Phase I and clinical pharmacological evaluation of a parenteral hexamethylmelamine formulation.

Hexamethylmelamine has been evaluated in single agent and combination regimen studies for many years, but only following p.o. administration. Pharmacological studies in animals and humans have shown that systematic availability of parent drug following p.o. administration is relatively low and variable due to extensive first-pass metabolism rather than due to poor absorption. Two Phase I clinical trials, with accompanying pharmacokinetic studies, have been conducted by using a parenteral formulation in which hexamethylmelamine was prepared by Intralipid 10%. The parenteral formulation was well tolerated by all patients receiving hexamethylmelamine by 1-day and by daily for 5-days schedules. Nausea and vomiting were the dose-limiting toxicities. Maximally tolerated doses on the 1-day and daily for 5-days schedules were approximately 850 mg/m2 and 630 mg/m2/day, respectively. No responses were observed in either study. Following i.v. administration of 540 mg/m2 hexamethylmelamine, plasma elimination was best described by a three-compartment open model with terminal half-life, total body clearance, and steady-state volume of distribution values of 10.4 h, 0.75 liter/min/m2 and 460 liters/m2, respectively. Twenty-four h urinary recoveries of parent drug were less than 1% for all patients. Accumulation of hexamethylmelamine during the 5-day treatment at 945 mg/m2 suggested possible saturation of parent drug elimination at that dose. Phase II studies are currently under way with the parenteral formulation of hexamethylmelamine.

Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion.

A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Four-drug combination chemotherapy (methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: a Cancer and Leukemia Group B study.

Ninety-eight evaluable patients with nonresectable regional or metastatic non-small cell bronchogenic carcinoma were treated with a four-drug combination chemotherapy program of methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU (MCHC). Fifteen partial or complete responses (15%) were obtained, all but one of which occurred in good performance status (0-1) patients. While "responders lived longer than non-responders", this was due more to initial performance status among responding patients than to achievement of partial (greater than 50%) or complete disease regression. Evaluation of those patients with good performance status (PS 0-1), indicated no statistically significant differences in median survival time for complete response and partial response patients compared to patients with "improved" or "stable" disease status in this group. This combination of modestly active single agents produced disappointing results in our lung cancer population. A search for more active single agents in lung cancer is necessary.

Chemotherapy of drug-resistant ovarian cancer: a Southwest Oncology Group Study.

We present a final analysis, including pathology review, of a cooperative group study of drug-resistant ovarian cancer. Of 200 patients registered, 112 were eligible and evaluable, with a response rate of 26% and median survival of 7 months. Because these results are poorer than those reported in the preliminary and interim analyses of this study, we scrutinized the 88 excluded patients, most of whom failed to meet our strict pathologic criteria for a diagnosis of ovarian cancer of epithelial type, and who, as a heterogeneous group, fared better than patients who did meet the eligibility criteria. We believe this analysis provides insight into the spectrum of diseases that are frequently called ovarian cancer, but might be more properly labeled abdominal carcinomatosis.

A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Hyperventilation as a variant of tardive dyskinesia.

Respiratory dyskinesia, a variant of tardive dyskinesia, may mimic chronic psychogenic hyperventilation syndrome, hence pseudopsychogenic hyperventilation. Respiratory alkalosis and sympathetic discharge may occur in both conditions. Neurological symptoms, dyspnea, chest pain, muscle spasms may also occur. Ventilation increases with stress and disappears with sleep in both conditions. However, respiratory dyskinesia has been seen in association with other choreiform movement disorders. Speech is interrupted by breathing and breathing is interrupted by grunts and groans. Respiratory dyskinesia is under partial voluntary control and is not due to a "psychological problems."

Combination chemotherapy of advanced ovarian cancer with hexamethylmelamine, cis-Platinum, and doxorubicin after failure of prior therapy.

Forty-nine women received a combination of cis-platinum and hexamethylmelamine (36 also received doxorubicin) for advanced ovarian cancer progressing after therapy that included an alkylating agent or extended field radiation. Twenty-six (53%) had an objective remission that lasted a median of 6 months from start of treatment. Response rate was independent of age, extent of prior therapy, and performance status. A long interval from initial diagnosis to entry, response to therapy, and ambulatory performance predicted improved survival from entry. No patient is surviving free of disease. Myelosuppression and vomiting were moderately severe but tolerable. Azotemia and peripheral neuropathy were infrequent and milk. These drugs have major activity in this poor-risk group and should be studied as part of initial therapy when enhanced efficacy and reduced toxicity are to be expected.

