Worse Adverse Events Research Articles

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

Docetaxel Plus Cisplatin and S-1 versus Cisplatin and S-1 in Patients with Advanced Gastric Cancer (JCOG1013): An Open-Label, Randomised, Phase 3 Trial

Background: We investigated the superiority of docetaxel plus cisplatin and S-1 (DCS) compared with cisplatin plus S-1 (CS) in chemotherapy-naive patients with advanced gastric cancer. Methods: This randomised, open-label, phase 3 trial was conducted at 56 hospitals in Japan. Patients were randomised (1:1) to receive DCS (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 40-60 mg twice a day for 2 weeks, every 4 weeks) or CS (cisplatin 60 mg/m2 on day 8, and S-1 40-60 mg twice a day for 3 weeks, every 5 weeks). The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMI07652. Findings: Between April 3, 2012, and March 18, 2016, 741 patients were randomised to DCS (n=370) or CS (n=371). Median overall survival was 14·2 months (95% CI 12·9-15·9) in the DCS group and 15·3 months (14·2-16·2) in the CS group (hazard ratio [HR] 0·99, 95% CI 0·85-1·16; one-sided stratified log-rank p=0·47). Median progression-free survival was 7·4 months for DCS and 6·5 months for CS (HR 0·99; 95% CI, 0·86-1·15; p=0·92), and the overall response rate was 59% for DCS and 56% for CS (p=0·50). In the safety analysis set, the most common grade 3 or worse adverse events were neutropenia (209 [58%] of 358 patients in the DCS group vs 117 [32%] of 367 patients in the CS group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). Interpretation: DCS did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, CS remains the standard first-line chemotherapy. Trial Registration Number: The study is registered with UMIN-CTR, number UMI07652. Funding: Ministry of Health, Labour and Welfare, and Japan Agency for Medical Research and Development. Declaration of Interest: YY reports personal fees from Taiho, Chugai, Eli Lilly (EL), Yakult, Nipponkayaku, Ono, Eisai, Bristol-Myers Squibb (BMS), Janssen, 1 AMED and research grant from Daiichi-Sankyo (DS). NB has received grants and honoraria from Taiho and BMS, and honoraria from Ono, Chugai, EL. JM, HF, and SK reports grants and non-financial support from MHLW and AMED, and SK personal fees from Johnson & Johnson (J&J). SI reports personal fees and others from EL and Chugai, personal fees from Taiho and Ono, others from BMS, Eisai, DS, Novartis, Merck-Serono (MS), Bayer, Otsuka. SK reports grants and personal fees from EL, Taiho, Ono, BMS, grants from Boehringer-Ingelheim (BI), personal fees from Chugai, MS, Bayer, Eisai, and Yakult. KS reports grants and personal fees from EL, Ono, Novartis, Yakult, personal fees from Astellas, BMS, Takeda, Pfizer, Novartis, and Abbvie, grants from Dainippon-Sumitomo, DS, Taiho, Chugai, and MSD. TT reports grants from AMED, Ono, BMS, Takeda, personal fees from MS and Takeda. HH reports grants from AstraZeneca, DS, Dainippon-Sumitomo, EL, MS, MSD, Taiho, Chugai, Eisai, LSK BioPharma, Incyte, Pfizer, BI, Beigene, Ono, and BMS. TY reports personal fees from Ono, BMS, EL, Taiho, Chugai, Yakult, DS, NipponKayaku, Olympus, Covidien, J&J, and Terumo. MS reports personal fees from Taiho, Chugai, EL, Ono, DS, Yakult, Merck Sharp and Dohme. MT reports personal fees from Taiho, Chugai, Ono, BMS, Yakult, Takeda, EL, Pfizer, and DS. NN, MA, KC, HH, MN, and HY have nothing to disclose. Ethical Approval: The trial protocol was approved by the JCOG Protocol Review Committee and the institutional review boards of each participating centre.

