A randomized phase II study evaluating different maintenance schedules of nab-paclitaxel in the first-line treatment of metastatic breast cancer: final results of the IBCSG 42-12/BIG 2-12 SNAP trial

BackgroundThe phase II SNAP trial was designed to evaluate the efficacy of alternative chemotherapy schedules for prolonged administration in HER2-negative metastatic breast cancer (MBC), after a short induction at conventional doses.Patients and methodsBetween April 2013 and August 2015, 258 women untreated with chemotherapy for MBC were randomly assigned to receive three different maintenance chemotherapy schedules after three cycles of identical induction chemotherapy: arm A, nab-paclitaxel 150 mg/m² days 1 and 15 Q28; arm B, nab-paclitaxel 100 mg/m² days 1, 8 and 15 Q28; arm C, nab-paclitaxel 75 mg/m² days 1, 8, 15 and 22 Q28. Induction was three cycles nab-paclitaxel 150/125 mg/m², days 1, 8 and 15 Q28. The primary objective was to evaluate the efficacy of each maintenance schedule, in terms of progression-free survival (PFS), as compared with the historical reference of 7-month median PFS reported by previous studies with first-line docetaxel. One-sample, one-sided log-rank tests were utilized. Quality-of-life (QoL) evaluation was carried out, and the global indicator for physical well-being was defined as the primary QoL end point; completion rates of QoL forms were >90%.ResultsIn total, 255 patients were assessable for the primary end point. After 18.2-month median follow-up, 182 PFS events were observed. Median PFS was 7.9 months [90% confidence interval CI 6.8–8.4] in arm A, 9.0 months (90% CI 8.1–10.9) in arm B and 8.5 months (90% CI 6.7–9.5) in arm C. PFS in arm B was significantly longer than the historical reference of first-line docetaxel (P = 0.03). Grade ≥2 sensory neuropathy was reported in 37.9%, 36.1% and 31.2% of the patients in arm A, B and C, respectively (Grade ≥3 in 9.1%, 5.6% and 6.6% of the patients, respectively). Noteworthy, the QoL scores for sensory neuropathy did not worsen with prolonged nab-paclitaxel administration in any of the maintenance arms.ConclusionThe SNAP trial demonstrated that alternative nab-paclitaxel maintenance schedules with reduced dosages after a short induction at conventional doses are feasible and active in the first-line treatment of MBC.Registration: ClinicalTrials.gov NCT01746225     

A randomized,phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small-cell lung cancer (NSCLC)

Background: This trial investigated the efficacy and safety of weekly cetuximab combined with two different schedules of paclitaxel/carboplatin for stage IIIB/IV non-small-cell lung cancer (NSCLC).Methods: A total of 168 patients with previously untreated stage IIIB/IV NSCLC were randomized to arm A, cetuximab (400 mg/m² day 1 followed by weekly 250 mg/m²) + paclitaxel (Taxol) (225 mg/m²)/carboplatin (AUC6) day 1 every 3 weeks or arm B, same cetuximab regimen plus paclitaxel (100 mg/m²) days 1, 8, and 15 every 3 weeks and carboplatin (AUC6) day 1 every 4 weeks. Treatment continued for a four-cycle maximum. Patients with a complete response, partial response, or stable disease after four cycles could receive cetuximab 250 mg/m²/week until disease progression or unacceptable toxicity. The primary end point was to evaluate progression-free survival (PFS).Results: Median PFS was 4.7 and 4.3 months for arms A and B, respectively (6-month PFS, 27.3% versus 30.9%). Median overall survival was 11.4 versus 9.8 months for arms A and B, respectively; estimated 1-year survival, 47.7% versus 39.3%; and objective response rate, 29.6% versus 25%. The regimen was well tolerated with rash and hematologic toxicity being most common.Conclusions: This study did not meet the prespecified benchmark of 35% 6-month PFS rate; both combination schedules of cetuximab plus paclitaxel/carboplatin were feasible and equivalent for treating advanced NSCLC.     

Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: Final results from a randomised phase ii study of bevacizumab plus 5-fluorouracil,leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study)

BackgroundThe combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.Patients and MethodsPatients received bevacizumab 7.5 mg/kg on day 1 plus XELIRI (irinotecan 200 mg/m² on day 1 and oral capecitabine 1000 mg/m² bid on days 1–14) every 3 weeks or bevacizumab 5 mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400 mg/m² on day 1 plus 2400 mg/m² as a 46-h infusion, leucovorin 400 mg/m² on day 1, and irinotecan 180 mg/m² on day 1) every 2 weeks. Patients aged ?65 years received a lower dose of capecitabine (800 mg/m² twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.ResultsA total of 145 patients were enrolled (bevacizumab–XELIRI, n = 72; bevacizumab–FOLFIRI, n = 73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71–90%) in the bevacizumab–XELIRI arm and 85% (95% CI 75–92%) in the bevacizumab–FOLFIRI arm. In both the bevacizumab–XELIRI and bevacizumab–FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab–XELIRI 18%; bevacizumab–FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).ConclusionsThis randomised non-comparative study demonstrates that bevacizumab–XELIRI and bevacizumab–FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.     

A randomized,phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BackgroundB490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).Patients and methodsEligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m²), then weekly (1-h infusions, 250 mg/m²). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m²; CetCisPac arm: 75 mg/m²) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m²) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy.ResultsA total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72–1.36,P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53–1.11,P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38–1.20,P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%,P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%).ConclusionThe two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced.Clinical trial numberEudraCT# 2011-002564-24.     

A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102

Background: This phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of cisplatin, standard infusion of gemcitabine and gefitinib in patients with advanced urothelial carcinoma.Patients and methods: Eligible patients had previously untreated measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of zero to two and creatinine clearance >50 ml/min. Treatment consisted of cisplatin 70 mg/m² day 1 and gemcitabine 1000 mg/m² on days 1 and 8 given every 3 weeks concurrent with gefitinib 500 mg/day orally for six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease.Results: Fifty-four of 58 patients were assessable. Twelve patients (22%) had node-only disease, and 25 (46%) had an ECOG performance status of zero. There were 23 objective responses for an overall response rate of 42.6% [95% confidence interval (CI) 29.2% to 56.8%]. The median survival time was 15.1 months (95% CI 11.1–21.7 months) and the median time to progression was 7.4 months (95% CI 5.6–9.2 months).Conclusions: The combination of cisplatin, gemcitabine and gefitinib is well tolerated and active in advanced transitional cell carcinoma. The addition of gefitinib does not appear to improve response rate or survival in comparison to historical controls of cisplatin and gemcitabine alone.     

A randomized trial of induction docetaxel–cisplatin–5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02)

BackgroundConcomitant chemotherapy (CT)–radiotherapy (RT) is a standard of care in locally advanced nasopharyngeal carcinoma (NPC) and a role for induction CT is not established.MethodsPatients with locally advanced NPC, WHO type 2 or 3, were randomized to induction TPF plus concomitant cisplatin-RT or concomitant cisplatin-RT alone. The TPF regimen consisted of three cycles of Docetaxel 75 mg/m² day 1; cisplatin 75 mg/m² day 1; 5FU 750 mg/m²/day days 1–5. RT consisted of 70 Gy in 7 weeks plus concomitant cisplatin 40 mg/m² weekly.ResultsA total of 83 patients were included in the study. Demographics and tumour characteristics were well balanced between both arms. Most of the patients (95%) in the TPF arm received three cycles of induction CT. The rate of grade 3–4 toxicity and the compliance (NCI-CTCAE v3) during cisplatin-RT were not different between both arms. With a median follow-up of 43.1 months, the 3-year PFS rate was 73.9% in the TPF arm versus 57.2% in the reference arm [hazard ratio (HR) = 0.44; 95% confidence interval (CI): 0.20–0.97, P = 0.042]. Similarly the 3 years overall survival rate was 86.3% in the TPF arm versus 68.9% in the reference arm (HR = 0.40; 95% CI: 0.15–1.04, P = 0.05).ConclusionIn conclusion, several important aspects can be emphasized: the compliance to induction TPF was good and TPF did not compromise the tolerance of the concomitant RT-cisplatin phase. The improved PFS and overall survival rates needs to be confirmed by further trials.     

