Phase II evaluation of menogaril (NSC-269148) in non-small cell lung carcinoma

Summary Forty-five patients with non-small cell lung cancer were treated in a phase II trial with menogaril 200 mg/m² IV every twenty-eight days by a one-hour infusion. One partial response was noted while twenty-two patients had stable disease (51 %). Progressive disease was noted in the remaining twenty-two patients. There was one fatal complication due to pancytopenia and pneumonia. Otherwise, the drug was reasonably well tolerated. At this dosage and schedule, menogaril has no substantial anti-tumor activity for patients with non-small cell lung cancer. Address for offprints: Southwest Oncology Group (SWOG-8567), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229, USA     

Phase II trial of menogaril in advanced colorectal cancer

Summary Menogaril, a new semisynthetic anthracycline antibiotic, was administered to 35 patients with advanced colorectal cancer. The drug was infused over 2 hr at a dose of 160 mg/sqm or 200 mg/sqm repeated every 4 weeks. Twenty-seven patients were evaluable for response and no objective responses were achieved. Myelosuppression, only leukopenia, was usually of mild-moderate degree and occurred in 63% of the patients. Twenty-seven percent of the patients experienced severe leukopenia. Local erythema and phlebitis were frequently observed and were severe in 13% of the patients. Nausea/vomiting (66%) and alopecia (50%) were of mild-moderate degree.This study suggests that menogaril at these doses and schedule had no activity in advanced colorectal cancer.for the EORTC Early Clinical Trials Group (EORTC/ECTG)     

A phase II study of menogaril in low-grade non-Hodgkin's lymphoma

Summary The NCI Canada Clinical Trials Group conducted a phase II study of menogaril given intravenously every 4 weeks in low-grade non-Hodgkin's lymphoma. Fifteen of 26 eligible patients had had no prior therapy. Partial responses were seen in 9 patients (35%). Toxicity was moderate including myelosuppression, nausea, phlebitis, alopecia, and lethargy. This drug has only modest activity in this potentially responsive group of patients.     

Phase II evaluation of menogaril in patients with advanced cervical carcinoma

Fourteen patients with advanced/recurrent squamous cell carcinoma of the uterine cervix received menogaril, 200 mg/m² by one hour intravenous infusion at four-week intervals. No objective regressions were observed. Median time to progression was less than two months and median survival was seven months. All patients experienced neutropenia. Platelet toxicity was negligible. Venous irritation and phlebitis occurred at the infusion site in 43% of patients. Menogaril as administered in this protocol is ineffective in treating previously irradiated advanced/recurrent squamous cell carcinoma of the uterine cervix and warrants no further investigation in this disease at the dosage and administration schedule used in this protocol. Address for offprints: H.J. Long, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA     

Phase II evaluation of menogaril in patients with advanced hypernephroma

Summary Fifteen patients with advanced renal cell carcinoma were treated with Menogaril, 200 mg/m² by one-hour, intravenous infusion at four-week intervals. No objective regressions were observed. Median time to progression was two months, and median survival was seven months. All patients experienced neutropenia. Platelet toxicity was negligible. Venous irritation and phlebitis at the infusion site was seen in 47% of patients. Menogaril as administered in this protocol is ineffective in advanced renal cell carcinoma.     

A phase II study of chemotherapy of metastatic colorectal carcinoma with 5-fluorouracil plus cisplatin

The combination of 5-fluorouracil and cisplatin has shown encouraging results in single institution pilot studies in colorectal carcinoma. This phase II SWOG study was undertaken to further evaluate this treatment. Cisplatin was administered at a dose of 60 mg/M² IV day 1, repeated every 21 days. 5-FU was given at a dose of 15 mg/Kg IV days 1, 8, and 15, with cycles repeated every 21 days. Among 47 eligible patients there were no complete responses and only three partial responses for an overall response rate of 6% with a 95% confidence interval of 1% to 18%. Seventeen patients (36%) had stable disease/no response and 22 (47%) progressed. Five patients (10%) had no evaluation and were assumed to have had no response, or were early deaths. Median survival was 9.1 months. Significant hematologic toxicity was seen with grade 3 leukopenia occurring in 11 patients. There were felt to be two deaths definitely related to treatment and two additional deaths possibly treatment related. The combination of 5-FU and cisplatin used in this dose and schedule is an ineffective and toxic regimen for treatment of colorectal carcinoma. Address for offprints: Southwest Oncology Group (SWOG-8424), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229-6197, USA     