A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer.

PURPOSE: The efficacy and pharmacokinetics of paclitaxel when combined with altretamine for ovarian cancer were studied. METHODS: A group of 30 patients, whose only chemotherapy was one or more cisplatin-based non-paclitaxel-containing regimens and whose ovarian cancer failed to respond or had relapsed within 6 months of their last platinum regimen, received paclitaxel as a 3-h intravenous infusion and altretamine given orally in four divided doses daily for 14 days repeated every 28 days. Doses were escalated from paclitaxel/altretamine 135/150 mg/m2 to 250/300 mg/m2 in cohorts of three patients. RESULTS: The dose-limiting toxicities at 250/300 mg/m2 were WHO grade 3 myalgias and arthralgias in two patients and grade 3 lethargy, stomach cramps, peripheral neuropathy and vomiting in single patients. Considering all dose levels in cycle 1, 16 patients had grade 3 or 4 neutropenia but there was only one episode of febrile neutropenia. Other grade 3 toxicities were vomiting in four patients, myalgias in three, peripheral neuropathy in two and lethargy in two. Grade 3 alopecia occurred in 23 patients. Three patients achieved a complete response and 12 achieved a partial response for an overall objective response rate of 50%. Responses occurred at all dose levels of 175/150 mg/m2 and higher. The median freedom from progression was 35 weeks, with a median survival of 55 weeks. Altretamine did not alter the pharmacokinetics of paclitaxel and there were no consistent differences in paclitaxel pharmacokinetic parameters or toxicities between course 1 and 2. No dose-response relationships were evident above paclitaxel/altretamine 175/150 mg/m2. CONCLUSION: Paclitaxel and altretamine can be safely combined and with a high response rate in relapsed ovarian cancer, justifying further studies with this combination.

The role of hexamethylmelamine in the combination chemotherapy of advanced ovarian cancer: a comparison of hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (H-CAP) versus cyclophosphamide, doxorubicin, and cisplatin (CAP).

To evaluate the contribution of hexamethylmelamine (HMM) to the treatment of advanced ovarian cancer with combination chemotherapy, we compared the results of treatment with HMM, cyclophosphamide, doxorubicin, and cisplatin (H-CAP regimen) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP regimen). The treatment regimens were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP at Vanderbilt University Hospital between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following six months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) had objective responses to H-CAP compared with 14 of 21 patients (67%) treated with CAP (p = 0.001). The pathologic complete response rate was also higher in the patients who received H-CAP (35% versus 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. When patients with limited residual disease (maximum tumor diameter less than or equal to 3 cm) were compared, the median survival also favored the H-CAP treatment (101 months versus 21 months, p = 0.002). The median time to progression was also greater in patients receiving H-CAP versus those receiving CAP (67 months versus 16 months, p = 0.045). Treatment-related toxicity did not differ substantially between the two regimens. Our findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival in patients with ovarian cancer and limited residual disease following cytoreductive surgery.

Hexamethylmelamine in advanced head and neck cancer. A phase II study.

The results of hexamethylmelamine therapy in 20 patients with advanced squamous cell head and neck cancer are reported. No patient had previously received chemotherapy. The dose of hexamethylmelamine was 8 mg/kg/day p.o. There was partial response in 3/20 (15%) patients. The duration of the response was 6-10 weeks. Twelve of 20 (12/20) patients had stable disease for a median of 8 weeks (range: 4-18 weeks). Hexamethylmelamine was well tolerated with the only significant toxicity being mild nausea and vomiting. This drug deserves further evaluation in the treatment of head and neck cancer.

Mitomycin-C, etoposide, cisplatin, and hexamethylmelamine (MEPH) as a second-line regimen in lung cancer.