Low Dose of Human scFv-Derived BCMA-Targeted CAR-T Cells Achieved Fast Response and High Complete Remission in Patients with Relapsed/Refractory Multiple Myeloma

▪Introduction: B Cell Mature Antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy emerges as promising treatment for patients with relapse/refractory multiple myeloma (RRMM). Previous studies indicate patients who receive high-dose CAR-T cells may achieve better remission but have worse adverse events, like cytokine release syndrome (CRS). To solve this dilemma, we have developed novel autologous CAR-T therapeutics CT053 that are genetically modified T cells comprising an extracellular anti-BCMA human scFv and an intracellular 4-1BB costimulatory motif connected to a CD3-zeta T cell activation domain.Methods: A multi-center investigator-initiated clinical study is designed to evaluate CT053 in patients with RRMM who have failed in the prior treatment with ≥2 regimens, including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 monoclonal antibody. All patients have ≥50% BCMA expression on malignant cells. Patients are subjected to the lymphodepletion with 20-25 mg/m2 fludarabine and 300-500 mg/m2 cyclophosphamide daily for 2-4 days prior to receiving single-dose infusion of CT053 CAR-T cells. In case of progressive disease, patient may be dosed again on basis of investigators' evaluation of the disease status, BCMA expression and CAR-T persistence. Most enrolled patients received a single dose of 1.5 x 108 cells, except for 1 patient who received 0.5 x 108 cells and 1 patient who was infused with 1.8 x 108 cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs) and CAR T related AEs. Additional outcome measures include clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, overall and progression-free survival, pharmacokinetics and pharmacodynamic of CT053.Results: The study was performed in compliance with the declaration of Helsinki. As of the data cut-off date (July 10th, 2018), 16 patients (median 55 [39 to 67] years old) with a median of 3.9 (0.4 to 16.7) years since MM diagnosis, were infused with CT053. Patients had a median of 4 prior different regimens (range 2 to 10), and 56% (9/16) patients received prior autologous or allogeneic stem cell transplant.Among 16 patients, no neurotoxicity and no dose-limiting toxicities (DLT) were observed. The most common grade≥3 CAR-T related AEs were 3 thrombocytopenia (19%), 3 leukopenia (19%), 2 anemia (13%), 2 neutropenia (13%), 2 fever (13%) (Figure 1A). CRS was reported in 3 patients, including 1 Grade 3, 1 Grade 2 and 1 Grade 1, who had rapid recovery after Tocilizumab administration.13/16 patients were eligible for initial evaluation of early clinical response with a median observation period of 8 (4 to 36) weeks. Overall response rate (ORR) in 13/13 patients was 100% post treatment. 12/13 patients (92%) quickly achieved partial response (4 PR), very good PR (6 VGPR), and complete response (2 CR) within 4 weeks post single-dose infusion (Figure 1B). 5/12 patients (42%) who were dosed at ≥1.5 x 108 CT053 CAR-T cells obtained CR at a median of 8 weeks post treatment. Durable responses from 4 weeks towards the data cut-off date were found in 12/13 patients (92%). One relapse from VGPR by the Week 12 was reported in a patient who had aggressive RRMM at enrollment and received the reduced dose of lymphodepletion regimen at 19 mg/m2 fludarabine and 192 mg/m2 cyclophosphamide for 2 days prior to CT053 infusion. Because positive BCMA expression on malignant cells was verified at relapse, the patient was re-dosed with CT053 at the Week 16 and subjected to the further evaluation.All patients had detectable CAR-T expansion from Day 3 post CT053 infusion. Expansion peaks were found on Day 7 (5/13), Day 14 (6/13) and Day 21 (2/13). 11/13 patients had notable persistence of CT053 CAR-T cells up to 4-6 months. The only relapsed patient had the lowest CAR-T expansion peak among 13 patients, indicating the potential correlation between CAR-T expansion and response outcome.Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT053 CAR-T cells. Major AEs were transient, manageable, and reversible. 100% ORR in 13/13 evaluable patients were reported post single-dose infusion of 0.5~1.8 x 108 cells. 5/12 patients who were dosed at ≥1.5 x 108 CAR-T cells rapidly achieved durable CR at median of 8 weeks, suggesting CT053 could be developed as competitive therapeutics to treat patients with RRMM. DisclosuresRuan:CARsgen Therapeutics: Employment. Xiao:CARsgen Therapeutics: Employment, Equity Ownership. Wang:CARsgen Therapeutics: Employment, Equity Ownership. Li:CARsgen Therapeutics: Employment, Equity Ownership.

