A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas

PurposeTo estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ?21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.Patients and methodsThree strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m²/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.ResultsOf the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m²/d, 1 of 10 at 250 mg/m²/d and 3 of 12 at 375 mg/m²/d. Subsequently a second patient at 250 mg/m²/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.ConclusionThis trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m²/d was selected for the phase II trial.     

Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer

BackgroundEverolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).Patients and methodsPhase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m² i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m² i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity.ResultsSixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31–75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred.ConclusionThe addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group.Clinical trial numberNCT00499603.     

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer

BackgroundThis study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m² given over 90 min i.v. and l-leucovorin 200 mg/m² given over 120 min on day 1, followed by 5-FU 400 mg/m² bolus and then 2400 mg/m² infused over 46 h) in untreated metastatic colorectal cancer (mCRC).Patients and methodsIn this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1–6. Efficacy was a secondary objective.ResultsThirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n = 1), grade 4 neutropenia (n = 4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n = 1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5–79.7).ConclusionsThe MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.     

Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast,ovarian and other solid tumors

BackgroundTo establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors.Patients and methodsPatients aged ≥18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50–200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1–5 or 1–10) in combination with cisplatin (60–75 mg/m² intravenously) on day 1 of each cycle.ResultsDose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m² with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m² with olaparib 100 mg bid days 1–10 or 50 mg bid days 1–5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1–5 and 60 mg/m², respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively.ConclusionsOlaparib in combination with cisplatin 75 mg/m² was not considered tolerable; intermittent olaparib (50 mg bid, days 1–5) with cisplatin 60 mg/m² improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation.     

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: Results of the Panitumumab,Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

BackgroundThe main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.MethodsSix hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m² (or 300 mg/m² if age >70 or performance status (PS) = 2) or 3-weekly irinotecan at 140 mg/m² (120 mg/m² if age >70 or PS = 2) with ciclosporin 3 mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ?3 diarrhoea within 12 weeks of randomisation.ResultsThe proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference = ?6.3%, 95% confidence interval (CI) [?13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of ?10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.InterpretationThe pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.FundingThe trial was funded by Cancer Research UK and supported by Amgen Pharma.     

PREPARE trial: a randomized phase III trial comparing preoperative,dose-dense,dose-intensified chemotherapy with epirubicin,paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery

BackgroundPreoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support.Patients and methodsPatients received neoadjuvant epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² followed by paclitaxel 175 mg/m² (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m² followed by paclitaxel 225 mg/m² with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m²) on days 1 and 8 (E_dd→T_dd→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377).ResultsPathological complete response (pCR) rate (breast) was higher with E_dd→T_dd→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E_dd→T_dd→CMF regimen showed more grade 3–4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055).ConclusionDose-dense and -intensified neoadjuvant chemotherapy with E_dd→T_dd→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.     

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 phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours

BackgroundThis phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m²; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m², which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m² (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133.     

S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized,open-label,phase III,noninferiority trial

BackgroundCombination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS).Patients and methodsPatients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m² and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m² twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m² and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m² twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin.ResultBetween June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6–11.6) in the control group and 14.0 months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher.ConclusionS-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment.Clinical trials numberUMIN000007834     

Radiotherapy combined with cetuximab for locally advanced head and neck cancer: Results and toxicity

PurposeTo describe the clinical results and tolerance of the combined treatment with radiotherapy and cetuximab for locally advanced head and neck cancer.Patients and methodsFrom August 2006 and October 2010, 36 patients with advanced squamous cell head and neck carcinoma were treated with radiotherapy (70 Gy/35 fractions) and cetuximab (400 mg/m² one week before radiotherapy, following by 250 mg/m² once weekly, until week 7 of radiotherapy). Tolerance was evaluated every week. All patients were examined every 3 months the first 3 years after therapy, and then every year.ResultsThe median follow-up was 14 months. The majority of patients were male (31 out of 36). Mean age was 59 years. The tumours sites were: oral cavity (n = 8); oropharynx (n = 15); hypopharynx (n = 5); larynx (n = 8). Ninety percent of tumors were T3 or T4, and 45% were N2 or N3. Complete response was seen in 74% of patients, partial response in 17% and no response in 9% of patients. The overall survival was 44.4%. Relapse occurred in six patients. Anaphylactic reaction during the first infusion of cetuximab was observed in one patient. One patient developed severe aplasia after 48 Gy and 5 weeks of cetuximab, and died of sepsis. Eighty percent of patients presented acne, 16 patients developed a mucositis grade 2–3 and 23 patients a grade 2 skin reaction.ConclusionThe concomitant use of cetuximab and radiotherapy in locally advanced head and neck carcinoma is well tolerated in this group of patients. The results seem comparable to those in the literature.     