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer

BackgroundSome trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer.Patients and methodsPatients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m² day 1, LV 100 mg/m² as 2 h infusion and 5-FU 400 mg/m² as bolus, days 1 and 2 followed by 600 mg/m²/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm).ResultsFrom February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively.ConclusionsA more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy.Clinical trial registrationClinicalTrials.gov Identifier: NCT01640782.     

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

BackgroundSorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC.Patients and methodsWe conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m², day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival.ResultsA total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated.ConclusionSorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC.Clinical Trial registrationUMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.     

A randomised phase II study of combination chemotherapy with epirubicin,cisplatin and capecitabine (ECX) or cisplatin and capecitabine (CX) in advanced gastric cancer

BackgroundBoth cisplatin/capecitabine (CX) and epirubicin plus CX (ECX) have clearly demonstrated efficacy against advanced gastric cancer (AGC).MethodsChemotherapy-naïve patients with histologically confirmed, measurable AGC were randomised to receive CX (cisplatin 75 mg/m² iv on day 1 and capecitabine 1000 mg/m² bid po on days 1–14) or ECX (epirubicin 50 mg/m² plus CX) every 3 weeks. The primary endpoint was progression-free survival (PFS).ResultsOf the 91 registered patients, 45 patients were treated with CX and 44 with ECX. A total of 241 CX (median, 6; range, 1–12) and 201 ECX (median, 5; range, 1–11) cycles were delivered. Treatment duration was similar for both arms (4.4 for CX versus 4.2 months for ECX). There was no relevant difference in the occurrence of overall grade 3 or 4 toxicities between the CX and ECX arms (80% versus 78%, respectively; P = 0.516). However, none in the CX and 12% in the ECX arm discontinued treatment because of toxicity. There were no significant differences in therapeutic efficacy between CX and ECX with respect to the response rate (38% versus 37%, respectively) and PFS (6.4 versus 6.5 months).ConclusionBoth CX and ECX appear to be active as first-line chemotherapy for AGC, and the safety profiles are acceptable. Given the comparable efficacy results, CX could be a reasonable standard chemotherapy for untreated AGC patients.     

Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel,and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802)

Background: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC–D) as first-line chemotherapy in metastatic breast cancer (MBC).Patients and methods: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40 mg/m² plus cyclophosphamide 500 mg/m²), D (60 mg/m²), or alternating treatment with AC–D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks.Results: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC–D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P = 0.13 for AC versus D, P = 0.14 for AC versus AC–D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P = 0.09 for AC versus D, P = 0.13 for AC versus AC–D) in the AC, D, and AC–D, respectively.Conclusion: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.     

Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients

BackgroundThe combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).Patients and methodsPatients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m² twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m² days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m² continuously days 1–7) plus daunorubicin (45 mg/m² days 3–5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.ResultsBetween February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33–45] versus 55% (95% CI: 49–61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).ConclusionThe dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.     