Total neoadjuvant treatment (CAPOX plus radiotherapy) for patients with locally advanced rectal cancer with high risk factors: A phase 2 trial

Background and purposeTo evaluate the safety and efficacy of Total neoadjuvant treatment (TNT) in patients with rectal cancer with high risk factors. Methods and materialsWe did this phase 2 trial in patients who were diagnosed with stage II–III rectal cancer with at least one of the high risk factors. Three cycles of induction CAPOX were followed by pelvic radiotherapy of 50.4 Gy/28 fractions and two cycles of concurrent CAPOX. Three cycles of consolidation CAPOX were delivered after radiotherapy. Primary endpoints were pathological complete response (pCR) and R0 resection. ResultsFifty patients were enrolled and 47 patients were evaluable. A total of 34 patients (72.3%) completed 6 to 8 cycles of chemotherapy and 46 patients (98%) completed the planned radiotherapy. 17 patients (36%) achieved a pCR or clinical complete response (cCR). Three cCR patients (6.4%) refused the operation and selected a watch-and-wait approach. The most common grade 3 or worse adverse events were leucopenia (10.6%) and radiation dermatitis (6.4%). The major surgical complications included pelvic abscesses/infection in 2 patients (4.3%), anastomotic leakage and hemorrhage in1 patient (2.2%), respectively, which were all addressed with conservative management. ConclusionsTNT is effective and safe in patients with locally advanced rectal cancer with high risk factors. Long-term efficacies of TNT need to be further evaluated.This trial is registered with Chinese Clinical Trial Registry, number ChiCTR-OIN-17012284.

Quality of Life Outcome in Patients with Localized Prostate Cancer after Hypofractionatied Carbon-Ion Radiation Therapy

Carbon ion radiotherapy (C-ion RT) has excellent dose conformity and greater biological effectiveness than X-ray and proton beam. Moreover hypofractionatied schedule is better than conventional fractionated schedule to treat prostate cancer (PC) from the view point of biological aspect. The excellent outcome of C-ion RT for the patients with localized PC was already published. In our country, national health insurance has started to cover C-ion RT for localized PC since April 2018. Our hypothesis is that quality of life (QOL) outcome is maintained after hypofractionatied C-ion RT. The purpose of this study is to assess QOL outcome of the patients with localized PC received hypofractionatied C-ion RT. QOL outcome of 213 patients with localized PC received C-ion RT from August 2013 to July 2014 were analyzed. The prescribed dose of the C-ion RT was 51.6 Gy (RBE) in 12 fractions in 3 weeks. The median age at the time of the C-ion RT was 68 (range 46-88). The number of the patients of low, intermediate and high risk according to D’Amico criteria were 28 (13.1%), 82 (38.5%) and 103 (48.4%), respectively. Out of the 213 patients, 186 patients (87.3%) received hormonal therapy (HT). Two QOL assessment questionnaires of International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) were used at 6 points; before the C-ion RT, the last day of the C-ion RT, and 6, 12, 24 and 36 months after the C-ion RT. Among a subgroup of the 23 low risk patients not received any HT, the EPIC sexual domain was assessed in addition. The median follow-up time was 38.3 months (range 0.7-52.1). At the time of this analysis, 9 patients recurred and no patient experienced grade 3 and worse adverse event. The EPIC scores were available for 97.7%, 90.6%, 86.9%, 85.0%, 80.8% and 75.1% at the 6 points as above, respectively. The average IPSS and EPIC scores of the analyzed 213 patients are noted in the table. The IPSS score and the EPIC urinary score worsened temporarily during the C-ion RT and recovered to the baseline level. The EPIC bowel, sexual and hormonal scores did not change. The EPIC sexual scores of the subgroup of the 23 low risk patients not received any HT are also noted in the table, the score slightly worsened temporarily during the C-ion RT and recovered to the baseline level.Abstract SU_35_2341; Table 1The average scores of IPSS and EPICBefore the C-ion RTThe last day of the C-ion RT6 months12 months24 months36 monthsIPSS7.912.26.76.75.32.6EPICUrinary91.584.691.691.792.493.6Bowel93.892.394.194.592.794.2Sexual33.332.835.136.037.538.8(subgroup*Twenty-three low-risk patients not received any HT.)43.741.346.945.447.644.2Hormonal83.384.385.788.791.093.0∗ Twenty-three low-risk patients not received any HT. Open table in a new tab It is suggested that the QOL outcome of the patients with localized PC is well maintained after the hypofractionatied C-ion RT. Further studies are required to asses QOL outcome more precisely especially sexual function because most patients in this analysis received HT.

