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 carbetimer in metastatic melanoma

A phase II study of the synthetic polyelectrolyte Carbetimer 6500 mg/m² IV daily for five days every 21-day cycle was conducted in patients with metastatic melanoma. No responses were seen in 18 evaluable patients. Two patients had stable disease for five months. Toxicity was generally manageable and included mild hyperphosphatemia, mild proteinuria, fatigue, pain at the injection site, and nausea. Carbetimer is inactive in metastatic melanoma at this dose and schedule.     

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 study of AMSA alone and in combination with DTIC in patients with metastatic melanoma

Summary A randomized phase II study of AMSA (amsacrine) alone and AMSA combined with DTIC (dacarbazine) was carried out in 31 and 39 patients with metastatic melanoma respectively. AMSA was used at a starting dose of 40 mg/m²/day × 3 days with escalation to 50–60 mg/m²/day × 3 days in 8 pts. For AMSA + DTIC the starting dose was: AMSA 30 mg/m²/day × 3 days; DTIC, 800 mg/m² × 1 day. Additionally, seven pts received AMSA in a similar dose schedule but DTIC was used in a 5-day schedule of 250 mg/m²/day. Twentyfive patients were evaluable for response in the AMSA group and 36 in the AMSA + DTIC group. The objective response to AMSA included 1(4%) partial response compared with 11 complete or partial responses (30%) with AMSA + DTIC therapy. The median lowest absolute granulocyte count was 1100/l in AMSA group compared with 1000/l in the AMSA + DTIC group. Severe neutropenia of < 500 granulocytes/l was observed in 5 pts in the AMSA group compared with 13 pts in the AMSA + DTIC group. We concluded that AMSA has no significant activity against melanoma, although the combination of AMSA + DTIC seemed to be more active than DTIC alone.     

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 I–II study of high-dose etoposide in patients with refractory breast cancer

Address for offprints: G. Fraschini, The University of Texas M.D. Anderson Cancer Center, Box 56, 1515 Holcombe Boulevard, Houston, TX, 77030, USA     

Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer

Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trial of daily oral etoposide 50 mg/m²/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1–5 day intravenous etoposide administration.from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapolis, IN; Department of Medicine, Indiana University, Indianapolis, IN, USADr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.     

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 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 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.     

Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide

AIMS: Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed. METHODS: Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro. RESULTS: Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml(-1) min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml(-1) min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 microm) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed. CONCLUSIONS: The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.     

Randomized phase II evaluation of aprinocarsen in combination with gemcitabine and cisplatin for patients with advanced/metastatic non-small cell lung cancer

Summary Aprinocarsen is a specific antisense oligonucleotide inhibitor of protein kinase C-. This study aimed to evaluate the response rate to combination therapy with aprinocarsen, gemcitabine and cisplatin, in chemonaive patients with advanced/metastatic NSCLC. Secondary objectives included comparison of response rate, time to event efficacy parameters, and toxicities on the 2 treatment arms. Patients with stage IV, or stage IIIB disease (N₃ and/or pleural/pericardial effusion), were randomized to either control or experimental arm. Patients on both arms received gemcitabine 1250 mg/m² on days 1 and 8, and cisplatin 80 mg/m² on day 1 of a 3-week cycle. Additionally, on the experimental arm, aprinocarsen was administered as 2 mg/kg continuous iv infusion on days 1–14, every 21 days. A total of 18 enrolled patients were randomized on the 2 arms. Further enrollment was terminated in March 2003 as a result of a phase III trial suggesting that aprinocarsen did not have an added survival benefit when combined with paclitaxel and carboplatin therapy in patients with NSCLC. Patients received a median of 4 cycles on control arm and 2.5 cycles on experimental arm. The response rate was 16.7% in the experimental arm and 44.4% in the control arm. Most frequent grade 3/4 toxicities were hematologic, with a higher incidence of thrombocytopenia in the experimental arm (87.5% vs. 33.3%). Despite the 14-day continuous infusion schedule, infection rate was not increased in the experimental arm. The present study did not show any advantage, in response rate or secondary endpoints, with aprinocarsen; however, the toxicity was not unduly increased, and aprinocarsen regimen was safely administered.     

