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.     

A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial

Background Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m² over 3 h on cycle 1, reduced to 45 mg/m² over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2–3.0) while median OS was 7.3 months (95% CI, 3.4–18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1–18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.     

A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma

Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity. Methods: This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy na?ve subjects were treated with YM155 at a dose of 4.8 mg/m²/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression. Results: One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3–2.7). Median overall survival was 9.9 months (95% CI; 7.0–14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions. Conclusions: YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.     

Phase II study of vinflunine in patients with metastatic renal cell carcinoma

Summary Purpose: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). Patients and methods: Patients with metastatic RCC were treated with vinflunine 350 mg/m² (n = 11) or 320 mg/m² (n = 22) administered intravenously every 21 days. Results: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m² and none in the group receiving 320 mg/m² resulting in a response rate in this population of 9.1% (95% CI: 0.2–41.3). Median progression free survival was 5.6 months (95% CI: 2.8–14.4) for patients treated at 350 mg/m², and 3.3 months (95% CI: 1.6–6.4) for those treated at 320 mg/m².The median survival time was 10.4 months (95% CI: 6.8–12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia —90.9% at 350 mg/m² and 68.1% at 320 mg/m², febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m² and in 5 patients (22.7%) at 320 mg/m². One episode of thromboembolic event was reported in 1 patient at each dose level. Conclusion: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m² than at 350 mg/m². Supported by Institute de Recherche Pierre Fabre Oncologie, Boulogne-Billancourt, France.     

Scheduled administration of low dose irinotecan before gemcitabine in the second line therapy of non-small cell lung cancer: a phase II study

We had previously demonstrated that low dose irinotecan (CPT-11) leads to increased accumulation of cells in S-phase and shows a therapeutic synergy with S-phase specific chemotherapy such as gemcitabine and 5-fluorouracil. In this phase II study, our objectives were to evaluate the tolerability and activity of low dose CPT-11 followed 24 h later by gemcitabine as second line therapy in patients with metastatic non-small cell lung cancer (NSCLC). CPT-11 (60 mg/m) was administered 24 h before gemcitabine (1000 mg/m) on days 1, 2, 8, and 9 every 3 weeks. Twenty-nine patients were evaluable for response. The median follow-up was 7.4 months. Partial response (PR) was seen in two (6.9, 95% confidence interval (CI): 0.009-0.228). PR and stable disease were seen in 22 patients (75.9, 95% CI: 0.564-0.897). The median survival time was 13.8 months (95% CI: 8.1-19.3). The median time to progression was 4.6 months (95% CI: 2.6-6.2). Thirty-eight patients were evaluable for toxicity. Neutropenia (grade 3 or 4) was observed in 27 patients (71%). Eight patients did not receive cycle 2 of therapy owing to prolonged neutropenia. No treatment-related deaths occurred. Scheduled administration of low dose CPT-11, 24 h before gemcitabine in the second line therapy of NSCLC yielded comparable disease control rates (PR and stable disease) when compared with other studies using the two chemotherapy drugs in the traditional sequence. However, this approach was associated with higher grade 3/4 neutropenia and is not recommended for further study in metastatic NSCLC.     

A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium

Purpose The Src family of kinases may play a role in the development and progression of gastric cancer. We evaluated the activity and safety of saracatinib an oral, anilinoquinazolone, non-receptor tyrosine kinase inhibitor targeting Src kinases, in patients with metastatic or locally advanced gastric carcinoma. Methods Eligible patients who had received ≤1 prior line of chemotherapy for metastatic disease received saracatinib 175 mg/day of a 28 day cycle until progression. The primary endpoint was the objective response and/or prolonged stable disease rate (pSD ≥ 16 weeks). Results Ten patients with gastric carcinoma and 11 with adenocarcinoma of the gastroesophageal junction received a median of 2 cycles (range 1–10 cycles) of treatment per patient. 17 patients were evaluable for response. No objective response was seen. One patient experienced prolonged Stable disease (pSD). Three patients had SD and 13 progressive disease. Median overall survival was 7.8 months (95% CI, 3.9–12.2 months) and median time to progression was 1.8 months (95% CI: 1.5–1.9 months). Grade 3 events possibly related to saracatinib included: fatigue (2 patients), hypoxia (2) anemia (3) and lymphopenia (2). Conclusion Saracatinib has insufficient activity as a single agent in patients with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibition.     

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 celecoxib,gemcitabine, and cisplatin in advanced pancreatic cancer

Summary Background. Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m² over 100 minutes, cisplatin 35 mg/m² I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results. Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6–7.6 months). The probability of survival at 6 months was 46% (90% CI, 27–62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.     