Strontium-89 Chloride Delivery for Painful Bone Metastasis in Patients with History of Previous Radiation

Re-irradiation of previously irradiated site must be done with careful consideration to minimizing dose to organs at risk. In particular, re-irradiation of the spine carries significant morbidity due to risk of myelitis. Strontium-89 chloride (Sr-89) is widely used for treatment of painful bone metastasis. The purpose of this study is to evaluate pain response and safety of Sr-89 administration for painful bone metastasis in the setting of prior radiation. After institutional review board approval, records of patients who received Sr-89 injection for painful bone metastasis in previously irradiated sites were retrospectively reviewed. Patients with follow-up of less than 1 month were excluded from analysis. Efficacy of pain control was evaluated with the verbal rating scale (VRS), documentation of the analgesic dose employing the World Health Organization (WHO) pain relief ladder. Adverse events were measured using CTCAE v4.0. Twenty-three patients met study inclusion criteria, of which 12 were male and 11 were female. Median age at treatment was 69 years (50-83). Primary sites were lung (n=11), prostate (n=3), breast (n=2), uterine cervix (n=2), kidney (n=1), and other (n=4). Median follow-up was 8 (1-49) months. Twelve patients treated with SR-89 had prior history of palliative radiation therapy for bone metastasis. The remainder had received radiation for non-bony metastasis as follows: concurrent chemo-radiotherapy (CCRT) for lung cancer (n=7), post-operative radiotherapy to regional lymph nodes of breast cancer (n=1), pre-operative CCRT for rectal cancer (n=1), radical CCRT for cervical cancer (n=1), and radiotherapy to tumor bed for recurrent prostate cancer (n=1). Prior to administration of Sr-89, the VRS grade of 0/1/2/3 was n=1/5/12/5, respectively. Analgesic score 0/1/2/3/4/5/6 was n=3/9/2/4/3/1/1, respectively. After administration of Sr-89, VRS grade didn’t change in 3 patients, and improved in 20; 17 occurred after 1 month, 2 after 2 months, and 1 after 3 months. Analgesic score didn’t change in 15 but improved in 8 patients; 4 after 1 month, 2 after 2 months, 2 after 3 months. In two patients neither the VRS nor the analgesic score improved and in two patients the VRS improved but the analgesic score increased, hence difficult to evaluate efficacy of SR-89. This made the response rate of evaluable patients 90.1%. Flare phenomenon was observed in 3 patients, but all were controlled with analgesic and improved within one week. No grade 2 or worse adverse events was observed. Administration of strontium-89 chloride to patients with painful bone metastasis at previously irradiated sites is an effective and safe treatment options for palliation of symptoms at the end of life.

Efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer.