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 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 epirubicin in advanced malignant melanoma

Summary Twenty patients with advanced malignant melanoma refractory to conventional chemotherapy, were entered into a Phase II study of epirubicin, one of the new doxorubicin analogues. The drug was given at a dose of 90 mg/m² IV every 3 weeks. One partial response and three disease stabilizations were observed. Nausea and vomiting and alopecia were common. Mild to moderate leukopenia occurred in 6 patients. Three cases of reversible ST-T changes were recorded. The observed response rate of 5% with a 39.2% probability of a true response rate 10%, does not suggest that epirubicin, in the dose and schedule chosen, is active in metastatic malignant melanoma.     

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.     

依托泊苷微乳相图的研究

目的确定o／w型依托泊苷微乳处方。方法选用油酸、十四酸异丙酯和十六酸异丙酯作为油相，Tween80、Cremophor EL和Cremophor RH40作为表面活性剂，乙醇、1，2-丙二醇、异丙醇、甘油和PEG400为助表面活性剂，通过滴定法绘制伪三元相图，以o／w型微乳区大小为指标筛选处方。结果确定了最终空白微乳处方为Cremophor RH40：乙醇：PEG 400：水：十四酸异丙酯=19．0：19．0：19．0：38．2：4．8（w／w）。结论所选择的微乳处方可以满足依托泊苷载药量的要求。     

Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma

We conducted a phase II evaluation of edatrexate in 17 previously untreated patients with advanced adenocarcinoma of the pancreas; 14 patients had at least one month of therapy. The initial dose was 80 mg/m²iv. Treatment was administered weekly for 5 weeks, then every other week. Toxicity was generally mild. The median WBC nadir was 5.4 (range 0.6–7.4)×10³/l, and the median platelet nadir was 164.0 (range 62.0–341.0)×10³/l. One patient died with sepsis and gastrointestinal bleeding associated with pancytopenia. Five patients had a mild rash. Nausea occurred in 6 patients, including 3 who had vomiting. In addition, 11 patients complained of vague malaise which seemed to begin within 24–48 hours after administration of edatrexate, and lasted for 2 to 3 days, resolving within 6 days of drug administration. Median survival was 85 days. Although 5 patients had stable disease, including one with relief of pain, no major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.     

Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma

Metastatic melanoma carries a dismal prognosis and there is a need to develop new treatment strategies. Vinca alkaloids have shown consistent activity in melanoma patients, as monotherapy and as part of combination regimens. The current study evaluates the clinical activity and tolerability of vinorelbine as first-line monotherapy in patients with metastatic melanoma. Patients were eligible if they presented metastatic melanoma not amenable to curative resection, had received no prior systemic therapy for advanced disease and had an adequate performance status (ECOG 0-1). Patients received vinorelbine at a dose of 30 mg/m2 on days 1 and 8 of a 21-day cycle, on an outpatient basis. Thirteen patients were accrued into the study and received 64 cycles. All patients were assessable for response, toxicity and survival. No objective responses were documented, for an overall response rate of 0% [95% confidence interval (CI) 0-19%] and the trial was terminated in accordance to the predetermined early discontinuation rule. The median progression-free survival was 3.3 months (95% CI 2.3-4.3 months) and the estimated median overall survival was 8.1 months (95% CI 6.0-10.2 months). No life-threatening toxicities occurred. Neutropenia was the main hematologic toxicity, but none of the three episodes of grade 3-4 neutropenia were complicated by infection. The most common non-hematologic toxicities were asthenia, nausea, neuropathy and myalgia. We conclude that vinorelbine as a single agent on days 1 and 8 of a 21-day cycle has a favorable toxicity profile, but appears to have no relevant clinical activity in patients with metastatic melanoma.     

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.