Treosulfan and gemcitabine in metastatic uveal melanoma patients: results of a multicenter feasibility study

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54-133 weeks], the progression-free survival was 28.5 weeks (95% CI 13-62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.     

Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck

Summary Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m² IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3–2.3) months, median survival was 3.5 (95% CI 2.8–7.8) months, and 1 year overall survival was 20% (95% CI 8.3–48.1%). The most frequent attributable grades III–V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule. Presented in part at the European Society for Medical Oncology, Istanbul, Turkey, September 29–October 3, 2006.     

Docetaxel and epirubicin salvage regimen in relapsed anthracycline-sensitive metastatic breast cancer patients after anthracycline-containing adjuvant therapy

Summary  Our aim in this paper is to verify the efficacy and safety of a epirubicin and docetaxel salvage regimen for anthracycline sensitive metastatic breast cancer patients who have relapsed after anthracycline-containing adjuvant therapy. Thirty-two metastatic breast cancer patients were treated with epirubicin and docetaxel every 21 days. Of the 31 evaluable patients, there were 13/31 (41.9%) partial responses and no complete responses. Median time to progression was 12 months (95% CI, 4–60 months) and median survival duration was 41 months (95% CI, 1.2–80.8 months). According to the Cox model, ECOG performance and response group were statistically significant variables, and visceral metastasis was a borderline significant variable with regards to overall survival. Although this salvage regimen showed a high rate of hematologic toxicities, it was a relatively active regimen with manageable toxicities and no cardiac dysfunction. We propose that this salvage regimen could be carefully used in anthracycline sensitive metastatic breast cancer patients who have relapsed after anthracycline-containing adjuvant therapy.     

A phase II clinical trial of ZD1839 (Iressa™) in combination with docetaxel as first-line treatment in patients with advanced breast cancer

Summary This was a phase II multi-institutional trial to determine the efficacy and tolerability of gefitinib (Iressa™) and docetaxel as first-line treatment in patients with metastatic breast cancer. All patients had histologically confirmed breast cancer with metastatic disease. They were permitted to have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m² every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Thirty-three patients were enrolled and received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5–69.2%). There were 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9–57.9%). Four patients had stable disease for ≥24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0–17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (ten patients). Toxicities were mainly attributable to docetaxel, including ≥grade 3 neutropenia in 43% of patients. The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer, with a clinical benefit rate and toxicity profile in the range of that reported for docetaxel alone. This trial was funded by AstraZeneca Pharmaceuticals, Wilmington, DE. Dr. Swain was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or U.S. Government. The ClinTrials.gov Identifier for this study is: NCT00052169     

Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial

Summary Background: Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. Methods: Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16–0.24 mg/kg per day for 5–6 days per week for 3–4 weeks, followed by one-week rest. Tumor response was assessed every 2 cycles. Primary endpoint was the percentage of patients with 6-month disease stabilization. Results: Twenty-nine patients (median age, 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1–6). One patient had partial response. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1–27). The median overall survival was 4.8 months (95% CI, 1.4–8.2) and one-year survival was 30%. Conclusion: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC.     

Weekly Gemcitabine for the Treatment of Biliary Tract and Gallbladder Cancer

Objectives: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naïve patients with advanced biliary tract and gallbladder cancer. Patients and methods: Gemcitabine at a dose of 800?mg/m² was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. Results: A total of 30 patients (median age 66 years; range 54–72 years) were included in the study. A median of 14 (range, 4–33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5–34). Overall response rate was superior in patients with cancer of the gallbladder (ORR=35.7%) compared with those patients with biliary duct cancer (ORR=27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6–7.1 months) versus 3.6 months (95% CI, 2.9–4.3 months; p=0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8–18.5 months) versus 11.4 months (95% CI, 10.2–12.6 months, p=0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. Conclusions: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naïve patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.     

Weekly paclitaxel, 5-fluorouracil and folinic acid with granulocyte colony-stimulating factor support in metastatic breast cancer patients: a phase II study

We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m, folinic acid 10 mg/m and bolus infusion of 5-FU 300 mg/m every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% CI 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% CI 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (CI 77.8-100), with one complete response and 11 partial responses (84.6% CI 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% CI 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.     

Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer

Our objective was to evaluate the efficacy and safety of capecitabine in chemotherapy-naive patients with unresectable advanced or metastatic gastric cancer. An open-label multicenter phase II study was conducted for previously untreated patients with advanced or metastatic gastric cancer. Oral capecitabine 828 mg/m2 twice daily was given on days 1-21 every 4 weeks. Baseline characteristics of 60 enrolled patients were: male/female 49/11, median age 64 years (range 28-74), good performance status (ECOG 0-1) in 98% of patients and 27 patients had prior gastrectomy (45%). A median of 4 treatment cycles were administered (range 1-37). Five patients were excluded from the efficacy analysis because they did not meet eligibility criteria. The overall response rate (RR) in the evaluable patient population (n=55) was 26% [95% confidence interval (95% CI) 15-39%] and a further 29% of patients had stable disease. The overall RR in the intent-to-treat population (n=60) was 23% (95% CI 13-36.0%). Median time to progression in the evaluable patient population was 3.4 months (95% CI 1.8-6.1) and overall survival time in the intent-to-treat population was 10.0 months (95% CI 6.4-13.6). The most frequent grade 3/4 drug-related adverse event was hand-foot syndrome (13%), but this was readily managed by treatment interruption and dose reduction. No patients developed grade 3/4 drug-related diarrhea, vomiting, leukopenia or thrombocytopenia. We conclude that this 4-week regimen of capecitabine showed promising activity and was well tolerated as first-line therapy for advanced/metastatic gastric cancer. Further investigation of this regimen is warranted.     

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 study of gemcitabine plus cisplatin in metastatic breast cancer

Our objectives were to assess the efficacy and toxicity of gemcitabine plus cisplatin as first-line therapy in metastatic breast cancer (MBC). Patients with stage IV MBC and no prior chemotherapy for metastatic disease were treated with gemcitabine 1200 mg/m on days 1 and 8, and cisplatin 75 mg/m on day 1 every 21 days. Up to 6 cycles were given. A total of 46 patients with a median age of 49 years (range 24-77) and Karnofsky performance status of 80 or above were enrolled. In total, 238 cycles were administered. Of the 42 patients evaluable for response, seven (17%) achieved a complete response and 27 (64%) a partial response, for an overall response rate of 81% [95% confidence interval (CI) 69-93%]. Median time to progression was 14.9 months (95% CI 0-30.2 months). Median duration of response was 24.2 months (95% CI 11.2-37.3 months). The median survival was 27.9 months (95% CI 23.1-32.7 months), and the 1- and 2-year survival probabilities were 71.4 and 61.4%, respectively. All patients were evaluable for toxicity, and grade 3/4 WHO toxicities included neutropenia (41.3%), anemia (8.7%), thrombocytopenia (8.7%), alopecia (26.1%) and nausea/vomiting (32.6%). We conclude that gemcitabine plus cisplatin is a highly effective and safe first-line treatment for patients with MBC. The time to progression of 14.9 months compares favorably with other standard treatments (anthracyclines, taxanes). A randomized study is required to further investigate the role of this combination as first-line treatment for MBC.     

A phase 2 study of SP1049C,doxorubicin in P-glycoprotein-targeting pluronics,in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction

Purpose To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Patients and Methods Patients with metastatic or locally advanced unresectable adenocarcinoma of the esophagus or GEJ who had not previously received systemic chemotherapy and had measurable disease were treated with SP1049C 75 mg/m² (doxorubicin equivalents) as a brief intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate in patients who had received a least one course of SP1049C and had undergone tumor assessment, whereas, secondary endpoints included the objective response rate, progression-free survival (PFS), overall survival, and safety in the intent-to-treat (ITT) population. A review of scans was also conducted post-hoc by a blinded panel of radiologists. Results Twenty-one patients, of which 19 were evaluable for response, were treated with at least one dose of SP1049C. Nine patients had a partial response (PR) and eight patients had either a minor response or stable disease as their best response. The objective response rate was 47% (95% CI: 24.4–71) in the evaluable patient population, whereas the objective response rate was 43% (95% CI: 21.8–65.9) in the ITT population. The post-hoc radiological review confirmed that all nine responders had a PR; seven of the nine had a PR that was confirmed by a subsequent scan, whilst two patients had unconfirmed PRs. The median overall survival and PFS were 10.0 months (95%CI: 4.8–11.2) and 6.6 months (95% CI: 4.5–7.6), respectively. Neutropenia was the principal toxicity of SP1049C. Four patients developed an absolute percentage decrement of at least 15% in their left ventricular ejection fraction, none of which decreased to below 45% nor were symptomatic. Conclusion SP1049C has a notable single-agent activity in patients with adenocarcinoma of the esophagus and GEJ, as well as an acceptable safety profile. These results, in addition to the results of preclinical studies demonstrating superior antitumor activity of SP1049C compared with doxorubicin in a standard formulation, indicate that further evaluations of SP1049C alone or combined with other relevant therapeutics in this disease setting are warranted.     

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.