Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: A multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08.

BACKGROUND: Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). PATIENTS AND METHODS: This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. RESULTS: Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. CONCLUSIONS: The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

BACKGROUND: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09.

OBJECTIVE: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced non-small-cell lung cancer are promising for further investigation. METHODS: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. RESULTS: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16 cycles. PFS at 6 months was 70%, median PFS was 14 months, and ORR was 70%. Biopsy at progression was safe and successful in 71% of the cases. CONCLUSIONS: Both combination therapies were promising for further studies. Biopsy at progression was feasible and will be part of future SAKK studies to investigate molecular mechanisms of resistance.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - A twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.

Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.

BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI).

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.

BACKGROUND: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS: In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION: Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.

Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study).

Background: In ∼5% of advanced NSCLC tumours, ALK tyrosine kinase is constitutively activated after translocation of ALK. ALK+ NSCLC was shown to be highly sensitive to the first approved ALK inhibitor, crizotinib. However, all pts eventually relapse on crizotinib mainly due to secondary ALK mutations/amplification or CNS metastases. Alectinib is a highly selective, potent, oral next-generation ALK inhibitor. Clinical phase II alectinib data in 46 crizotinib-naïve pts with ALK+ NSCLC reported an objective response rate (ORR) of 93.5% and a 1-year progression-free rate of 83% (95% CI: 68-92) (Inoue et al. J Thorac Oncol 2013). CNS activity was seen: of 14 pts with baseline brain metastasis, 11 had prior CNS radiation, 9 of these experienced CNS and systemic PFS of >12 months; of the 3 pts without prior CNS radiation, 2 were >15 months progression free. Trial design: Randomised, multicentre, phase III, open-label study in pts with treatment-naïve ALK+ advanced, recurrent, or metastatic NSCLC. All pts must provide pretreatment tumour tissue to confirm ALK rearrangement (by IHC). Pts (∼286 from ∼180 centres, ∼30 countries worldwide) will be randomised to alectinib (600mg oral bid, with food) or crizotinib (250mg oral bid, with/without food) until disease progression (PD), unacceptable toxicity, withdrawal of consent, or death. Stratification factors are: ECOG PS (0/1 vs 2), race (Asian vs non-Asian), baseline CNS metastases (yes vs no). Primary endpoint: PFS by investigators (RECIST v1.1). Secondary endpoints: PFS by Independent Review Committee (IRC); ORR; duration of response; OS; safety; pharmacokinetics; quality of life. Additionally, time to CNS progression will be evaluated (MRI) for the first time in a prospective randomised NSCLC trial as a secondary endpoint. Pts with isolated asymptomatic CNS progression will be allowed to continue treatment beyond documented progression until systemic PD and/or symptomatic CNS progression, according to investigator opinion. Time to CNS progression will be retrospectively assessed by the IRC using two separate criteria, RECIST and RANO. Further details: ClinicalTrials.gov (NCT02075840). Disclosure: T.S.K. Mok: Advisory boards: AZ, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; board of directors: IASLC; corporate sponsored research: AZ; M. Perol: Advisory boards: Roche; S.I. Ou: Consulting: Pfizer, Chugai, Genentech Speaker Bureau: Pfizer, Genentech, Boehringer Ingelheim; I. Bara: Employee: F. Hoffmann-La Roche Ltd; V. Henschel: Employee and stock: F. Hoffmann-La Roche Ltd.; D.R. Camidge: Honoraria: Roche/Genentech. All other authors have declared no conflicts of interest.

Neoadjuvant chemotherapy and extrapleural pneumonectomy (EPP) of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04.

Aim: We have previously documented the feasibility of neoadjuvant chemotherapy and EPP in a multicenter trial of MPM (Weder, Ann Oncol 18: 1196, 2007). The objectives of the trimodality trial SAKK17/04 (NCT00334594) were to evaluate the time to loco-regional relapse with or without high dose hemithoracic radiotherapy in a prospective multicenter randomized phase II trial in patients with R0 and R1 resection after neoadjuvant chemotherapy and EPP. Methods: Eligible patients had pathologically confirmed MPM, surgically resectable TNM stage (T1-3 N0-2 M0), PS0-1, ages 18-70 years. Part 1 had a phase II design, and included neoadjuvant chemotherapy with 3 cycles of cisplatin and pemetrexed, followed by restaging and EPP. The primary endpoint of part 1 was complete macroscopic resection (R0-1). Part 2 randomized consenting patients with R0-1 resection into two parallel phase II arms (control arm A and radiotherapy arm B). The primary endpoint for part 2 was loco-regional relapse-free survival (RFS). To detect a 1 year increase with 80% power and 10% alpha, 37 patients were needed for arm B. Secondary endpoints included operability, tolerability of chemotherapy and radiotherapy, survival, and translational research Results: Because accrual of part 2 was slower than planned, the trial was stopped in 2013. Overall, 153 patients entered the trial, of whom 125 underwent surgery and 99 had a complete macroscopic resection (primary endpoint part 1). Of the later patients, 54 could be randomized 1:1 into each arm. Reasons for non-randomization included patient refusal in 24 and ineligibility or protocol deviations in 21. Of the 27 patients randomized to hemithoracic radiotherapy, 25 completed the treatment as planned. For part 1 the median RFS was 8.8 (95%CI: 7.3-10.7) and median OS was 15.0 (95% CI: 12.1-19.3) months. For part 2 the median local RFS for group A was 7.6 (95%CI: 5.5-10.7) and for group B 9.4 (95%CI: 6.5-11.9) months (primary endpoint part 2), while the overall RFS and OS for group A were 5.7 (95%CI: 3.5-8.8) and 16.9 (95%CI: 10.7-23.6) months and for group B 7.6 (95% CI:5.2-10.6) and 14.9 (95%CI: 7.0-17.6) months. Conclusions: This study did not reach the primary endpoint which was defined as one-year increase in loco-regional relapse-free survival and thus does not support the routine use of hemithoracic RT after neoadjuvant chemotherapy and EPP. Disclosure: All authors have declared no conflicts of interest.