Fifty-three patients with advanced lung cancer refractory to chemotherapy with MACC (methotrexate, adriamycin, cyclophosphamide, and CCNU) were treated with a combination of mitomycin-C, etoposide, cisplatin, and hexamethylmelamine (MEPH). Among 45 evaluable patients, there were seven partial responders (16%), including 2/18 adenocarcinomas, 3/13 small cell anaplastic carcinomas, 1/5 large cell anaplastic carcinomas, and 1/9 squamous cell carcinomas. Major toxic side effects included thrombocytopenia (30/45 patients), leukopenia (22/45 patients), and emesis. Renal toxicity occurred in three patients, and cardiac arrhythmia was observed in one patient. Despite a low response rate, which was expected in this group of heavily pretreated patients with poor prognostic characteristics, these data suggest a lack of cross-resistance between MEPH and MACC.

Acute myelocytic leukemia in a patient treated with hexamethylmelamine.

This case report describes a 76-year-old white woman who was found to have ovarian cancer and underwent chemotherapy with hexamethylmelamine. After 34 months of therapy, she developed an acute myelocytic leukemia. Although commonly reported as a side effect of alkylating agents, this is believed to be the first reported case of an acute nonlymphocytic leukemia associated with hexamethylmelamine use.

[Treatment of cancers of the ovary. Phase II trial of increase of the dose of cisplatin]. / Traitement des cancers de l'ovaire. Essai phase II d'une augmentation de la dose de cisplatine.

Between March 1985 and December 1987, 34 women who had advanced adenocarcinoma of the ovary with macroscopic residual disease entered in a phase II trial of chemotherapy. Treatment consisted of a 3-month induction with monthly ifosfamide combined with 5-fluorouracil and high-dose cisplatin, and a maintenance treatment with ifosfamide, 5-fluorouracil, cisplatin and hexamethylmelamine in monthly cycles. At the end of the treatment patients with complete remission were evaluated by surgery. Neurotoxicity was a limiting factor, and treatment had to be prematurely withdrawn in 10 patients. The above treatment was found to be effective with a 94 percent objective response rate, a 54-month median survival and a 51-month median relapse-free survival. Because of the neurotoxicity, a shorter therapy and the use of neuroprotective agents may be envisaged.

[Effectiveness of ftorafur and hexamethylmelamine in advanced breast cancer]. / Effektivnost' ftorafura i geksametilmelamina pri zapushchennom rake molochnoi zhelezy.

In 7 oncological institutions of the Soviet Union a correlation was made between the efficacy of fluorofur, hexamethylmelanin and their combination for advanced cancer of the mammary gland in 136 patients. The therapeutic effect was estimated in 104 patients. Fluorofur yielded a considerable tumor regression (more than 50%) in 14 of 36 patients (40%), the duration of the remission in effectively treated patients was 2--5 months. Hexamethylmelanin induced a therapeutic effect in 18 of 37 patients (48%), the regression being complete in 6 patients (16%), its duration was 2--7 months. The combination of these drugs proved to be of an insignificant effect, the therapeutic effect was obtained in 5 of 31 patients (16%), the remission lasted for 1.5--5 months. The fluorofur therapy is rarely accompanied with adverse side effects (leucopenia--in 17%), while with hexamethylmelanin the incidence of leucopenia was 46%, a combination of the drugs reducing it up to 17%. Hexamethylmelanin combined with fluorofur was tolerated much more poorly (vomiting). Fluorofur and hexamethylmelanin are effective drugs for treatment of patients with advanced breast cancer.

[Combination chemotherapy with hexamethylamine (Hexalen, Altretamine, Hexastat) and sarcolysine in advanced ovarian carcinoma]. / Kombinirovannaia khimioterapiia geksametilmelaminom (Geksalenom, Altretaminom, Geksastatom) i sarkolizinom pri rasprostranennom rake iaichnikov.

Combination chemotherapy with hexamethylmelamine (hexalen, altretamine, hexastat), 100 mg, thrice a day, per os, 14 days (out of a 28-day course) and sarcolysin, 15 mg, per os, during the first 5 days of the course, was received by 24 patients with primary advanced tumors of the ovaries, prior to or after cytoreductive surgery. Total apparent response to chemotherapy among 19 patients of the study group was 47.2%, clinically significant (plus stabilization)--94.5%, without significant untoward side-effects (vomiting--19%; leukopenia degree II-III--33% and thrombocytopenia--19%). The drug proved an active component of combination therapy for advanced ovarian carcinoma.