Phase II study of carbetimer in non-small cell lung cancer

The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.     

Phase II trial of N-methylformamide in patients with metastatic melanoma

Summary Sixteen patients with metastatic melanoma were treated with N-methylformamide (NMF), a polar-planar compound with in vitro cytotoxic and differentiating properties. Sixteen patients were evaluable for toxicity and 14 for response. The initial four patients received an intravenous bolus of NMF 800 mg/m² daily for 5 consecutive days every 28 days. Because of excessive gastrointestinal toxicity, the dose was reduced to 700 mg/m²/day for the subsequent 12 patients. Two patients had immediate adverse effects from NMF; one had a grand mal seizure and the other developed severe abdominal pain. Nausea, vomiting and abdominal pain were dose-limiting. Transient elevation of liver function tests occurred in all patients. Myelosuppression was not observed. There were no objective responses among 14 evaluable patients (95% confidence limits 0–20%). One patient with pulmonary metastases had a minor response lasting 13 months. Median time to progression of disease was one month. NMF in these doses and schedule lacks clinical efficacy in the treatment of metastatic melanoma.     

Phase II trial of cisplatin and etoposide in patients with metastatic melanoma

Summary Fourteen patients with metastatic melanoma were treated with cisplatin and etoposide by bolus intravenous infusion daily for 5 consecutive days each month. All patients were evaluable for toxicity and twelve for response. Eight patients were treated with cisplatin 20 mg/m² and etoposide 100 mg/m² daily. Because of excessive myelosuppression, the daily dose of etoposide was reduced to 75 mg/m² in the remaining six patients. There were no major responses among 12 evaluable patients (major response rate 24% with 95% confidence). The median time to progression was one month. One patient with a liver metastasis had a minor response lasting 6 + months. The combination of cisplatin and etoposide in these doses and schedule lacked sufficient clinical efficacy in the treatment of metastatic melanoma.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Phase II study of alpha-interferon and 13-cis-retinoic acid in metastatic melanoma

Summary The combination of alpha-interferon and 13-cis-retinoic acid has shown significant activity against a number of human tumors. We conducted a phase II trial to test whether the combination would have a major response rate of 30% or more in patients with refractory, metastatic melanoma. Eleven patients were treated on the study. Alpha-interferon was administered subcutaneously three times a week at a dose of 10 million U/m² and 13-cis-retinoic acid was administered orally at a dose of 1 mg/kg/day. No patient achieved a partial or complete remission. The combination of alpha-interferon and 13-cis-retinoic acid is unlikely to have significantly higher therapeutic activity than alpha-interferon alone.     

Phase II trial of fotemustine in patients with metastatic malignant melanoma

Summary Fotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier. Preliminary French studies reported encouraging results with fotemustine in patients with cerebral metastases of malignant melanoma. Thirty-one patients with histologically confirmed metastatic malignant melanoma were entered on a phase II trial. The treatment regimen consisted of fotemustine, administered intravenously as a rapid infusion, at a dose of 100 mg/m² on day 1, 8 and 15 every 4 to 5 weeks. Objective response (CR+PR) was documented in 3 patients. Median time to treatment failure (TTF) was 44 days and median survival was 164 days. Life threatening toxicity did not occur; hematological toxicity and nausea and vomiting were the most common toxicities. Despite a somewhat disappointing response rate, objective responses were documented in patients with cerebral metastases. Since no other chemotherapeutic agent has shown therapeutic efficacy in cerebral metastases from malignant melanoma fotemustine therefore warrants further study.     

Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study

Malignant melanoma is increasing infrequency at a rapid rate in the UnitedStates. Metastatic disease ischemoresistant with DTIC considered themost active single agent. CI-980 is asynthetic mitotic inhibitor that blocks theassembly of tubulin and microtubules. Ithas shown cytotoxic activity against abroad spectrum of murine and human tumorcell tines. CI-980 can cross the bloodbrain barrier, is effective when givenorally or parenterally, and is activeagainst multidrug resistant cell linesoverexpressing P-glycoprotein. In thistrial, patients with disseminated melanomawith measurable disease, SWOG performancestatus of 0–1, no prior chemotherapy orimmunotherapy for metastatic disease, andadequate hepatic and renal function, wereenrolled. Treatment with CI-980 was givenby 72 h continuous IV infusion at a doseof 4.5 mg/m²/day, days 1–3 every 21 days. Twenty-four patients were registered onthis study with no patients ineligible. They ranged in age from 33–78 withperformance status of 0 in 15 patients and1 in 9 patients. Nineteen patients hadvisceral disease with 12 having liverinvolvement. There were no confirmedresponses. The overall response rate was0% (95% CI 0%–14%). The medianoverall survival is eleven months (95% CI4–14 months). The most common toxicitieswere hematologic and consisted ofleukopenia/granulocytopenia and anemia,with nausea/vomiting andmalaise/fatigue/weakness also frequent. CI-980 administered at this dose andschedule has insufficient activity in thetreatment of disseminated malignantmelanoma to warrant furtherinvestigation.     

