Controlled study of DTIC versus DTIC plus epirubicin in metastatic malignant melanoma

Summary Forty-two previously untreated patients with metastatic malignant melanoma were randomized to receive DTIC at a dose of 250 mg/m²/day 4 IV on days 1–5 or the same drug plus epirubicin (Epi-DX) at a dose of 90 mg/m² on day 1. Cycles were repeated every 3 weeks. Partial responses were observed in two out of 22 patients (9.1%) treated with DTIC, and in four out of 19 evaluable patients (21.1%) treated with Epi-DX+DTIC. Overall, Epi-DX+DTIC combination was well tolerated, thus permitting administration after a 3-week interval of the full drug dosages in all but two patients. No major cardiotoxicity was observed. Although patients in the Epi-DX+DTIC group had a better response rate than those in the DTIC group, the difference was not statistically significant, and the 21.1% response rate observed with the two-drug combination does not differ from that reported with DTIC used alone.     

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 study with 4′ -deoxydoxorubicin

Summary 4-Deoxydoxorubicin (dxDx), a new doxorubicin analogue, was administered intravenously on a 3-week schedule to 73 patients affected by advanced malignant neoplasms. Sixty-five patients, treated with eight dose levels ranging from 10 to 45 mg/m², were evaluable. The dose-limiting toxicity was myelosuppression, mainly leukopenia. About one third of the patients complained of vomiting which was almost always mild. Minimal hair loss was also documented in about 40% of patients. No hepatic or renal toxicity was observed. Transient and aspecific electrocardiographic changes were recorded in 6% of patients after 1 h and in 3% after 24 h from drug injection. Left ventricular ejection fraction was decreased in two patients after a cumulative dose of 90 mg/m². One patient died with cardiorespiratory insufficiency and his initial cardiovascular disease might have been aggravated by dxDx. No changes in myocardial function parameters were documented in 18 patients who reached higher cumulative doses, i.e. 100 mg/m² and 200 mg/m². The highest total dose administered in this study was 340 mg/m². Therapeutic activity was observed with doses ranging from 25 to 45 mg/m². Partial response was documented in pancreatic, colon, anal and breast carcinomas as well as in non-Hodgkin's lymphoma. Minor response was observed in prostatic, thyroid, and renal carcinomas as well as in chronic lymphocytic leukemia. The maximum tolerated dose was assessed to be between 40 and 45 mg/m². A Phase II trial is ongoing utilizing the dose of 35 mg/m² every 3 weeks.     

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.     

A phase II trial of piroxantrone in disseminated malignant melanoma

Summary Piroxantrone is one of the anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. It has shown activity in metastatic melanoma during phase I trials. The Southwest Oncology Group (SWOG) conducted a phase II trial in disseminated malignant melanoma with piroxantrone administered at 150 mg/m² intravenously over 1 h every 21 days, based upon the phase I experience. Forty-six eligible patients were registered to the trial and 44 were evaluable for response. Two partial responses, Wayne of 6 and 9 months duration were observed for an overall response rate of 5% (95% confidence interval 1%–15%). Thirty-six of 46 eligible patients have died with an estimated median survival of 5 months (95% confidence interval 3–8 months). Toxicities were tolerable with granulocytopenia being the predominant toxicity. Based upon the observed response rate, it is concluded that piroxantrone administered at this dose and schedule has detectable but minimal activity, and does not warrant further investigation in this disease.     

A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial

Summary To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m² once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received ≥90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.     

Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27–81), with performance status 0–2 were treated with merbarone 1000 mg/m²/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-reponders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%–19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval of six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%), malaise (23%), weakness (20%), alopecia (17%), diarrhea (17%), anorexia (14%), transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5nucleotidase increase (9%), and fever (9%). Hematologictoxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.     

Phase I trial of adjuvant chemotherapy with cyclophosphamide,epirubicin and 5-fluorouracil (CEF) for stage II breast cancer

Summary Epirubicin is a new anthracycline with a potentially more favorable toxicity profile than the parent compound, doxorubicin. Accordingly, the feasibility and toxicity of 6 courses of adjuvant chemotherapy with cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) were assessed in 10 patients with Stage 2 (node positive) breast cancer. Doses of C and F were 600 mg/m² and E was 75 mg/m². Moderate granulocytopenia (median count = 610/mm³) occurred on day 14 of the first 21 day treatment course and was the main toxicity encountered with treatment, although there were no episodes of granulocytopenic fever. Grade 3 or 4 vomiting occurred in 40% and significant alopecia in 30% of patients. Four patients experienced transient asymptomatic decreases in calculated radionuclide cardiac ejection fraction of 10% but no signs or symptoms of cardiac failure were observed. If epirubicin proves to be less cardiotoxic than doxorubicin, this combination would merit further evaluation as potential adjuvant therapy for early breast cancer.     

