Phase II evaluation of menogaril in advanced prostate cancer: Eastern Cooperative Oncology Group EST P-A885.

Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

Phase II trial of menogaril in patients with previously treated multiple myeloma or chronic lymphocytic leukemia.

Menogaril is a semisynthetic anthracycline with relative lack of cardiotoxicity. Ten patients with multiple myeloma (MM), seven patients with chronic lymphocytic leukemia (CLL), and one patient with diffuse well-differentiated lymphocytic lymphoma (DWDL) were treated with menogaril, 160 mg/m2 (for MM) or 200 mg/m2 (for CLL/DWDL), given as a 2-hour intravenous infusion, repeated every 28 days. All patients except one with CLL had been previously treated with one chemotherapy regimen and had either not responded or had relapsed after a response to prior treatment. There were no objective responses to treatment. Among the six evaluable patients with MM, two had stable disease with subjective improvement in symptoms for five to 25 cycles, and among the eight patients with CLL/DWDL, five patients remained stable for two to eight cycles on treatment. The remainder of the patients had progressive disease after one to two cycles of chemotherapy. Five grade 4 hematologic toxicities were observed. There was one fatal neutropenic sepsis. Menogaril, as administered in this study, does not appear to have significant activity in patients with previously treated MM or CLL.

Phase II trial of menogaril in non-Hodgkin's lymphomas: a Southwest Oncology Group trial.

PURPOSE: To assess the efficacy and toxicity of menogaril against non-Hodgkin's lymphoma (NHL) in a group of previously treated patients. PATIENTS AND METHODS: Sixty-two eligible patients with a histologic diagnosis of NHL were enrolled, 35 of who had intermediate or high-grade histologies and 27 of who had low-grade lymphomas. Patients with intermediate or high-grade lymphomas had received only 1 prior chemotherapy regimen, while patients with low-grade histologies had received 1 or 2 prior chemotherapy regimens. Menogaril was administered at 160 mg/m2 intravenously over 1 hour, once every 28 days. RESULTS: Among the 35 patients with intermediate or high-grade lymphomas who were evaluable for response, 6 of 35 patients achieved a partial response (PR) for a response rate of 17% (95% confidence interval: 7%-34%). Median survival in this group of patients was 13 months. For those patients with low-grade lymphoma, 5 of 26 patients achieved a PR for a response rate of 19% (95% confidence interval: 6%-38%). No complete responses were observed in either patient group. The incidence of serious (grade 3 or 4) toxicity for those with intermediate/high-grade and low-grade lymphomas was 43% and 44%, respectively. Most of these toxic effects consisted of reversible myelosuppression. Menogaril was discontinued in 2 patients due to prolonged neutropenia. Cardiotoxicity was observed in 4 patients, requiring discontinuation of the drug in 1 patient. No treatment-related deaths occurred and the overall toxicity was felt to be acceptable. CONCLUSION: The observed antitumor activity of single agent menogaril against both intermediate/high-grade and low-grade lymphomas was modest. Further exploration of this agent in patients with non-Hodgkin's lymphomas does not seem warranted.

New agents in the treatment of small cell lung cancer.

The treatment of small cell lung cancer (SCLC) has evolved significantly over the past 3 decades. Single-agent and combination chemotherapies given with radiotherapy have greatly improved response rates and median survival. Combination regimens such as cisplatin/etoposide, carboplatin/etoposide, ifosfamide/carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine, and etoposide/ifosfamide/cisplatin have all achieved good response rates. Improving long-term survival, however, has remained problematic. Treatment with biological response modifiers (interferons alpha and gamma) has not shown promise in this setting. New agents showing good preliminary single-agent activity in untreated SCLC include paclitaxel, vinorelbine, gemcitabine, topotecan, and teniposide. Results obtained with single-agent docetaxel and CPT-11 are thus far inconclusive. Studies evaluating response and survival rates of these new agents in combination with agents of known activity are underway.

[TUT-7 early phase II clinical study for various solid tumors and hematologic malignancies].