The treatment efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer is unclear. We defined refractory relapse as treatment-free interval <90 days and poor-risk as Eastern Cooperative Oncology Group Performance Status ≥2. We retrospectively examined the medical record data of patients who were treated at our hospital between September 2002 and December 2014. Twenty-three poor-risk patients with refractory-relapsed small-cell lung cancer were treated in our hospital. The characteristics of patients at the time of first-line treatment were as follows: median age (range) 71 (57-83) years; male 74%; extensive disease 96%; proportion of patients with PS 0 or 1 and those with 2-4 was 43 and 57%, respectively; median treatment-free interval 26 days. Amrubicin was the most commonly used drug and was administered in 15 patients (65%). The overall response rate of all patients was 22%. Median progression-free survival and overall survival was 2.2 and 3.7 months, respectively. Among patients treated with amrubicin, overall response rate was 13%, median progression-free survival was 2.2 months, and median overall survival was 3.9 months. The most common grade 3 or worse adverse events were hematologic toxicities, including leukopenia (66%), neutropenia (69%), thrombocytopenia (9%) and anemia (22%). Febrile neutropenia was observed in two patients (9%). Second-line chemotherapy might have poor efficacy to poor-risk patients with refractory-relapsed small-cell lung cancer.

Feasibility of a novel liquid fiducial marker for use in image guided radiotherapy of oesophageal cancer.

To evaluate the feasibility of a new liquid fiducial marker for use in image-guided radiotherapy for oesophageal cancer. Liquid fiducial markers were implanted in patients with metastatic or inoperable locally advanced oesophageal or gastro-oesophageal junction cancer receiving radiotherapy. Markers were implanted using a conventional gastroscope equipped with a 22 G Wang needle. Marker visibility was evaluated on fluoroscopy, CT, MRI and conebeam CT scans. Liquid markers (n = 16) were injected in four patients. No Grade 2 or worse adverse events were observed in relation to the implantation procedure, during treatment or in the follow-up period. 12/16 (75%) markers were available at the planning CT-scan and throughout the treatment- and follow-up period. The implanted markers were adequately visible in CT and cone beam CT but were difficult to distinguish in fluoroscopy and MRI without information from the corresponding CT image. Liquid fiducial marker placement in the oesophagus proved safe and clinically feasible. This paper presents the first clinical use of a new liquid fiducial marker in patients with oesophageal cancer and demonstrates that marker implantation using standard gastroscopic equipment and subsequent use in three-dimensional image-guided radiation therapy is safe and clinically feasible.

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial

Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. AstraZeneca.

Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study

Twice a week carfilzomib at 27 mg/m2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib. In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m2) or twice a week (27 mg/m2). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m2 day 1 [cycle 1]; 70 mg/m2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 days 1 and 2 during cycle 1; 27 mg/m2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1-9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients. Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6-13·0] vs 7·6 months [5·8-9·2]; hazard ratio [HR] 0·69, 95% CI 0·54-0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff. Once weekly carfilzomib at 70 mg/m2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma. Amgen, Inc.

AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial.

1007 Background: The PI3K/AKT signalling pathway is frequently activated in triple-negative breast cancer (TNBC). AZD5363 is a highly-selective, oral, small molecule AKT inhibitor. The PAKT trial investigated the addition of AZD5363 to paclitaxel as 1st-line therapy for TNBC. Methods: This investigator-led, double-blind, placebo-controlled, randomised phase II trial, recruited women with previously untreated, metastatic TNBC at 42 sites in 6 countries. Patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, & 15) with either AZD5363 (400mg BD) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), PFS in the subgroup with PIK3CA/AKT1/PTEN-alterations, response, and safety. Results: Between 05/2014 and 06/2017, 140 patients were randomised to paclitaxel + AZD5363 (n = 70) or paclitaxel + placebo (n = 70). Median duration of follow-up was 18.2 months (95% CI, 13.6 to 24.0). In the ITT analysis, median PFS was 5.9 months (m) for AZD5363 compared to 4.2m for placebo (hazard ratio [HR], 0.75; 95% CI, 0.52 to 1.08; one-sided p = 0.06; two-sided p = 0.11 [predefined significance level of 0.10, one-sided]). Median OS was 19.1m for AZD5363 compared to 12.6m for placebo (HR, 0.64; 95% CI, 0.40 to 1.01; one-sided p = 0.02; two-sided p = 0.04). Results for the subgroup with PIK3CA/AKT1/PTEN-altered tumours will be presented. Most common grade 3 or worse adverse events were diarrhoea (12% [8/68] of AZD5363-treated patients vs 1% [1/70] of placebo-treated patients), infection (4% vs 1%), neutropenia (3% vs 3%), rash (4% vs 0) and fatigue (4% vs 0). Conclusions: The trial met its primary endpoint. Addition of AZD5363 to 1st-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. AZD5363 warrants further investigation for the treatment of TNBC. Clinical trial information: NCT02423603.

Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial

Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed. Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients. Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. Sanofi.

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial

SummaryBackgroundAlthough women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer.MethodsPORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.Results686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1–73·1). 5-year overall survival was 81·8% (95% CI 77·5–86·2) with chemoradiotherapy versus 76·7% (72·1–81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54–1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3–79·9) versus 68·6% (63·1–73·4; HR 0·71, 95% CI 0·53–0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity.InterpretationAdjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival.FundingDutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

Randomized phase II study to compare docetaxel plus S-1 with cisplatin plus S-1 in advanced gastric cancer without measurable lesions (HERBIS-3).

119 Background: Cisplatin and S-1 (CS) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. Docetaxel is a well-known agent with high anti-tumor effect for peritoneal metastasis from gastric cancer. A previous phase III study showed docetaxel plus S-1 (DS) regimen was recommended especially for advanced gastric cancer without measurable lesions. However, there was no study comparing the efficacy and safety of these two regimens. Methods: Eligibility criteria included HER2-negative unresectable or recurrent gastric adenocarcinoma, no measurable lesion according to RECIST v1.1, no massive peritoneal metastasis, no prior chemotherapy or radiotherapy, age ≤75, PS 0-2, adequate oral intake, and preserved organ functions. Patients were randomized to receive CS (cisplatin 60 mg/m² on day 8, S-1 40–60 mg twice a day for 3 weeks, every 5 weeks) or DS (docetaxel 40 mg/m² on day 1, S-1 40–60 mg twice a day for 2 weeks, every 3 weeks). Primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and adverse events. Results: Sixty-one patients were randomly allocated the CS group (n = 31) or the DS group (n = 30) between Aug 2011 and Sep 2015. All were unresectable primary cases, and baseline characteristics were well balanced between the two groups. One patient was ineligible due to HER2-positive. There was no treatment-related death. The main grade 3 or worse adverse events were neutropenia (27% in CS vs. 40% in DS), anemia (10% in CS vs. 10% in DS), fatigue (13% in CS vs. 7% in DS), anorexia (10% in CS vs. 3% in DS), and diarrhea (10% in CS vs. 3% in DS). The median OS time were 15.8 months in CS and 20.0 months in DS, respectively (log-rank P = 0.113). Hazard ratio for OS was 0.617 (95%CI, 0.337 – 1.128). The median PFS time were 9.6 months in CS and 11.2 months in DS, respectively (log-rank P = 0.196). Hazard ratio for PFS was 0.698 (95%CI, 0.404 – 1.208). Conclusions: DS showed less toxic and more active profiles than CS for treatment of advanced gastric cancer without measurable lesions. The clinical benefit of DS regimen should be demonstrated in a phase III study. Clinical trial information: UMIN000006179.

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials

Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma. We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797. Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths. Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted. Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.

