Long-term results of weekly paclitaxel carboplatin induction therapy: An effective and well-tolerated treatment in patients with platinum-resistant ovarian cancer

BackgroundWeekly paclitaxel/cisplatin is effective in platinum-resistant epithelial ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin.Patients and methodsPatients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m² and carboplatin area under the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. End-points were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity.ResultsMedian progression free interval after last platinum was 9 (0–81) months in 108 patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin <6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 1–21) and 13 (1–46) months, median OS 15 (1–69) and 26 (4–93) months, respectively. The 13 platinum-resistant patients with a platinum-therapy free interval <6 months had a significant shorter PFS (4 versus 10 months, p = 0.035) and OS (9 versus 15 months, p = 0.002).ConclusionSix cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.     

Randomised,double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29

IntroductionThis randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1–3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer.MethodsEligible patients received paclitaxel (200 mg/m²) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20 mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4–6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽0.70.ResultsThe trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66–1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71–1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69–1.30, p = 0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia.ConclusionsThe addition of cediranib 20 mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.     

Weekly dose-dense paclitaxel and carboplatin in recurrent ovarian carcinoma: A phase II trial

PurposeThe aim of this study was to investigate efficacy and toxicity of the dose-dense weekly paclitaxel (T) and carboplatin (C) in the management of platinum-resistant/sensitive recurrent epithelial ovarian cancer (EOC) previously treated with 3 weekly paclitaxel/carboplatin.MethodsThirty two patients with recurrent EOC who had received 3 weekly TC before were enrolled. Nine patients relapsed within 6 months (platinum-resistant), 13 patients relapsed after 12 months (platinum-sensitive) and in 10 patients recurrence occurred between 6 and 12 months (intermediate platinum-sensitive). Weekly (T) at a dose of 80 mg/m², followed by weekly (C) AUC 2 on day 1, 8, and 15 of a 28-day cycle for 6 planned cycles were administrated. End-points were overall response rate (ORR), progression free survival (PFS), overall survival (OS) and toxicity.ResultsThe ORR was 62.5%. For the platinum-resistant, intermediate platinum-sensitive and platinum-sensitive patients the ORR was 44.4% (4/9), 60% (6/10) and 76.9% (10/13), respectively, and 1 (11.1%), 2 (20%) and 5 (38.46%) patients, respectively had CR. PFS was 9.1 months (6.13, 9.1 and 12.17 months, for the 3 groups, respectively) (P < 0.001). OS was 14 months (9.17, 15.2, and 19.23 months, for the 3 groups, respectively) (P < 0.001). Treatment-related adverse events were manageable with only 1 patient (3.1%) suffering from grade 4 neutropenia. Grade 3 hematological and non-hematological toxicities were neutropenia in 8 (25%), and peripheral neuropathy in 4 (12.5%) patients, respectively.ConclusionWeekly TC is active and well-tolerated in platinum-resistant and platinum-sensitive patients with recurrent EOC previously treated with TC given every 3 weeks.     

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.     

Efficacy and safety results from OCTAVIA,a single-arm phase II study evaluating front-line bevacizumab,carboplatin and weekly paclitaxel for ovarian cancer

PurposeThe single-arm OCTAVIA study evaluated front-line bevacizumab plus weekly paclitaxel and q3w carboplatin.Patients and methodsPatients with newly diagnosed ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IIb–IV or grade 3/clear-cell stage I/IIA) received bevacizumab (7.5 mg/kg, day 1), weekly paclitaxel (80 mg/m² days 1, 8, 15) and carboplatin (area under the curve 6 [AUC6], day 1) intravenously q3w for 6–8 cycles, followed by single-agent bevacizumab (total 1 year). The primary objective was to demonstrate median progression-free survival (PFS) > 18 months according to the lower 90% confidence limit. Secondary end-points included objective response rate, overall survival, safety and tolerability.ResultsMost (74%) of the 189 treated patients had stage IIIC/IV disease, similar to the ICON7 population. Patients received a median of six chemotherapy and 17 bevacizumab cycles. At the predefined cutoff 24 months after last patient enrolment, 99 patients (52%) had progressed and 19 (10%) had died, all from ovarian cancer. Median PFS was 23.7 months (95% confidence interval [CI], 19.8–26.4 months), 1-year PFS rate was 85.6%, Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 84.6% and median response duration was 14.7 months. Most patients (?90%) completed at least six chemotherapy cycles. Grade ?3 peripheral sensory neuropathy occurred in 5% and febrile neutropenia in 0.5%. Grade ?3 adverse events typical of bevacizumab were no more common than in phase III bevacizumab ovarian cancer trials. There was one case of gastrointestinal perforation (0.5%) and no treatment-related deaths.ConclusionOCTAVIA met its primary objective, demonstrating median PFS of approximately 2 years. This bevacizumab-containing regimen is active and tolerable.     