An early Phase II study with TUT-7 (menogaril), a new anthracycline antitumor antibiotic, was conducted in patients with various malignant tumors at 81 departments of 65 institutions nationwide. One course of TUT-7 treatment consisted of seven (7) or fourteen (14) consecutive days of administration at 75 or 100 mg/body/day with two-week drug withdrawal; at least two courses of treatment were given in principle. Among the 165 patients registered, 145 patients were eligible and 128 patients were evaluable for antitumor efficacy. In 11 patients with malignant lymphoma, one (1) had CR and five (5) had PR (54.5%); in three (3) patients with prostate cancer, one (1) had PR (33.3%); and in 12 patients with uterine cervical cancer, two (2) had PR (16.7%). Adverse drug reactions frequently observed were digestive organ disorders (anorexia and nausea/vomiting) and malaise. The abnormality in laboratory tests observed frequently was myelosuppression (leukopenia and neutropenia).

Activity of menogaril against various malignant lymphoma cell lines and a human lymphoma xenograft in mice.

Menogaril is an antitumor agent different from other anthracyclines in that it is active after oral administration; therefore, extravasation is not a side effect. In this basic study, we examined the antitumor activity of menogaril against malignant lymphoma. We compared its activity towards experimental malignant lymphoma with that of Adriamycin, epirubicin, pirarubicin, vincristine, and etoposide, treating mice with each drug at the dose schedule usually used for patients. Menogaril rapidly penetrated lymphoma cells and remained there at least 3 hours after the drug was washed out. Menogaril cleaved more double-stranded DNA in lymphoma cells than Adriamycin, epirubicin, pirarubicin, or etoposide. Menogaril had stronger antitumor activity against experimental malignant lymphoma in mice than Adriamycin, epirubicin, vincristine, and etoposide. Menogaril significantly lengthened the life span of mice bearing one of three lymphoma cell lines resistant to cisplatin, vincristine, or cyclophosphamide. Menogaril had stronger antitumor activity against the human malignant lymphoma xenograft LM-3 than Adriamycin. The strength of the cytotoxic activity of Menogaril might arise from its ready penetration into cells and its cleavage of double-stranded DNA. Therefore, Menogaril might become a useful drug for the treatment of patients with malignant lymphoma by oral administration; 7 days of administration was effective in the in vivo experiments.

A phase II study of menogaril (7R-O-methylnogarol) in patients with relapsed/refractory acute myeloid leukemia: a study of the Eastern Cooperative Oncology Group.

Fifty-one patients (47 evaluable) with AML, 27 in first relapse and 20 either in second relapse or refractory were treated with menogaril, 100 mg/m2/day as a 90-min infusion daily for 5 days. The complete response (CR) rate was 17% (8/47), and there was one partial response. Seven of eight responders were in first relapse with a 26% response rate among first relapse patients (7/27). The median duration of survival was 3 months for all first relapse patients and 4.3 months for all other patients. Toxicity included grades 3-4 pancytopenia and fever (100% of patients) and grades 3-4 stomatitis and hepatic enzyme elevation (25% of patients). Grades 3-4 cardiac toxicity occurred in three patients (two grade 3 arrhythmias and one heart block). All had previously received anthracyclines. Remission duration was 1.6-48+ months; two patients underwent bone marrow transplantation and continue in CR at 36+ and 48+ months. The nontransplanted patients remained in CR 1.6, 2.0, 3, 7, 14 and 27 months. Activity and toxicity of menogaril in this study were comparable to that of other clinically useful anthracyclines in AML. Further investigation of this agent in AML is warranted.

Hepatocellular carcinoma. An ECOG randomized phase II study of beta-interferon and menogaril.

