Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment.

BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 µg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.

Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. METHODS: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. RESULTS: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved ≥30, ≥50, and ≥90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. CONCLUSIONS: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.

Phase II trial of S-1 as second-line therapy in patients with advanced non-small cell lung cancer.

PURPOSE: Currently available agents for the treatment of advanced stage non-small cell lung cancer (NSCLC) have limited efficacy. S-1 is a novel formulation of oral fluoropyrimidine shown to be tolerable and active in patients with NSCLC in Japan. We conducted a multicenter phase II study in previously treated patients with NSCLC to evaluate the efficacy of single-agent S-1 in a predominantly non-Asian population. PATIENTS AND METHODS: Patients with advanced NSCLC and previously treated with only one line of chemotherapy received oral S-1 at 30 mg/m every 12 hours for 14 consecutive days followed by a 7-day rest until meeting discontinuation criteria. The primary end point was to evaluate the overall response rate. RESULTS: Fifty-seven patients were accrued from 21 centers across the United States. Overall response rates and stable disease according to independent review were 7.1% and 48.2%, respectively, with a disease control rate of 55.3%. Progression-free survival was 2.9 months, median overall survival 7.3 months, and 1-year survival 31.6%. There were no significant differences in survival according to histologic subtype. The treatment was well tolerated, with the most common treatment-related side effects being nausea (54%) and diarrhea (49%). CONCLUSION: Single-agent S-1 is well tolerated and has activity comparable with the other agents approved for use in recurrent/relapsed NSCLC.

A phase II trial of carboplatin and weekly topotecan in the first-line treatment of patients with extensive stage small cell lung cancer.

BACKGROUND: Carboplatin and topotecan are commonly used in the treatment of small cell lung cancer (SCLC); however, there are no data for this combination in the first-line setting using weekly topotecan. In this multicenter, community-based phase II trial, we evaluated carboplatin and weekly topotecan in the previously untreated patients with extensive stage SCLC. METHODS: This trial was designed to achieve an objective response rate (ORR) of 70% (alpha = 0.05; beta = 0.20); secondary aims were to assess time to progression, toxicity, and overall survival (OS). Patients with Eastern Cooperative Oncology Group performance status 0 to 1, measurable disease, and adequate organ function were eligible. TREATMENT: carboplatin area under the concentration-time curve = 5 (intravenous) on day 1 and topotecan 4 mg/m(2) (intravenous) on days 1 and 8, every 21 days for up to six cycles, with restaging every 6 weeks (per RECIST). RESULTS: Between June 2006 and November 2008, 61 patients were enrolled. The median follow-up is 40 weeks (range 27-109 weeks). Patient characteristics were as follows: median age 67 years (range 40-84 years); male, 53%; and Eastern Cooperative Oncology Group performance status 0, 28%. Complete responses were seen in two patients and partial responses in 33 patients; ORR was 57% (95% confidence interval [CI] 44-70). Stable disease was seen in 12 patients (20%), and progressive disease was seen in two patients (3%). The median time to progression was 5.5 months (95% CI 4.0-6.3 months). The median OS was 8.5 months (95% CI 7.2-11.4 months). One-year OS was 29%. Grade 3/4 toxicity in >5%: neutropenia (66%), thrombocytopenia (48%), leukopenia (40%), anemia (30%), fatigue (13%), dehydration (8%), infection (8%), and pain (7%). CONCLUSIONS: The ORR achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line extensive stage SCLC setting. This regimen was generally well tolerated, with myelosuppression as its primary toxicity.

Single agent vinflunine in the salvage treatment of patients with castration-resistant prostate cancer: a phase II trial of the Sarah Cannon research consortium.

Patients with metastatic prostate cancer resistant to hormones and docetaxel were treated with vinflunine (320 mg/m(2) every 21 days), a new vinca alkaloid with improved preclinical activity. Only 1 of 36 patients (3%) had partial response; the median progression-free survival (PFS) was 2.1 months. Treatment was well tolerated, with myelosuppression as the only frequent toxicity. Vinflunine has a low level of activity in the treatment of refractory metastatic prostate cancer, and should not be further developed for this indication.

Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network.

PURPOSE: This prospective randomized study compared overall survival (OS) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) when treated with the platinum agent-based triple drug combination of paclitaxel/carboplatin/gemcitabine (PCG) versus the nonplatinum agent-based doublet drug combination of gemcitabine/vinorelbine. PATIENTS AND METHODS: Advanced (stages IIIB, IV, and recurrent) chemotherapy-naive patients with NSCLC and performance status 0-2 were randomly assigned to the PCG arm (paclitaxel 200 mg/m(2) on day 1, carboplatin area under the concentration-time curve of 5 on day 1, and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days) or to the gemcitabine/vinorelbine arm (gemcitabine 1000 mg/m(2) on days 1, 8, and 15 and vinorelbine 25 mg/m(2) on days 1, 8, and 15, every 28 days). RESULTS: A total of 337 patients were randomly assigned to the 2 arms. The median time to progression was 6 months for PCG and 3.9 months for gemcitabine/vinorelbine with 1- and 2-year progression-free survival rates of 13% and 2% versus 14% and 4% (P = .324 log rank). Median OS for PCG was 10.3 months versus 10.7 months for gemcitabine/vinorelbine with 1-, 2-, and 3-year OS rates of 38%, 12%, and 2% versus 45%, 12%, and 6%, respectively (P = 0.269 log rank). Grade 3/4 thrombocytopenia, nausea/vomiting, myalgia/arthralgia, and neuropathy were significantly greater in the PCG arm. CONCLUSION: There was no difference in OS or progression-free survival when comparing PCG and gemcitabine/vinorelbine, and gemcitabine/vinorelbine was significantly less toxic. Gemcitabine/vinorelbine is a reasonable nonplatinum agent-based doublet therapy for patients with advanced NSCLC.

Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.

BACKGROUND: The aim of this study was to compare the efficacy of single-agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and/or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Previously untreated patients with stage IIIB/IV NSCLC who were either >65 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status 2 were eligible. Patients were randomized to receive weekly docetaxel (36 mg/m(2)) Days 1, 8, and 15 or docetaxel (30 mg/m(2))/gemcitabine (800 mg/m(2)) Days 1, 8, and 15. Both regimens were repeated on 28-day cycles for 6 cycles or until disease progression. RESULTS: Three hundred fifty patients were randomized, and 345 received treatment. The median age of patients was 74 years; 38% were >75 years old, and 35% had ECOG performance status 2. Intent-to-treat analysis showed median survivals of 5.5 months versus 5.1 months in the groups receiving docetaxel/gemcitabine versus weekly docetaxel, respectively (P = .65). There were no survival differences detected with docetaxel/gemcitabine versus weekly docetaxel in the 223 patients with good performance status (7.2 months vs 8.0 months, respectively) or in the 122 poor performance status patients (3.8 months vs 2.9 months, respectively). Median time-to-progression was longer in patients who received docetaxel/gemcitabine (4.8 months vs 2.9 months; P = .004). Both regimens were generally well tolerated. CONCLUSIONS: Treatment with docetaxel/gemcitabine produced a modest improvement in time-to-progression but had no impact on survival when compared with single-agent weekly docetaxel in this group of patients. Results with both regimens were disappointing, particularly in patients with poor performance status. Improved treatment for these patients will require the introduction of novel, well-tolerated, targeted agents.