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy

BackgroundPaclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure.Methods and materialsPatients were randomized 1 : 1 to DHP107 (200 mg/m² orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m² day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25.ResultsBaseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7–4.0) months for DHP107 and 2.6 (95% CI 1.8–2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64–1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70–1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 − 11.5) months for DHP107 versus 8.9 (95% CI 7.1–12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76–1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%).ConclusionsDHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC.ClinicalTrials.govNCT01839773.     

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.     

A randomized phase II study comparing paclitaxel–carboplatin–bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)

BackgroundNitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity.Patients and methodsIn this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)–paclitaxel (200 mg/m²)–bevacizumab 15 mg/kg on day 1 every 3 weeks with or without NTG patches 15 mg (day -2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed.ResultsBetween 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6–7.3) and 5.1 months (4.2–5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96–1.67). Overall survival (OS) was 11.6 months (8.8–13.6) in control arm and 9.4 months (7.8–11.3) in experimental arm, HR 1.02 (95% CI 0.71–1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG).ConclusionAdding NTG to first-line carboplatin–paclitaxel–bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.     

Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study

BackgroundWe undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix.Patients and methodsOne hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m², daily, on days 1–3 and cisplatin 70 mg/m² on day 2) or the same combination with the addition of paclitaxel 175 mg/m² on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis.ResultsA modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet.ConclusionThe ITP combination merits further investigation in randomized phase III studies.     

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.     

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized,double-blind,multicenter phase 2 trial

BackgroundIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).DesignPatients (n = 130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m²)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.ResultsPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64; P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.ConclusionThese results suggest further investigation of ipilimumab in ED-SCLC.     

Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)

BackgroundBevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial.Patients and methodsPatients (n = 1043) received cisplatin 80 mg/m² and gemcitabine 1250 mg/m² for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point.ResultsSignificant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64–0.87), P = 0.0003 and 0.85 (0.73–1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78–1.11), P = 0.420 and 1.03 (0.86–1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported.ConclusionsFinal analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin–gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.     

Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer

BackgroundThe prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear.Patients and methodsIn this 2×2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m² for 21 d with 1 week rest)/cisplatin (60 mg/m² at day 8) or PC (80 and 25 mg/m², respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS).ResultsBetween October 2009 and July 2011, 83 patients received 2 courses of SC (n = 21), 4 courses of SC (n = 20), 2 courses of PC (n = 21) and 4 courses of PC (n = 21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses.ConclusionsTwo courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer.Clinical trial numberUMIN-000002595.     

Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours

AimMicropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models.MethodsA phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m²/d was administered iv days 1–5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment.ResultsEighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6 – not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2–5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue.ConclusionsBelinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.     

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with cisplatin and 5-fluorouracil in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: a multicentre,open-label,phase II clinical trial