This study was undertaken to investigate the response rate, time to treatment failure and survival time of patients with hepatocellular cancer (HCC) treated with beta-interferon or menogaril. Sixty-nine patients with histologically confirmed, advanced, measurable hepatocellular carcinoma were randomized to receive beta-interferon or menogaril. Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3, as well as adequate kidney and liver function and hematologic reserve. The number of patients with lethal, life-threatening, and severe toxicities on beta-interferon were 1, 3, and 12 and on menogaril 2, 5, and 10, respectively. No objective responses were documented among the 61 patients who had HCC, histologically reviewed and confirmed. The time to treatment failure was 6.7 weeks on beta-interferon and 8.6 weeks on menogaril. The median survival time was 11.1 weeks on beta-interferon and 23.1 weeks on menogaril (South African patients 10.1 weeks). The difference is not significant. Poor prognostic factors were jaundice, age, and associated hepatitis. After controlling for other covariates, beta-interferon appears to increase the relative risk of dying by 2.7. This trial reconfirms the importance, previously reported by ECOG of jaundice and age in the prognosis of patients with HCC. It shows that further trials with neither beta-interferon nor menogaril are warranted.

Pharmacokinetics and acute cardiovascular effects of menogaril in patients with metastatic tumors.

The new anthracyclin, menogaril [7-(R)-0-methylnogarol], is reported to produce less cardiotoxicity than doxorubicin after multiple doses. This study was designed to assess acute hemodynamic changes during the first administration of menogaril and to relate these changes to plasma concentrations. Menogaril (200 mg/mg) was infused over 90 minutes to 4 patients with metastatic colon or prostate cancer. Cardiac output (CO) and stroke volume (SV) were measured noninvasively by Doppler ultrasound. Menogaril plasma concentrations were measured by HPLC and a 3-compartment mammillary model was used for pharmacokinetic analysis of the results. Steady-state volume of distribution, elimination clearance, and elimination half-life averaged 1,114 +/- 340 l/m2, 38 +/- 16 l/h/m2 and 40.3 +/- 30.3 hours, respectively. All patients were normotensive (baseline blood pressure = 135 +/- 10/73.5 +/- 8 mmHg) and ejection fractions were in normal range (EF = 68 +/- 7%). Transient increase in mean arterial pressure (MAP) from 93 +/- 3 to 107 +/- 4 mmHg (p < or = 0.001) were seen during and shortly after the end of menogaril infusion in all patients. Heart rate (78 +/- 5 min-1) remained constant. CO fell slightly and total peripheral resistance (TPR) increased by 36.8% in the last 2 patients. The increase in MAP was analyzed by a linear-effect model and averaged 0.028 +/- 0.017 mmHg per ng/ml of menogaril in the hypothetical biophase. The half-life for menogaril equilibration between plasma and this biophase was 41 +/- 22 minutes. We conclude that during acute administration of menogaril, blood pressure increases transiently secondary to an increase in TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential role of oral anthracyclines in older patients with cancer.

Two anthracycline analogues, idarubicin and menogaril, have acceptable bioavailability via the oral route of administration. Encouraging antitumour activity of oral idarubicin has been reported in breast cancer, non-lymphocytic leukaemia, non-Hodgkin's lymphoma and myeloma. The outlook for menogaril is less clear, given the modest antitumour activity reported so far. Although the oral formulations of idarubicin and menogaril remain investigational, they represent a step forward in the direction of developing new active anticancer drugs with oral bio-availability. Further prospective studies of the orally-active anthracyclines in elderly patients with cancer are justified. These studies should address specific issues such as optimal dosage regimens as a function of 'physiological age', and quality of life.

Phase II trial of menogaril in patients with squamous carcinoma of the cervix: a Gynecologic Oncology Group study.

A phase II trial of 200 mg/m2 menogaril was conducted by the Gynecologic Oncology Group (GOG) in women with advanced or recurrent squamous carcinoma of the cervix who had received no previous chemotherapy. Twenty-three patients were placed on the study; 22 are evaluable for toxicity and for response. One patient had incomplete data and was inevaluable. Nine patients (40.9%) had previously undergone surgery, and 21 (95.5%) had received radiotherapy before this trial. GOG grade 3 granulocytopenia occurred in 1 patient (4.5%) but none developed grade 3 or 4 thrombocytopenia. One patient (4.5%) had grade 3 gastrointestinal toxicity. Neither complete nor partial responses were observed in this trial, although 9 patients (40.9%) had stable disease lasting 2 months or more. Menogaril at this dose and schedule is inactive in advanced or recurrent squamous carcinoma of the cervix.