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 trial of topotecan in advanced or metastatic adenocarcinoma of the pancreas

SummaryPurpose A phase II trial of topotecan, an inhibitor of topoisomerase I, was conducted in patients with advanced or metastatic adenocarcinoma of the pancreas to determine the activity and toxicity of topotecan.Patients and Materials 35 patients, previously untreated with chemotherapy, received topotecan 1.5 mg/ m²/d for five days intravenously and repeated every 21 days. Patients were assessed for response after 3 cycles. Those with either clinical response or stable disease received additional cycles of the drug until toxicity developed or disease progression occurred.Results Among 30 patients evaluable for response there were no complete responses and 3 partial responses (10%) for a total response rate of 10% (95% confidence interval = 0–20.6%). Stable disease for at least eight weeks was seen in 11 patients (36%). Median survival was 19 weeks (95% confidence interval 11 to 26 weeks). Therapy was generally well tolerated, with reversible granulocytopenia being the most common toxicity.Conclusion Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity. Further exploration of topotecan in pancreatic carcinoma using different dosing schedules is warranted.     

Phase II trial of carboplatin in patients with advanced melanoma

Summary We report the results of a phase II evaluation of carboplatin (CBDCA) in 45 patients with advanced malignant melanoma. Of the 43 evaluable patients, 6 had been treated previously with chemotherapy; 11 had been treated with immunotherapy. The initial dose was 400 mg/m² i.v. every 4 weeks; the dose was modified as required to achieve moderate myelosuppression. There was one complete response (duration 16 months) and six partial responses, for a major objective response rate of 16%. Toxicity consisted primarily of acute nausea and vomiting, and thrombocytopenia. The activity of CBDCA in this disease is similar to that of cisplatin and dacarbazine.     

Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma

Fourteen patients with metastatic renal cell carcinoma (RCC)were treated on a Phase II trial with arsenic trioxide(As₂O₃). Eligible patients had metastatic renal cellcarcinoma with bidimensionally measurable disease, a Karnofskyperformance status of at least 70%, life expectancy ofgreater than three months, and no evidence of brainmetastases. Arsenic trioxide was given intravenously at a doseof 0.3 mg/kg/day for five consecutive days every four weeks.The most common toxicity observed was grade II elevation inliver function tests (36%), anemia (21%), renalinsufficiency (14%), rash (7%), and diarrhea (7%). Bestresponse was stable disease in 3 patients with one patientremaining on study at 8+ months At the dose and schedule usedin this trial, arsenic trioxide did not achieve a complete orpartial response in metastatic renal cell carcinoma.     

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.     

Phase II trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma

Summary We treated 34 chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer with trimetrexate 150–200 mg/m² intravenously over 30 minutes every two weeks. Six of 31 evaluable patients (19%) achieved a partial response. The major toxic effects from this regimen were myelosuppression, nausea/vomiting, and skin rash. We conclude that this well-tolerated schedule of trimetrexate has significant activity as a single agent against non-small cell lung cancer.     

Phase II trial of recombinant Beta (IFN-Betaser) interferon in the treatment of metastatic breast cancer

Summary Nine patients with metastatic breast cancer received 30 × 10⁶ I.U. of Interferon — Beta_ser (Betaseron) intravenously daily times five for two consecutive weeks followed by a two week rest period. Only one patient received more than one such cycle of Betaseron. The drug was well tolerated in eight of these patients. One patient, with liver metastases and liver dysfunction, developed hepatic decompensation during therapy. Toxicity consisted of anorexia, chills, fever, fatigue and nausea with an occasional patient having emesis. One patient developed severe thrombocytopenia, two, significant leukopenia and nine, mild elevations of serum transaminase. Two patients developed beta interferon binding antibodies but none developed neutralizing antibodies. No anti-tumor responses were seen and disease progression occurred rapidly during the four week cycle in eight of nine patients.     

Phase II evaluation of bisantrene hydrochloride in refractory malignant melanoma

Patients with a pathologically proven diagnosis of malignant melanoma were entered into a phase II trial of bisantrene. Eligibility criteria included: measurable, metastatic disease; performance status 0–2 SWOG; and adriamycin total cumulative dose of < 400 mg/m². The initial bisantrene dosing schedule was 260 mg/m² every three weeks for good risk patients. Due to the absence of an objective response and the lack of severe toxicity in the first 25 bisantrene treated patients, the starting dose was increased to 300 mg/m² for good risk patients. Fifty-one patients received a median of two bisantrene courses (range 1–11 courses). Leukopenia was the major toxicity. Fifteen (68%) of the 22 good risk, intermediate dose patients (260 mg/m²), and 8 (80%) of the 10 good risk, high dose patients (300 mg/m²) evaluable for toxicity experienced mild-severe leukopenia. None of the 51 patients experienced a complete or partial response to bisantrene. Median survival was 3.3 months. We conclude that bisantrene is ineffective in the treatment of metastatic melanoma. Address for offprints: Southwest Oncology Group (SWOG-8118), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229, USA     

A phase II study of dihydroxyanthracenedione (DHAD,Mitoxantrone, NSC 301739) in advanced malignant melanoma

Summary The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of Dihydroxyanthracenedione (DHAD, Mitoxantrone, NSC 301739) in 28 patients with advanced malignant melanoma, none of whom had received prior cytotoxic chemotherapy. 27 of 28 patients were ECOG performance status 0 or 1. Mitoxantrone was administered at a dose of 12 mg/M² as a 30–45 minute intravenous infusion repeated every 3 weeks as toxicity and response permitted. Dose limiting toxicity was myelosuppression. No cardiotoxicity was encountered in this study. In this optimal group of patients, only one partial response to Mitoxantrone was observed. At this dose and schedule, Mitoxantrone has no clinically worthwhile activity against malignant melanomas.     

Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma

Summary Purpose: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content.Patients and methods: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria.Results: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8–12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition.Conclusions: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.