phase-II Trial Research Articles

Contrast-enhanced Sonothrombolysis to Accelerate Treatment of Acute Peripheral Arterial Occlusions: The Preliminary Results of the Must Trial (A Feasibility and Safety Phase-II Trial)

Introduction: Catheter-directed thrombolysis is a well-established less-invasive alternative to surgical thrombo-embolectomy. However, the risk of hemorrhagic events in patients with an acute peripheral arterial occlusion remains high with up to 10% of patients experiencing bleeding complications, 2% of which are intracranial hemorrhages. The addition of microbubbles and ultrasound (i.e. contrast enhanced sonothrombolysis) could make the thrombus more susceptible for thrombolysis. We are the first to investigate the safety and technical feasibility of this therapy in patients with an acute peripheral arterial occlusion. Methods: The MUST (Microbubble-accelerated sonothrombolysis) trial is a single-centre phase-II trial focusing on patients with acute peripheral arterial occlusions. In this study, 20 patients will receive intravenous infusion of microbubbles and ultrasound in the first hour of the thrombolytic therapy. Primary endpoints are mortality and other serious adverse events. Secondary endpoints are technical, angiographic and clinical success, conversion, additional interventions, treatment duration and complications. During hospitalization, treatment efficacy will be monitored by daily angiography, duplex examination every six hours, ankle-branchial index, microcirculation and pain scores. Results: Currently, we have included 7 out of 20 patients. No mortality or serious adverse events related to the experimental treatment occurred. In 6 patients, thrombolysis was successful and revascularisation was established after 52.3 hours (range 8.0-81.0). The total therapy duration was on average 70.8 hours (range 49.5-99.5). Additional endovascular interventions included three percutaneous transluminal angioplasties and one thrombosuction. In one patient, open surgical treatment was required after 24 hours of unsuccessful thrombolysis due to no inflow in an occluded iliaco-crucal prosthetic bypass proximal of the treated lesion. Conclusion: Preliminary results show promising study outcomes without major complications. We report no mortality or treatment-related serious adverse events. Further inclusions are necessary to evaluate the safety and feasibility of contrast-enhanced sonothrombolysis for patients with acute peripheral arterial occlusions. Successive studies would help to determine the success of this treatment and its applicability in clinical practice worldwide.

Rituximab and Bendamustine for First-Line Treatment of Frail or Elderly Patients with Aggressive B-Cell Lymphoma: Final Results of the Prospective Phase-II Brenda Trial of GLA (German Lymphoma Alliance)

Rituximab and Bendamustine for First-Line Treatment of Frail or Elderly Patients with Aggressive B-Cell Lymphoma: Final Results of the Prospective Phase-II Brenda Trial of GLA (German Lymphoma Alliance)

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

PDTM-36. WHOLE EXOME SEQUENCING (WES) OF DIPG PATIENTS FROM THE BIOMEDE TRIAL REVEALS NEW PROGNOSTIC SUBGROUPS WITH SPECIFIC ONCOGENIC PROGRAMMES

Abstract BACKGROUND & METHODS. The BIOlogical MEdicines for DIPG Eradication (BIOMEDE) trial is a randomized multi-arm multi-stage program (drop-the-loser adaptive design). The first trial was an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets. All patients underwent a biopsy at diagnosis to confirm the DIPG molecularly and establish the expression of pre-specified biomarkers. Patient samples were explored by WES with a sequencing depth average >100X for the tumor and >60X for the blood. RESULTS. Unsupervised clustering of copy-number-variations (CNV) identified 4 groups corresponding to a new stratification of DIPG: cluster 1 (n=42) with high CNV, cluster 2 (n=23) with chromosome 1q + chromosome 2 gains, cluster 3 (n=9) with low CNV and cluster 4 (n=21) with isolated 1q gain. Clusters 1 had higher hazard-ratio for death than the others (mean HR 1.959, range 1.054–3.643, p< 0.0001, adjusted Cox model). Extensive structural rearrangements/chromotrypsis were significantly more frequent in TP53-mutated samples. Indeed, when stratiftying patients in 4 groups based on type of histone H3 mutated at K27 and the presence of a TP53 pathway alteration the subgroup with TP53 altered pathway had a significantly higher hazard-ratio for death than the others (mean HR 3.450, p=0.0017, adjusted Cox model). Additional drug targets were identified, especially in the DNA repair machinery that could be exploited for new targeted therapies. CONCLUSION. WES at diagnosis was feasible in most patients and brings new prognostic and theranostic informations. This allows a better patients stratification and the development of personalized medicine in DIPG.