Phase II study of spirogermanium in patients with advanced colorectal carcinoma

Twenty one evaluable patients with advanced colorectal carcinoma were treated with continuous infusion of spirogermanium at a median daily dose of 150 mg/m² (range 120–210) for five consecutive days every 14 days. Treatments were accomplished by using outpatient infusion devices. Fifteen patients had not received any prior radiation therapy, immunotherapy, or chemotherapy. Nineteen patients were previously untreated with chemotherapy. Five patients had received prior immunotherapy with copovithane and only two patients had received radiation therapy prior to spirogermanium therapy. None of the patients achieved a complete or partial remission. Minor tumor regressions were observed in two patients, both were < 12 weeks in duration. The major toxicities included nausea and vomiting and neurologic side effects; however, the toxicity was completely reversible. Spirogermanium is not effective in the treatment of patients with advanced colorectal carcinoma.     

A phase I clinical and pharmacokinetic study of the oral and the oral/ intravenous administration of menogaril

Summary Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m² to 625 mg/m². An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m² IV; 250–500 mg/m² oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m² dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m² and 625 mg/m², leukopenia < 3000/l occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with nonsmall cell lung cancer experienced a 30% reduction in metastatic tumor nodules.For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (±SD) terminal disposition half-life after oral dosing was 29.3 ±9.2 hours; mean systemic bioavailability was 33.6±10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00±0.96% and 0.44±0.16%, respectively.Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.     

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer

Objective: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). Methods: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate-organ function, and be 18 years old. Patients were treated with NSC-655649 at a dose of 165mg/m² daily i.v. over 30–60min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. Results: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42–76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. Conclusion: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.     

Phase II trial of menogaril in metastatic adenocarcinoma of the prostate

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 signficant antitumor activity in metastatic adenocarcinoma of the prostate.     

Phase II study of prolonged infusion of Taxol in patients with metastatic colorectal carcinoma

Purpose: Taxol represents a new class of anticancer agents with activity against a wide variety of solid tumors. In preclinical systems, its cytotoxicity is schedule dependent with prolonged exposure being more effective. We studied a 120-hour infusion schedule of Taxol in patients with metastatic measurable colorectal carcinoma who had had one prior 5-FU-based chemotherapy. Methods: Patients with measurable metastatic colorectal carcinoma were eligible. Patients had to have normal liver, renal, and bone marrow functions. Written informed consent was obtained from all patients. The starting dose of Taxol was 150 mg/m2 infused over 120-hours in the outpatient setting. Taxol was repeated every 21 days. Results: Fifteen patients were registered. Among 14 evaluable patients, we did not observe any complete or partial response. Major toxicity included myelosuppression and mucositis. There was no treatment-related death. Conclusion: Taxol administered by this schedule was found ineffective in patients with metastatic colorectal carcinoma who had previously received one 5-FU-based chemotherapy.     

Menogaril in the treatment of malignant mesothelioma: A phase II study

Summary Menogaril is a new semisynthetic anthracycline agent derived from the antitumor antibiotic Nogalomycin. Compared to doxorubicin it has similar or improved activity in anti-tumor cell line screening; human tumor cloning assays suggest modest anti-tumor activity as well. Menogaril is much less cardiotoxic than doxorubicin. We performed a phase II trial of this agent in 22 patients with advanced malignant mesothelioma. At a dose of 200 mg/m² iv every 4 weeks (160 mg/m² in previously radiated patients) only 1 of 22 (5%) evaluable patients had a partial remission lasting 4 months. (95% confidence limits 0.1–23%). The major toxic effects included pain at the site of infusion and granulocytopenia. While well tolerated, Menogaril has minimal activity in malignant mesothelioma. We do not plan further studies with Menogaril in this disease.     