Protective Effects of Salidroside on Epirubicin-Induced Early Left Ventricular Regional Systolic Dysfunction in Patients with Breast Cancer

Background

Salidroside [2-(4-hydroxyphenyl)ethyl-β-D-glucopyranoside], one of the most potent ingredients extracted from the plant Rhodiola rosea L., has been shown to have a cardiovascular protective effect as an antioxidant, and early treatment of epirubicin-induced cardiotoxicity has been the focus of clinical chemotherapy in patients with breast cancer. However, the cardioprotective effects of salidroside on epirubicin-induced cardiotoxicity, especially early left ventricular regional systolic dysfunction, have to date been sparsely investigated.

Objective

The aim of this study was to investigate the protective effects of salidroside in preventing early left ventricular regional systolic dysfunction induced by epirubicin.

Methods

Sixty patients with histologically confirmed breast cancer were enrolled. Eligible patients were randomized to receive salidroside (600 mg/day; n= 30) or placebo (n = 30) starting 1 week before chemotherapy. Patients were investigated by means of echocardiography and strain rate (SR) imaging. We also measured plasma concentrations of reactive oxygen species (ROS). All parameters were assessed at baseline and 7 days after each new epirubicin dose of 100 mg/m².

Results

A decline of the SR peak was observed at an epirubicin dose of 200 mg/m², with no significant differences between salidroside and placebo (1.35 ± 0.36 vs 1.42 ± 0.49/second). At growing cumulative doses of epirubicin, the SR normalized only with salidroside, showing a significant difference in comparison with placebo at epirubicin doses of 300 mg/m² (1.67 ± 0.43 vs 1.32 ± 0.53/second, p< 0.05) and 400 mg/m² (1.68±0.29 vs 1.40 ± 0.23/second, p < 0.05). Moreover, a significant increase in plasma concentrations of ROS was found with placebo, but they remained unchanged with salidroside.

Conclusion

Salidroside can provide a protective effect on epirubicin-induced early left ventricular regional systolic dysfunction in patients with breast cancer.     

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 I study of escalating dose mitoxantrone in combination with α-2-interferon in patients with advanced solid tumors

In vitro and preclinical in vivo data have shown a synergistic antitumor activity between -interferon and some antiproliferative agents. A phase I study of the concurrent administration of interferon- 2 and mito-xantrone was initiated, to determine the maximum tolerated dose of mitoxantrone given i.v. every 3 weeks in escalating doses combined with a fixed dose of s.c. interferon 2 (6 × 10⁶ IU three times per week³), in patients with advanced solid tumors resistant to conventional chemotherapy. At least three evaluable patients were entered in each dose level of mitoxantrone starting at 4 mg/m², with no escalations allowed in the same patient. Twenty-seven patients received a total of 101 cycles and five dose-levels were explored (4-6-8-10-12 mg/m² of mitoxantrone). The dose-limiting toxicities were leukopenia and granulocytopenia at 12 mg/m² of mitoxantrone, at which dose hematological toxicity occurred in > 50% of cases, with one patient presenting grade 4 leuko-granulocytopenia. No severe thrombocytopenia occurred. In the majority of patients transient hepatic enzyme elevations and a flu-like syndrome due to interferon a 2 were observed in all dose-levels explored. These observations suggest that the hepatotoxic effects of interferon a 2 do not emphasize mitoxantrone side-effects if given simultaneously. When mitoxantrone is administered with 6 × 10⁶ IU of interferon 2, the recommended dose for future phase II studies is 10 mg/m²/weeks³ with escalation up to 12 mg/m² in selected patients if such a combination is well tolerated in terms of myelosuppression. Regarding therapeutic activity, four out of 25 (16%) cases evaluable for response achieved a partial response. In conclusion the concomitant administration of recombinant interferon 2 and mitoxantrone allows the possibility to give a therapeutic dosage of both agents. Because the combination of the two agents was fairly well tolerated and antitumor activity was observed, phase II trials are warranted.     

Evaluation of amonafide in disseminated malignant melanoma

Amonafide (AMF), NSC 308847 is an investigational anticancer drug acting as a DNA intercalating agent. This paper presents results of a phase II clinical study of AMF in disseminated malignant melanoma. Twenty patients, eleven males and nine females, with biopsy proven malignant melanoma, performance status 0–2; median age 59 (range 29–74), and no previous chemotherapy, were treated with AMF 300 mg/m²/day by 60 min I.V. infusion for five days repeated every three weeks. Fifteen patients had lung (9 patients) and/or liver (8 patients) involvement. None had known brain metastasis at entry. All 20 patients were evaluated for response and toxicity. Six patients had stable disease and fourteen had increasing disease. With 0/20 responses, the upper 95% confidence limit for the response rate was 14%. The median survival time was 5.7 months. Hematologic toxicity was dose limiting with the incidence of leucopenia 45% and thrombocytopenia 20%. The nonhematologic toxicities included nausea and vomiting (60%), alopecia (20%), headaches (15%), diarrhea (10%), and phlebitis (10%). We conclude that AMF administered at this dose and schedule is not active in the treatment of patients with malignant melanoma, previously untreated with chemotherapy.     