A multicentre randomised trial comparing weekly paclitaxel + S-1 with weekly paclitaxel + 5-fluorouracil for patients with advanced gastric cancer

PurposeThis study aimed to compare the efficacy and toxicity of weekly paclitaxel plus S-1 with weekly paclitaxel plus 5-fluorouracil in treating advanced gastric cancer as first line regimen. The primary end-point was disease control rate (DCR).MethodsPatients with advanced or recurrent gastric cancer were randomly assigned to an experimental arm or a control arm. The experimental arm’s dosage schedule was paclitaxel 60 mg/m² (intravenous infusion) on days 1, 8 and 15 and S-1 80–120 mg/d (oral administration) on days 1–14. Control arm patients were given the same paclitaxel, combined with 5-fluorouracil 500 mg/m² (continuous intravenous infusion) on days 1–5; and leucovorin 20 mg/m² (intravenous infusion) on days 1–5. All schedules were repeated every 28 d.ResultsA total of 240 patients were enrolled and equally randomised into two arms. The overall response rate and DCR of the experimental arm was non-inferior to that of the control arm both in the per-protocol set and the full analysis set. The secondary end-point median progression-free survival (PFS) of the experimental and control arms was 153 and 129 d, with the hazard ratio of 0.641 (95% CI: 0.473–0.868, P = 0.004). The hazard ratio of the time to treatment failure of the two arms was 1.449 (95% CI: 0.705–2.980, P = 0.229). The six-month PFS rates of both arms were similar (31.3% versus 31.8%, P = 0.94). Cox regression analysis indicated that only treatment regimen and age were independent predictive factors for PFS. The most common adverse events were haematological and gastrointestinal. The rates of grade 3–4 adverse events were not significantly different between the two study arms and were mostly lower than 5%.ConclusionWeekly paclitaxel combined with S-1 is an active and well-tolerated regimen, supporting the view that S-1 can be an alternative for infusional 5-fluorouracil for advanced gastric cancer.     

Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer

Background: The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection.Methods: Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU.Results: The initial dose of HAI FUDR was fixed at 0.12 mg/kg × pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m² and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m². The LV dose was fixed at 400 mg/m². Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively.Conclusions: Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m² and 5-FU by continuous infusion at 2000 g/m² with LV at 400 mg/m² is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.     

Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane

BackgroundCapecitabine is an approved standard therapy for anthracycline- and taxane-pretreated locally advanced or metastatic breast cancer (BC). Vinflunine has demonstrated single-agent activity in phase II studies in this setting and activity and tolerability when combined with capecitabine. We compared the combination of vinflunine plus capecitabine (VC) with single-agent capecitabine.Patients and methodsPatients with locally recurrent/metastatic BC previously treated or resistant to an anthracycline and resistant to taxane therapy were randomly assigned to either vinflunine (280 mg/m², day 1) plus oral capecitabine [825 mg/m² twice daily (b.i.d.), days 1–14] every 3 weeks (q3w) or single-agent oral capecitabine (1250 mg/m² b.i.d., days 1–14) q3w. The primary end point was progression-free survival (PFS) assessed by an independent review committee. The study had 90% power to detect a 30% improvement in PFS.ResultsOverall, 770 patients were randomised. PFS was significantly longer with VC than with capecitabine alone [hazard ratio, 0.84, 95% confidence interval (CI), 0.71–0.99; log-rank P = 0.043; median 5.6 versus 4.3 months, respectively]. Median overall survival was 13.9 versus 11.7 months with VC versus capecitabine alone, respectively (hazard ratio, 0.98; 95% CI, 0.83–1.15; log-rank P = 0.77). No difference in quality of life was observed between the two treatment arms. The most common adverse events (NCI CTCAE version 3.0) in the combination arm were haematological and gastrointestinal. Grade 4 neutropenia was more frequent with VC (12% versus 1% with capecitabine alone); febrile neutropenia occurred in 2% versus 0.5%, respectively. Hand-foot syndrome was less frequent with VC (grade 3: 4% versus 19% for capecitabine alone). Peripheral neuropathy was uncommon in both arms (grade 3: 1% versus 0.3%).ConclusionsVinflunine combined with capecitabine demonstrated a modest improvement in PFS and an acceptable safety profile compared with capecitabine alone in patients with anthracycline- and taxane-pretreated locally recurrent/metastatic BC.ClinicalTrials.govNCT01095003.     

Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003)

BackgroundThis phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC.Patients and methodsPatients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35 mg/m², cisplatin 70 mg/m² i.v. on day 1, fluorouracil 700 mg/m² continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70 mg/m², cisplatin 70 mg/m² i.v. on day 1, fluorouracil 700 mg/m² continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat.ResultsBetween October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P = 0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33–0.83, P = 0.0057) and 78.6% versus 65.4% (P = 0.08), respectively.ConclusionCompared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC.Clinical Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616).     

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial

AimThe optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy.MethodsAGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m²; CDDP, 30 mg/m², q2w) or CPT-11 (150 mg/m², q2w).ResultsSixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8–17.6) and 12.7 (95% CI: 10.3–17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596–1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4–5.9] versus 4.1 [95% CI: 3.3–4.9] months) and response rate (16.9% [95% CI: 8.8–28.3] versus 15.4% [95% CI: 7.6–26.5]). The incidences of grade 3–4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019).ConclusionNo survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.     

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised,phase 3 trial

BackgroundIn the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population.MethodsIn this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874.FindingsBetween 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N = 114) and gefitinib monotherapy (N = 118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p = 0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63–1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p = 0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3–4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p = 0.002).InterpretationIn the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer.FundingEli Lilly and Company.     

A randomized,phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer

BackgroundPaclitaxel–carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen.Patients and methodsA total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m² on days 1 and 8 plus carboplatin area under the concentration–time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m² on days 1 and 8 plus paclitaxel 200 mg/m² on day 1 (GP), or paclitaxel 225 mg/m² plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression.ResultsMedian survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC.ConclusionsNon-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.     

A randomised,open-label,phase II study of neo/adjuvant doxorubicin and ifosfamide versus gemcitabine and docetaxel in patients with localised,high-risk,soft tissue sarcoma

BackgroundDoxorubicin and ifosfamide (AI) is standard therapy for high-risk soft tissue sarcoma (STS) but often causes severe toxicities resulting in hospitalisation. Gemcitabine and docetaxel (GD) has efficacy in metastatic STS and may be better tolerated. We conducted a study to compare toxicities and efficacies of these regimens.MethodsThis open-label, phase II, single institution trial randomised 80 patients with localised, resectable, high grade STS ⩾5 cm to either neo/adjuvant AI or GD. AI was doxorubicin (75 mg/m²) and ifosfamide (2.5 g/m²/d) on days 1–3 with mesna 500 mg/m²/dose. GD was gemcitabine 900 mg/m² on days 1, 8 and docetaxel 100 mg/m² day 8. Both arms included filgrastim. The primary end-point was hospitalisation rate. Secondary end-points included disease-free survival (DFS) and overall survival (OS).ResultsBetween November 2004 and August 2012, 80 evaluable patients were randomised, 37 to AI and 43 to GT. In the AI arm, 13/37 (35%) patients were hospitalised versus 11/43 (26%) in the GD arm (p = 0.25). Hospitalisation rates were not significantly different after adjusting for age, gender, location, chemotherapy and number of cycles (p = 0.17). The 2-year and median DFS in the AI arm were 57% and 37 months, respectively, and 74% and not yet reached, respectively, in the GD arm. The most common serious adverse events with AI were haematologic. Metabolic derangements and constitutional symptoms were most common with GD.ConclusionsHospitalisation rate was less with GD but not statistically significant. There was a trend towards longer DFS with GD, and the regimen was tolerable, suggesting GD merits further study.FundingEli Lilly and Sanofi-Aventis.     

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary

Background: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.Methods: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.Results: Thirty patients received a total of 142 treatment cycles of the PLD–ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m² on days 1, 8, and 15 plus PLD 30 mg/m² given on day 1, repeated every 4 weeks. Hand–foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.Conclusion: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.