of dianhydrogalactitol in advanced head and neck carcinomas.

Twenty-eight patients with advanced squamous cell carcinomas and adenocarcinomas of the head and neck were treated with dianhydrogalactitol at a dose of 25 mg/m2 iv on each of 5 consecutive days monthly. All patients except one had received previous surgical and/or radiotherapeutic treatments and 12 had received previous chemotherapy. Disease progression (or symptomatic deterioration) occurred in nine patients after the initial course and in eight others after two courses. In 11 patients, the disease remained stable during at least three courses; however, no instances of objective regression of disease were observed during treatment with dianhydrogalactitol despite significant toxic effects in most patients.

Dianhydrogalactitol and radiation therapy. Treatment of supratentorial glioma.

Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.

Phase II study of single-agent therapy with megestrol acetate, VP-16-213, cyclophosphamide, and dianhydrogalactitol in advanced renal cell cancer.

One hundred and forty-four patients with advanced renal cell cancer were evaluated for objective response to single-agent treatment with megestrol acetate, VP-16-213, cyclophosphamide, or dianhydrogalactitol. In view of the low order of response observed, these agents do not appear to be effective in the treatment of metastatic renal cell cancer. Performance status and a relatively long interval from onset of primary symptoms to study entry were the most favorable prognostic variables affecting time to progression and survival for patients in this study.