Prevalence of Gilbert Syndrome in Bangladesh

Background: Gilbert syndrome (GS) is characterized by an elevated serum bil-irubin due to a polymorphism in Uridine Diphosphate Glucuronosyl Transferase (UGT1A1) gene. Several studies have found high prevalence of Gilbert Syn-drome in some Asian countries but still haven’t explored in Bangladesh. Aim of this study was to determine the allele frequencies of two different variants of UGT1A1 polymorphisms (UGT1A1 6 and UGT1A1 28) among Bangladeshi population. Materials and method: Total 150 unrelated volunteer from outpa-tient unit of the Central Hospital Limited, and Bangabandhu Sheikh Mujib Medical University, Dhaka were enrolled in this study. Peripheral blood was obtained from each subject and DNA extraction was done by Genomic DNA Isolation Kit. Polymorphisms of UGT1A1*6 (c.211G>A) was genotyped using the TaqMan Assay-on-Demand SNP Typing System and UGT1A1*28 (c.-53_-52TA) promoter repeat number polymorphism was determined by PCR method on an ABI PRISM 3130 Genetic Analyzer. Results: 57.3% of the study participants were male, mean age of them was 4.05 years. Minor allele fre-quency (MAF) was 0.442 (44.2%) for UGT1A1*28 and 0.047 (4.7%) for UGT1A1*6. Conclusion: This is the first ever study conducted among Bangla-deshi population to identify the Gilbert syndrome and found very high prevalence. Drugs those who are conjugated by UGT1A1 may lead to worse adverse event due to UGT1A1 polymorphism. Infants having decreased UGT1A1 enzyme activity develop neonatal jaundice and its further complication like Ker-nicterus. Higher incidence of Gilbert syndrome among Bangladeshi might be the alert for the clinicians treating neonatal jaundice.

Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial

The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib. In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA. Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a day with at least one of grade 3 thrombocytopenia, anaemia, or bleeding at grade 3 or worse, with palpable spleen of at least 5 cm and without grade 2 or greater peripheral neuropathy were included in the study. Patients were randomly assigned (2:1) to either 24 weeks of open-label momelotinib 200 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions), after which all patients could receive extended momelotinib treatment. Patients were randomly assigned to treatment by an interactive web response system and the randomisation was stratified by transfusion dependence and by baseline total symptom score (TSS). Results were analysed on an intention-to-treat basis. The primary endpoint was a reduction by at least 35% in the spleen volume at 24 weeks compared with baseline. Safety analyses included adverse event monitoring. The trial is registered with ClinicalTrials.gov, number NCT02101268. Between June 19, 2014, and July 28, 2016, 156 patients were recruited to the study; 104 received momelotinib and 52 received BAT. BAT was ruxolitinib in 46 (89%) of 52 patients. 73 (70%) of 104 patients in the momelotinib group and 40 (77%) of 52 patients in the BAT group completed the 24-week treatment phase. Seven (7%) of 104 patients in the momelotinib group and three (6%) of 52 in the BAT group had a reduction in the spleen volume by at least 35% compared with baseline (proportion difference [Cochran-Mantel-Haenszel method], 0·01; 95% CI -0·09 to 0·10), p=0·90). The most common grade 3 or worse adverse events were anaemia (14 [14%] of 104 in the momelotinib group vs seven [14%] of 52 in the BAT group), thrombocytopenia (seven [7%] vs three [6%]), and abdominal pain (one [1%] vs three [6%]). Peripheral neuropathy occurred in 11 (11%) of 104 patients receiving momelotinib (one of which was grade 3) and in no patients in the BAT group. Serious events were reported for 36 (35%) patients in the momelotinib group and 12 (23%) of patients in the BAT group. Deaths due to adverse events were reported for six patients (6%) receiving momelotinib (acute myeloid leukaemia [n=2], respiratory failure [n=2, with one considered possibly related to momelotinib], cardiac arrest [n=1, considered possibly related to momelotinib], and bacterial sepsis [n=1]); and four patients (8%) receiving BAT (lung adenocarcinoma [n=1], myelofibrosis [n=1], and sepsis [n=2]). In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the reduction of spleen size by at least 35% compared with baseline. Gilead Sciences, Inc.

Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial

Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population. Acerta Pharma, a member of the AstraZeneca Group.

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404

ObjectiveIn advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. Materials and methodsUntreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level −1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. ResultsNineteen patients were enrolled (level 0:5, level −1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level −1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level −1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. ConclusionAfatinib plus bevacizumab (level −1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study

Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC. We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8-44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9-32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6-22·3]; hazard ratio [HR] 0·60, 95% CI 0·42-0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.