Phase II Study of Perifosine in Previously Untreated Patients with Metastatic Melanoma

Summary Purpose: To assess the response rate and toxicity of the alkylphosphocholine analogue, perifosine, in patients with metastatic or recurrent malignant melanoma. Patients and Methods: Patients had histologically proven, unidimensionally measurable disease which was incurable by standard therapy. Prior adjuvant immunotherapy was allowed but patients had not received prior chemotherapy. Perisfosine was given orally as a loading dose of 900 mg on day 1 followed by a maintenance dose of 150 mg po on days 2–21 in a 28 day cycle. The loading dose was 300 mg on day 1 of all subsequent cycles. Tumour response was assessed every 2 cycles. Results: 18 patients were accrued over 7 mos. No objective responses occurred in the 14 evaluable patients. Three patients (21%) achieved stable disease after 2 cycles and 11 had progression. Seventeen patients were evaluable for toxicity. Grade 3 or 4 non-hematologic toxicities included: diarrhea (12%), arthralgia (12%), nausea (6%), headache (6%), and fatigue (6%). No grade 3 or 4 hematological or biochemical toxicity were observed. Seventy-seven percent of patients received ≥90% of planned cycle 1 dose intensity and 58% received ≥90% of planned dose for cycle 2+. Four patients required dose reductions; treatment was delayed in 5 patients; and 5 patients missed doses because of toxicity. Conclusions: Perifosine can be safely administered when given as an initial loading dose followed by daily maintenance therapy over 28 days. Gastrointestinal toxicity is common but generally of low grade. Hematological toxicity is minimal. No objective responses were observed. No further development of single-agent perifosine is recommended in malignant melanoma.     

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 trimetrexate in advanced esophageal cancer: A southwest oncology group study

Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily × 5 schedule, every 3 weeks; a starting dose of 12 mg/m² was used for patients with no prior irradiation, and of 8 mg/m² for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.     

Phase II trial of 4′ deoxydoxorubicin (DXDX) for unresectable non-small cell bronchogenic carcinoma

Summary A phase II trial of 4 Deoxydoxorubicin (DXDX) was conducted in unresectable previously untreated non-small cell lung cancer patients. DXDX was administered every 3 weeks by short intravenous infusion at a starting dose of 30 mg/m², with dose escalation to 40 mg/m² toxicity permitting. Four responses, all partial, were observed in 35 evaluable patients, for a response rate of 11% (95% confidence limits 3.2% and 26.7%). Myelosuppression was the dose-limiting toxicity. Cardiotoxicity was not seen. DXDX has minimal activity against non-small cell lung cancer as a single agent at the dosage used in this study.Supported in part by Public Health Service Grant CA-21742 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services     

Epirubicin/docetaxel regimen in progressive breast cancer-a phase II study

The purpose of this investigation was to evaluate the efficacy and toxicity of 6 months' treatment with the combination of epirubicin and docetaxel in metastatic breast cancer. Thirty-eight women (mean age 51 years, range 35-72) with metastatic breast cancer were treated with a regimen of epirubicin 75 mg/m and docetaxel 75 mg/m every 3 weeks, given 4 times if progression was seen upon evaluation after 4 courses or 8 times in responding/stable patients. The patients received 285 cycles of combination treatment and two treatments with docetaxel or epirubicin alone. When neutropenia with fever was observed, further cycles were given with dose reduction. The median cumulative docetaxel dose was 462 mg/m (range 199-600) and that of epirubicin 476 mg/m (range 199-740). The overall response rate was 54% (95% CI 37-71), with a median duration of response of 14.8 months (95% CI 8.8-27.8). Median time to progression was 12 months, median survival 26 months. Neutropenia below 0.5 x 10 /l occurred following 113 (39%) of the total of 285 cycles given; 21 patients (55%) were hospitalized for febrile neutropenia. We conclude that dose tailoring is required in treatment with an epirubicin and docetaxel regimen to avoid grade 3/4 adverse effects in a significant number of patients treated for metastatic breast cancer.     

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.     

A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer

The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0–2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m² without G-CSF and 175/90 mg/m² with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m² paclitaxel and 90 mg/m² epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m² and epirubicin 75 mg/m² is recommended for phase II and III studies.     

A Clinical Screening Cooperative Group phase II evaluation of lobaplatin (ASTA D-19466) in advanced head and neck cancer

Summary We evaluated the efficacy and tolerability of lobaplatin, a new platinum compound, given at the dose of 50 mg/m² by i.v. bolus every 4 weeks, in 49 patients with advanced and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). One complete and 2 partial responses were observed in 43 eligible patients for an overall response rate of 7% (95% confidence interval: 1–19%). The duration of responses was 11, 16 and 32 weeks. Toxicities of WHO grade 3 were hematologic: thrombocytopenia in 26%, granulocytopenia in 12% and anemia in 12% of patients. There was no therapy-related death. Nausea/vomiting, diarrhoea and paresthesia were mild and rare. In conclusion, lobaplatin was well tolerated, but its efficacy in advanced SCCHN at the presented dose and schedule, was marginal.