Phase II trial of menogaril in metastatic adenocarcinoma of the prostate. A Southwest Oncology Group study.

Menogaril, a semisynthetic anthracycline antibiotic, was administered to patients with metastatic adenocarcinoma of the prostate. Forty-five patients with measurable disease and 45 patients with evaluable disease received 150-200 mg/m2 over 1 hour every 28 days. There were three partial responses (PR) among 87 patients evaluable for response. Myelosuppression was dose limiting. There were two deaths related to leukepenia. Other toxicities included phlebitis, alopecia, nausea and vomiting. One patient developed acute nonlymphocytic leukemia. Menogaril at these doses and schedule is toxic and has no significant antitumor activity in metastatic adenocarcinoma of the prostate.

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia.

Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m2/day to 130 mg/m2/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2+ months. Both patients were treated at a dose of 100 mg/m2/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.

[New anthracyclines].

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Anticancer activities of orally administered menogaril against human stomach and breast cancers implanted in nude mice.

The therapeutic effects of orally administered menogaril, a semisynthetic analog of the anthracycline antibiotic nogalamycin, were studied on a panel of human stomach and breast cancer xenografts. The maximum tolerated dose (200 mg/kg) of menogaril was administered 3 times every 4 days and its growth-inhibitory effects on subcutaneously implanted tumors in nude mice were evaluated. Menogaril significantly retarded the growth of 3 out of 7 stomach cancers, SC-2, SC-9 and 4-1ST, and 3 out of 4 breast cancers, H-31, MC-2 and MX-1, with overall response rates of 43 and 75% for stomach and breast cancers, respectively. Some of these relatively responsive cancers were also treated by daily oral administration for 5 consecutive days, but the anticancer effects of the intermittent administration seemed to be better. These results suggest that menogaril may be effective against stomach and breast cancers when orally administered.

[New anthracycline analogues in the treatment of lung cancer].

Doxorubicin is one of the most potent drugs for the treatment of small cell lung cancer (SCLC), but less potent for non-small eell lung cancer (NSCLC). The prevalent use of doxorubicin is limited by the development of cardiomyopathy. Therefore, TUT-7 SM-5887, and ME2303 have been under the clinical studies to find new anthracyclines with less cardiotoxicity and higher therapeutic indices not only for SCLC but also for NSCLC. The dose-limiting factor of these drugs determined in phase I studies was leukocytopenia. Phase II studies which are currently under way have indicated that SM-5887 is possibly most potent for the treatment of NSCLC, and that these drugs have less cardiotoxicity compared to the mother compound, doxorubicin.

Phase II study of weekly intravenous menogaril in the treatment of recurrent astrocytomas in adults.

Twenty patients with astrocytomas recurrent after surgery +/- radiation were treated on a phase II protocol of the new anthracycline derivative menogaril 115 mg/m2 administered intravenously once per week. Sixteen patients were evaluable for treatment efficacy. No patient achieved a major therapeutic response. Three patients (19%) had stable disease for greater than 8 weeks, including one who showed minor evidence of tumor regression, but less than 50%. Thirteen patients failed. Treatment was well tolerated. One patient developed granulocytopenia, while none developed thrombocytopenia. Four patients required an interruption in their treatment for one to two weeks because of development of granulocytopenia (one patient) or other reasons. Other toxic effects included arm vein phlebitis and skin irritation, skin discoloration of the infused arm, mild to moderate nausea and vomiting, diarrhea, stomatitis, and a fatal central venous catheter infection. Despite the fact that menogaril appeared to have therapeutic activity against recurrent astrocytomas in our phase I studies, we could not document any activity in this phase II study.