A phase II study of fotemustine plus dacarbazine with dendritic cell vaccines as first-line therapy for Chinese patients with advanced acral lentiginous melanoma

Objective: To investigate fotemustine plus dacarbazine (DTIC) with dendritic cell (DC) vaccines on patients with advanced acral lentiginous melanoma (ALM). Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with (DTIC). DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods: This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m2, d1, 12, DTIC 400 mg/d d2(6, DC vaccines subcutaneously d7, 9, 13 repeated every 28 days. Ten HLA-A02+24+ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 (Mart-1) and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival (PFS). Secondary end-points were overall survival (OS), overall response rate (ORR) and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors (RECIST). Results: The 15 men and 13 women had a median age of 51 years. 16 patients had stage M1c disease and 11/16 had liver metastasis. Patients received an average of 3.82(1.25 cycles. Follow-up for the 18 surviving patients ranged from 7(41 months with a median of 12 months. Median PFS was 8.5 months (95% CI: 7.86(15.21) with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months (95% CI: 10.33(18.24). ORR (CR+PR) was 35.7% including 3 complete response (CR) and 7 partial response (PR). Six patients had disease stable. A total of 19 Grade III/IV toxicities were observed including thrombocytopenia (n=8), neutropenia (n=5), fatigue (n=6) and hypersensitivity reaction (n=1). One patient died of Grade IV thrombocytopenia. Conclusion: Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The regimen brings clinical benefit with a higher ORR and may provide a survival advantage. Updated survival data will be presented.     

Positive phase II study in the treatment of advanced malignant melanoma with fotemustine

Summary To date, dacarbazine (DTIC) has been the most effective drug in the treatment of advanced metastatic melanoma, achieving response rates of up to 28% (mean, 21%). Multidrug responses were generally no better than those obtained using monotherapy. A quite promising clinical trial was conducted using the new nitrosourea fotemustine. A total of 19 patients presenting with advanced malignant melanoma (clinical stage IV according to the 1987 UICC classification system) underwent treatment involving a more rapid infusion of the drug and a reduction in the rest period from 5 to 3 weeks. This monotherapy with fotemustine yielded two complete responses and seven partial responses; in addition, four patients showed no change and six cases progressed after the induction cycle (median duration of response to date, 7.6 months, including four cases that have not relapsed). Fotemustine was well tolerated by the patients, with the only mild side effects being thrombocytopenia, leukocytopenia and easily controlled nausea/vomiting. Preclinical studies performed previously indicated that fotemustine inhibits enzymes involved in the ribonucleotide reduction pathway (i.e. DNA synthesis), whereby responding patients (n=3) appeared to favor the thioredoxin reductase/thioredoxin electron transfer to ribonucleotide reductase, whereas non-responders (n=4) expressed the alternate glutathione reductase/glutaredoxin mechanism. The 47% response rate obtained in these studies vs the 24% reported previously for fotemustine may reflect variations in enzymes in the ribonucleotide reduction pathway in different patients. However, the efficacy of fotemustine against advanced melanoma warrants more extensive trials of this drug, especially since the quality of life of the patients during and after chemotherapy was not severely affected.     

Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma. PATIENTS AND METHODS: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression. RESULTS: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases. CONCLUSION: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.     

Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: Temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma. PATIENTS AND METHODS: Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. RESULTS: Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. CONCLUSION: The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.     

A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma

The purpose of this study was to compare the response rate, overall and 1-year survival in patients with advanced melanoma treated with a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin and tamoxifen (DBCT). Treatment toxicity and time spent in hospital were secondary end points. One hundred and five patients (of whom 100 were eligible) were randomized to receive either DTIC/IFN or DBCT. The trial was designed to detect a 25% absolute difference in response rate or in 1-year survival with 80% power. There was no significant difference in response rate: this was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival was similar at 199 and 202 days respectively. One-year survival rate favoured standard treatment (30.6 vs 22.6%), but did not differ significantly between arms. DBCT was associated with significantly greater haematological toxicity, and a greater need for time spent in hospital (5.75 days/treatment cycle vs 2.29 with dacarbazine and interferon). DBCT combination therapy cannot be recommended as standard treatment for advanced melanoma. Dacarbazine remains the standard chemotherapy for this condition.     

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma.

There is increasing experimental evidence to suggest that expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the O6-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m-1) at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800 mg m-2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > or = 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.     

Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.     

Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (CDDP) is able to down-regulate the AGAT activity, suggesting that CDDP could enhance the antitumor activity of TMZ. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination versus single-agent TMZ in patients with advanced melanoma. PATIENTS AND METHODS: From January 2000 to April 2002, 132 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the two arms. Patients with cerebral metastases were included. Patients received TMZ 200 mg/m(2)/day orally for five consecutive days every 4 weeks or TMZ + CDDP 200 mg/m(2) daily on days 1-5 and 75 mg/m(2) of CDDP on day 1. RESULTS: Tumor responses (complete and partial responses) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.8 months in arm A and 5.8 months in arm B. The median overall survival (OS) was 11.5 months in arm A and 12 months in arm B. The difference between treatment arms regarding objective response rates, TTP and OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralgias/myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. CONCLUSIONS: No clear benefit in terms of response rates, median TTP or OS was shown with the combination of TMZ + CDDP. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis.     

Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study.

High response rates in patients with metastatic melanoma have been achieved with combination chemoimmunotherapy. A response rate of 62% in 45 patients has been reported for treatment with dacarbazine, bleomycin, vincristine, lomustine (BOLD) plus interferon alpha (IFN-alpha). We conducted a multicentre phase II study to confirm these results. Melanoma patients with distant metastases were treated as outpatients with dacarbazine 200 mg m(-2) on days 1-5, vincristine 1 mg m(-2) on days 1 and 4, bleomycin 15 mg on days 2 and 5 i.v. and lomustine 80 mg orally on day 1, repeated every 4 weeks. IFN-alpha-2b was initiated s.c. on day 8 at 3 MU daily for 6 weeks, and 6 MU t.i.w. thereafter. Forty-three patients entered the study. The median number of metastatic sites was three (range 1-5), and 81% of patients had visceral metastases. Nine patients had brain metastases, and seven patients were systemically pretreated. Among the 41 patients that were evaluable for response, the response rate was 27% (95% CI 14-3%), with one complete and ten partial remissions. The response rate in 25 previously untreated patients without brain metastases was 40% (95% CI 21-61%). Median duration of response was 6 (range 2-14+) months; median overall survival was 5 (1-26) months. The main toxicity was malaise/fatigue. We confirm that BOLD plus IFN-alpha has activity in metastatic melanoma. The lower response rate in our study compared with the previous report is probably related to patient selection, as in the previous study 46% of patients had stage III disease, whereas all our patients had stage IV disease, which is associated with a worse prognosis.     

A phase II study of the sequential administration of dacarbazine and fotemustine in the treatment of cerebral metastases from malignant melanoma

34 patients with cerebral metastases from malignant melanoma received sequential dacarbazine at 250 mg/m² followed 2 h later by foteraustine at 100 mg/m²; this was repeated on day 8. Maintenance therapy was given every 4 weeks to patients with radiological evidence of response or stable disease until a maximum response was achieved plus two more cycles. A 12% response rate was obtained for cerebral metastases, with 2 complete responses lasting 12 and 36+ months, and 2 partial responses lasting 2.5 and 3.75 months. Toxicity was mainly haematological with grade 3–4 leucopenia and thrombocytopenia in 23.5% of patients. No pulmonary toxicity was seen. This schedule of sequential dacarbazine and fotemustine has low activity against metastatic melanoma, and the response rate for cerebral metastases is not superior to that shown in other studies with single agent fotemustine, but the treatment was well tolerated and can be delivered on an outpatient basis.     

Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group.

BACKGROUND: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity. RESULTS: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34-76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1-11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3-4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia. CONCLUSIONS: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.     

Combination of cisplatin, vindesine, and dacarbazine in advanced malignant melanoma. A Phase II Study of the EORTC Malignant Melanoma Cooperative Group

A Phase II study combining cisplatin, vindesine, and dacarbazine was performed on patients with disseminated malignant melanoma by the European Organization for Research and Treatment of Cancer (EORTC) Malignant Melanoma Cooperative Group (MMCG). The treatment consisted of intravenous administrations of dacarbazine 450 mg/m2, vindesine 3 mg/m2, and cisplatin 50 mg/m2 on day 1 and 8 of each course. Courses were repeated every 4 weeks. Treatment was discontinued in case of progression after two courses, otherwise continued until progression or for a minimum of six courses. One hundred five patients entered the trial with 92 patients being evaluable. The response rate calculated after clearance by the Extramural Review Committee shows four complete and 18 partial responses, i.e., 24%, with a median remission duration of 23 weeks. Toxicity and subjective tolerance to this regimen were moderate, requiring 140 modifications of 642 administrations (22%). Main toxicities were nausea and vomiting (95%), leucopenia (70%), alopecia (56%), peripheral neuropathy (32%), and nephrotoxicity (17%). The discussion emphasizes some particular points of interest in the management of advanced malignant melanoma.     

Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week). RESULTS: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001). CONCLUSION: In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.     

Phase II study of interferon alpha-2a and dacarbazine in advanced melanoma

Based on the report of some activity of combination therapy with dacarbazine (DTIC) and interferon alpha-2a (rIFN alpha-2a) in disseminated melanoma, we conducted a phase II study to determine the feasibility and efficacy in a large series of patients. DTIC was administered in 79 patients at the dose of 800 mg/m2 every 3 weeks and rIFN alpha-2a was given daily at the dose of 9 X 10(6) IU for the first 10 weeks and three times a week thereafter. Among the 75 evaluable patients, 25% achieved an objective response, with 8% complete and 17% partial remissions. The regression occurred within a mean time of 1.9 +/- 1.03 months from starting therapy and the mean duration of response was 8.2 +/- 4.2 months. The major side effects were vomiting, anorexia, fever, fatigue, and myalgia. There was one death related to sepsis after myelosuppression. In the other patients bone marrow and liver toxicities were not remarkable. Our data reveal that a combination regimen of rIFN alpha-2a with a cytotoxic agent has some therapeutic activity in the management of advanced malignant melanoma.     

A phase II study of spirogermanium in advanced large bowel cancer. An Eastern Cooperative Oncology Group study

Thirty-one patients with advanced colorectal cancer were entered on a phase II study of spirogermanium. Of these, 23 received the drug at the dose of 200 mg/m2 intravenously (i.v.) over 4 h twice a week every week. There were 2 (9%) partial responses. No complete responses were noted. Two life-threatening and six severe toxicities were observed. We conclude that this drug has some activity against colorectal cancer.     

Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study

Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and fotemustine in metastatic melanoma patients with or without brain metastases. The addition of fotemustine to ipilimumab does not impair its immunomodulatory activity.BackgroundIn the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination.Patients and methodsThis analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3⁺CD4⁺ICOS⁺CD45RO⁺ or CD45RA⁺ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.ResultsEighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naïve’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome.ConclusionsLong-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab.EudraCT number2010-019356-50.CinicalTrials.govNCT01654692.     

A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-alpha, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.     

Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: A multicenter phase II study of the Hellenic Cooperative Oncology Group

Purpose: Both docetaxel and cisplatin have moderate activity in patients with advanced urothelial cancer. We performed a multicenter phase II study in order to assess the efficacy and toxicity of the combination of these two agents in patients with advanced carcinoma of the urothelium.Patients and methods: Sixty-six patients not amenable to curative surgery or irradiation were enrolled onto this cooperative group study and treated on an outpatient basis with docetaxel 75 mg/m² followed by cisplatin 75 mg/m², both administered intravenously. Granulocyte-colony stimulating factor was administered subcutaneously at a dose of 5 µg/kg daily from day 5 until resolution of neutropenia. The chemotherapy was administered every three weeks for a maximum of six courses in patients without evidence of progressive disease.Results: Thirty-four of sixty-six patients (52%, 95% confidence interval 40%–64%) demonstrated objective responses, with eight achieving clinical complete responses and twenty-six partial responses. A multivariate logistic regression analysis indicated that the patients most likely to respond were those without lung metastasis and without weight loss before treatment. The median duration of response was 6.1 months and the median times to progression and survival for all patients were 5 and 8 months, respectively. Absence of anemia, of liver metastases and of weight loss correlated with longer survival. Grade 3 toxicities included granulocytopenia in 33% of patients, anemia in 14%, diarrhea in 13% and emesis in 7% of patients.Conclusion: The combination of docetaxel and cisplatin appeared relatively well tolerated and moderately active in patients with advanced urothelial cancer. The patients most likely to benefit were those without weight loss and without lung or liver metastases.     

Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.

PURPOSE: To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m(2)/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m(2)/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P =.012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.