BackgroundWe conducted a single-arm phase II trial to evaluate the efficacy and adverse effects (AEs) of an anti-epidermal growth factor receptor monoclonal antibody, nimotuzumab, combined with cisplatin and 5-fluorouracil (PF) as first-line treatment in recurrent metastatic nasopharyngeal carcinoma after radical radiotherapy.MethodsPatients who met the eligibility criteria were recruited from ten institutions (ClinicalTrials.gov; NCT01616849). A Simon optimal two-stage design was used to calculate the sample size. All patients received weekly nimotuzumab (200 mg) added to cisplatin (100 mg/m² D1) and 5-fluorouracil (4 g/m² continuous infusion D1–4) every 3-weekly for a maximum of six cycles. Primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs.ResultsA total of 35 patients were enrolled (13 in stage 1 and 22 in stage 2). Overall ORR and DCR were 71.4% (25/35) and 85.7% (30/35), respectively. Median PFS and OS were 7.0 (95% CI 5.8–8.2) months and 16.3 (95% CI 11.4–21.3) months, respectively. Unplanned exploratory analyses suggest that patients who received ≥2400 mg nimotuzumab and ≥4 cycles of PF had superior ORR, PFS and OS than those who did not (88.9% versus 12.5%, P < 0.001; 7.4 versus 2.7 months, P = 0.081; 17.0 versus 8.0 months, P = 0.202). Favourable subgroups included patients with lung metastasis [HR_OS 0.324 (95% CI 0.146–0.717), P = 0.008] and disease-free interval of >12 months [HR_OS 0.307 (95% CI 0.131–0.724), P = 0.004], but no difference was observed for metastatic burden. The only major grade 3/4 AE was leukopenia (62.9%).ConclusionCombination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.     

Evaluation of paclitaxel/carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or primary metastatic cervical cancer

Background and aimsTo evaluate paclitaxel/carboplatin in a dose dense (TCdd) and weekly (TCw) regimen in recurrent or primary metastatic cervical cancer.MethodsSix courses of paclitaxel (90 mg/m²) and carboplatin (area under the curve (AUC) 4) were administered on d1, d8 q3 wks in TCdd. Eighteen courses of paclitaxel (60 mg/m²) and carboplatin (AUC 2.7) were administered weekly in TCw. Response rates were determined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Criteria.ResultsSixty-six patients were included (44 TCdd and 22 TCw). TCdd and TCw were administered as first-line chemotherapy in 48% and 41%, second-line in 43% and 18%, and third/fourth-line in 9% and 41%, respectively. Response (confirmed or unconfirmed) was observed in 58% and 36% for TCdd and TCw, respectively. As first-line, the response rates for TCdd and TCw were the same (55%). As second or more line, the response rates for TCdd and TCw were 61% and 29%, respectively. In patients, receiving TCdd as first-line systemic treatment, median overall survival (OS) and progression-free survival (PFS) was 10 and 5 months. As first-line, the median OS for TCw also was 10 months (median PFS not reached). There was no statistical difference in PFS or OS between patients treated with TCw or TCdd. Grade 3–4 toxicity was mostly bone-marrow related and was more common with TCdd. Febrile neutropenia was observed in 0% and 12% of the patients treated with TCw and TCdd, respectively.ConclusionsCombination of paclitaxel and carboplatin in a dose dense regimen or weekly regimen resulted in favourable response rate and toxicity profile compared with cisplatin-based combination regimens. TCdd appears to be more toxic than TCw, but resulted in higher response rates than TCw in patients with recurrent metastatic cervical cancer who received prior chemotherapy.     

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

BackgroundWe have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series.MethodsIn this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m² (day 1) and gemcitabine 1000 mg/m² (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients.ResultsFifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n = 8) and disease progression (n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective.¹ConclusionThe sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.     

Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: A multicentre,open-label,randomised phase 2 trial

BackgroundThe addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC.MethodsIn this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m² intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m² IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m² orally twice daily on days 1–14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83.FindingsMedian PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41–0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3–4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that 1) patients receiving capecitabine at some line for treatment have significantly improved OS and 2) a prognostic model can classify patients into three risk groups associated with OS.InterpretationIn patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease.FundingF. Hoffmann-La Roche Ltd, the Netherlands.     

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.     

Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052)

BackgroundThis was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)¹ as primary end-point.MethodsChemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m² on day 1 and bortezomib 1.3 mg/m² on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method.ResultsBetween 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42–64%). The overall survival (OS) was 13.5 months (95% CI 10.5–15) with 56% (95% CI 44–66%) alive at 1 year. The median PFS was 5.1 months (95% CI 3.3–6.5) and the response rate was 28.4% (95% CI 18.9–39.5%).The most frequent grade 3–4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74 days) due to acute pneumonitis and cardiac arrest.End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32–0.67), logrank test and C-index were 0.007 and 0.60.ConclusionThe 50% PFSR-18 for CB was contained within the 80% CI for (42–64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.