Phase II study of etoposide and alpha-interferon in patients with advanced measurable colorectal carcinoma

Summary Based on encouragingin vitro andin vivo data, 14 consecutive patients with measurable metastatic previously untreated colorectal carcinoma were treated with a combination of intravenous etoposide and subcutaneous alpha-interferon. Etoposide was given at 60 mg/m² intravenously on days 1–5 and alpha-interferon at 5 million units/m² subcutaneously on days 1–5; courses were repeated every 21 days. All 14 patients were evaluable for response and toxicity. None of the patients achieved a complete or partial remission. Toxicity of this combination was moderate. Our data suggest that this combination is ineffective against colorectal carcinoma.     

Phase II study of fludarabine phosphate in patients with advanced colorectal carcinoma

Summary For phase II studies in patients with solid tumors, the National Cancer Institute recommended that the starting dose of fludarabine phosphate be 20 mg/m²/day as a short intravenous infusion for 5 days every 21 days. Twenty-one patients with untreated, advanced, measurable colorectal carcinoma received fludarabine phosphate as a 30-minute infusion at a median dose of 25 mg/mVday (range 15–35 mg/m²day) for 5 consecutive days repeated every three weeks. Antitumor response was evaluated following two courses of therapy. No patient achieved complete or partial response. Minor regression of lung metastases occurred for less than 12 weeks in one patient. Therapy was generally well tolerated. Frequent toxicities included lymphopenia, mild nausea and vomiting, mucositis, and anorexia. One patient died of sepsis, bleeding, and progressive disease while she was severely myelosuppressed. Neurotoxicity was not observed in any patient. Fludarabine phosphate at this schedule and dose range is inactive against colorectal carcinoma.     

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

Summary 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.     

PCNU: Phase II evaluation in advanced colorectal carcinoma

Summary PCNU, a N-(2-chloroethyl)-N-nitrosourea, was administered to 37 previously treated patients with metastatic adenocarcinoma of the colon and rectum. The drug dose was 100 mg/m², intravenously, over one hour for good risk patients and 75 mg/m² for poor risk patients. Poor risk patients were defined as patients over 65 years of age or having liver enzymes greater than twice normal. The infusion was repeated at 6 week intervals. Seventeen patients (median performance status 80%) received PCNU at the 100 mg/m² dose; 20 patients (median performance status 70%) received PCNU at the 75 mg/m² dose. Complete responses were not observed. One patient treated with 100 mg/m² achieved a partial response. Toxicity was primarily hematological with life-threatening leukopenia and thrombocytopenia observed in six patients. PCNU administered in the described dose schedule demonstrated little therapeutic efficacy in this patient population.     

Phase II trial of intravenous melphalan in advanced colorectal carcinoma

SummaryBackground Relatively few studies have examined the activity of alkylating agents in the treatment of advanced colorectal adenocarcinoma. Recent reports have suggested possible therapeutic activity for high-dose intravenous melphalan administered with autologous bone marrow transplantation (BMT) support. We conducted a phase II study to determine the efficacy of administering intravenous melphalan at doses that do not require BMT support in patients with advanced colorectal adenocarcinoma.Patients and methods Fifteen patients with histologically proven, bidimensionally measurable disease were treated. The starting dose of melphalan was 30 mg/m², with dose escalation permitted.Results No objective responses were observed. Toxic effects were primarily reversible granulocytopenia and thrombocytopenia. There were no treatmentassociated deaths.Conclusion Melphalan's lack of efficacy at the doses administered does not disprove the steep chemotherapy dose-response relationship postulated for many solid tumors. However, we feel that it is unlikely that repetitive courses of high dose melphalan with autologous BMT support will be a practical approach to the management of advanced colorectal adenocarcinoma.