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).     

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.     

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.     

Cetuximab,gemcitabine and capecitabine in patients with inoperable biliary tract cancer: A phase 2 study

PurposeBiliary tract cancer is rare and has dismal prognosis. Chemotherapy has its role in inoperable disease but the role of targeted agents like cetuximab remains to be defined. On the basis of high epidermal growth factor receptor expression of biliary tract cancers this study aims to investigate the efficacy of cetuximab, gemcitabine and capecitabine in an exploratory phase 2 trial.Patients and methodsInoperable biliary tract cancer patients were treated with the combination of gemcitabine (1000 mg/m² on day 1 and 8), capecitabine (1300 mg/m²/d on day 1–14) and weekly cetuximab (400 mg/m² loading and 250 mg/m² maintenance dose) in 21-d cycles until progression or the appearance of intolerable side-effects.ResultsOut of 34 patients (mean age 59.7 years) accrued in this study 16 had intrahepatic, eight extrahepatic cholangiocarcinoma and 10 gall bladder cancer. The best overall response rate was 17.6% (two complete responses and four partial responses) and the clinical benefit rate was 76.5%. After a median of 15.4 months follow-up the median progression free survival was 34.3 weeks and the median overall survival was 62.8 weeks. The performance status and chemotherapy efficacy were independent and significant markers of survival. Only moderate side-effects were registered in this study. KRAS mutation was evaluable in 24 tumours, all of these were of wild type.ConclusionThe efficacy of cetuximab, gemcitabine and capecitabine combination is encouraging and a well tolerated treatment of inoperable biliary tract cancers.     

A Pilot Study of Continuous Infusional 5-Fluorouracil,Doxorubicin and Cyclophosphamide in Breast Cancer

The purpose of this study was to evaluate the toxicity and activity of continuous infusional 5- fluorouracil (5-FU) given at three dose levels in combination with cyclophosphamide and doxorubicin (FAC) in women with breast cancer.Thirty-nine patients with either primary tumours >3 cm prior to surgery (n = 24) or metastatic disease (n = 15) received cyclophosphamide 600 mg/m² and doxorubicin 50 mg/m² as an intravenous bolus every 3 weeks for six courses. Continuous infusional 5-FU was delivered via a central venous line for a maximum of 18 weeks at dose levels of 100 mg/m² per day (n = 6), 150 mg/m² per day (n = 3) and 200 mg/m² per day (n = 30).At the 200 mg/m² per day dose level, 36% of patients required dose delays and 23% dose reductions; there was one death due to neutropenic sepsis. Hickman line complications occurred at all dose levels, particularly thrombosis (18%) and infection (33%). The response rate was 62% (95% confidence interval (CI) 32–84) for metastatic disease, including five complete responses (CRs). The response rate for primary tumours prior to surgery was 81% (95% CI 57–95) including six clinical CRs.Infusional FAC is an active regimen and has an acceptable toxicity profile. It does not, however, appear to offer any significant advantage over other chemotherapy regimens. This study does not support the further evaluation of infusional 5-FU at these doses in combination with doxorubicin and cyclophosphamide.     

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS).MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m² 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m² i.v. q3wk, or doxorubicin 60 mg/m² i.v. plus ifosfamide (range, 6–9 g/m²) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point.ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.     

Randomised,placebo-controlled,double-blind,parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer

BackgroundThis phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer.Patients and methodsPatients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m² i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms.ResultsThe study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n = 275) versus 6.5 months in the gemcitabine plus aflibercept arm (n = 271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921–1.473, p = 0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%).ConclusionAdding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.     

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.     

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.Patients and methodsIn dose escalation, weekly paclitaxel (80 mg/m²) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.ResultsThe dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m² paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25).DiscussionIn this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.Clinical trial registrationClinicialTrials.gov identifier: CNCT02193633     

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: Final results of JCOG0205

BackgroundNSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection.MethodsPatients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m², l-LV 250 mg/m² on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m⁻² day⁻¹, LV 75 mg/day on days 1–28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193).FindingsBetween February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n = 550) or UFT/LV (n = 551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84–1.23), demonstrating the non-inferiority of UFT/LV (P = 0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported.InterpretationAdjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.