PDCT-01. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMAS ERADICATION (BIOMEDE): RESULTS OF THE THREE-ARM BIOMARKER-DRIVEN RANDOMIZED TRIAL IN THE FIRST 230 PATIENTS FROM EUROPE AND AUSTRALIA

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets) with a planned sample size of 250 patients. A stereotactic biopsy was performed at diagnosis to centrally confirm the diagnosis of DIPG (presence of histone H3K27M mutation or loss of K27 trimethylation) and assess biomarkers/targets (PTEN-loss, EGFR-overexpression). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. The main objective of the study was to compare the efficacy of randomized groups in terms of overall survival (OS). RESULTS At the 3rd interim analysis, based on 193 randomized patients among the 230 study patients, the IDMC concluded that the study was unlikely to meet its primary objective even if 250 patients were randomized. The median OS from the time of randomization was 10.9, 9.5 and 9 months for everolimus, dasatinib and erlotinib, respectively, which is comparable to historical controls. The median number of courses administered was 7, 5.5 and 6 respectively. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. CONCLUSION BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next step, BIOMEDE 2.0.

Booster vaccination with a fractional dose of an oral cholera vaccine induces comparable vaccine-specific antibody avidity as a full dose: A randomised clinical trial

Antibody avidity is an important measure of the quality of vaccine-induced immune responses. Murine and human studies suggest that antibody avidity may be augmented by limiting access to antigen. The primary objective of this study was to evaluate in primed Swedish adults if booster vaccination with fractional doses (1/5th and 1/25th) of a model oral vaccine, the cholera vaccine Dukoral®, results in higher avidity antibody responses compared to boosting with a full vaccine dose. We also evaluated if fractional booster vaccination elicited similar magnitudes of antibody response compared to a full dose, and if the previously observed increase in antibody avidity after booster vaccination 1–2 years later occurred when boosting after a shorter interval.To this end, a randomised, open-label, exploratory Phase-II trial was performed. Swedish adults (n = 44), primed with two full doses of Dukoral®, were randomised into three groups and given a booster dose at either full (n = 14), 1/5th (n = 17) or 1/25th (n = 13) dose four months later. Antibody responses to cholera toxin B-subunit (CTB) were measured in serum and mucosal antibody in lymphocyte secretions (ALS).We found that the 1/5th and 1/25th booster doses had similar abilities as the full dose to induce significantly higher avidity anti-CTB antibody responses in both ALS and serum samples, as compared to after priming vaccination. There was a non-significant trend to lower magnitudes of ALS and serum IgA responses after the 1/5th compared to the full booster dose, and responses after the 1/25th dose were significantly lower.Our findings suggest fractional booster doses of Dukoral® four months after priming result in anti-toxoid mucosal antibody responses with increased antibody avidity compared to after priming vaccinations.ISRCTN registry identifier 11806026.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Efficacy and Feasibility of Adding Induction Chemotherapy to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer: A Phase II Clinical Trial.

PurposeCurrently, neoadjuvant chemoradiation (CRT) followed by total mesorectal resection is considered the standard of care for treating locally advanced rectal cancer. This study aimed to investigate the efficacy and feasibility of adding induction chemotherapy to neoadjuvant CRT in locally advanced rectal cancer.MethodsThis phase-II clinical trial included 54 patients with newly diagnosed, locally advanced (clinical T3–4 and/or N1–2, M0) rectal cancer. All patients were treated with 3 cycles of preoperative chemotherapy using the XELOX (capecitabine + oxaliplatin) regimen before and after a concurrent standard long course of CRT (45–50.4 Gy) followed by standard radical surgery. Pathologic complete response (PCR) rate and toxicity were the primary and secondary endpoints, respectively.ResultsThe study participants included 37 males and 17 females, with a median age of 59 years (range, 20–80 years). Twenty-nine patients (54%) had clinical stage-II disease, and 25 patients (46%) had clinical stage-III disease. Larger tumor size (P = 0.006) and distal rectal location (P = 0.009) showed lower PCR compared to smaller tumor size and upper rectal location. Pathologic examinations showed significant tumor regression (6.1 ± 2.7 cm vs. 1.9 ± 1.8 cm, P < 0.001) with 10 PCRs (18.5%) compared to before the intervention. The surgical margin was free of cancer in 52 patients (96.3%). Treatment-related toxicities were easily tolerated, and all patients completed their planned treatment without interruption. Grade III and IV toxicities were infrequent.ConclusionThe addition of induction chemotherapy to neoadjuvant CRT is an effective and well-tolerated treatment approach in patients with rectal cancer.

Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

Glycemic impact of a diet and lifestyle intervention on diabetics and prediabetics during treatment for non-muscle invasive bladder cancer

Introduction: Patients with Type II Diabetes Mellitus (DM2) have increased risk of recurrence and progression of non-muscle invasive bladder cancer (NMIBC). Glucose control through lifestyle intervention is an uninvestigated, attractive strategy to decrease risk of cancer recurrence. We test the feasibility of a diet and exercise program and its glycemic impact in patients with DM2 and NMIBC.Materials/methods: Five participants with NMIBC and pre-diabetes or DM2 were recruited for a pilot, prospective clinical trial. Each participant received dietary counseling for 16 sessions during clinical visits. The intervention included a carbohydrate-restricted (CR) diet (<130 grams per day), 30 min, walking 5×/wk, and 5000 steps daily. Diet compliance was measured with 24-hour diet recall. Exercise was monitored with accelerometer and self-report.Results: Five participants enrolled and two participants completed the 12-month intervention. Adherence was 60% to CR diet and 84% to exercise goals. Participants reduced carbohydrate consumption by 44%. Participants showed reductions in fasting blood glucose, HbA1c, glucosuria, fasting blood insulin, and body weight, and increased euglycemia on continuous glucose monitoring.Conclusions: Adherence to a CR diet and exercise goals is feasible in patients with NMIBC and DM2 and also leads improved glucose control. A phase-II trial on bladder cancer-specific outcomes is warranted.

The therapeutic effects of 1540-nm nonablative fractional erbium laser on macular amyloidosis: a randomized clinical trial

Objective This aim of this study was to determine the effect of 1540-nm nonablative fractional erbium on macular amyloidosis. Methods This phase-II clinical trial study has been performed with parallel group with blinding of the evaluator. The skin lesions of the patients (15 patients and 30 lesions) with cutaneous macular amyloidosis were randomly assigned into laser and no-treatment groups. In the laser group, treatment was performed by 1540-nm nonablative fractional erbium laser. Thereafter, the patients’ lesions were compared in terms of pigmentation, rippling, thickness, and subjective response. Results The lesions of the intervention group significantly improved in the three-month follow-up compared to the control group (in the control and intervention group, improved pigmentation was observed in 20 and 53.3% with p = .02, improved rippling in 6.7 and 60% with p = .007, diminished lichenification in 0 and 53.1% with p = .007, and overall lesion improvement in 20 and 60% with p = .03, respectively). In investigating the subjective response through patient global assessment, the patients in the intervention group had a greater satisfaction (p = .01). There was a considerable improvement of pruritus in the intervention group (p = .001). Conclusions Use of 1540-nm nonablative fractional erbium laser offered a suitable efficacy to treat macular amyloidosis without significant complications.

Suprafascial Vancomycin Powder for Prevention of Surgical Site Infections After Instrumented Posterior Spinal Fusion: A Randomized Controlled Phase-II Trial

Suprafascial Vancomycin Powder for Prevention of Surgical Site Infections After Instrumented Posterior Spinal Fusion: A Randomized Controlled Phase-II Trial

Accelerated hypofractionated radiotherapy plus chemotherapy for inoperable locally advanced non-small-cell lung cancer: final results of a prospective phase-II trial with a long-term follow-up

BackgroundConcurrent chemotherapy and radiation using conventional fractionation is the standard treatment for inoperable, locally advanced non-small-cell lung cancer (NSCLC). We tested accelerated hypofractionated radiotherapy (AHR) and chemotherapy for the treatment of locally advanced NSCLC.MethodsEligible patients with locally advanced NSCLC were treated with induction chemotherapy (cisplatin and docetaxel), followed by AHR using tomotherapy and consolidation chemotherapy. The prescribed doses were 30 Gy/5 daily fractions at the reference isodose (60–70%) to the tumor, and 25 Gy/5 daily fractions to the clinically involved lymph nodes. The primary end-point was response rate (RR); the secondary end-points were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS). This trial closed before the first planned interim analysis due to poor accrual.ResultsFrom January 2009 to January 2012, 17 of the 23 enrolled patients were evaluable. Treatment yielded an overall RR of 82%. Median follow-up was 87 months (range: 6–87), local PFS was 19.8 months (95% CI 9.7 - not reached), MFS was 9.7 months (95% CI 5.8–46.0) and OS was 23 months (95% CI 8.4–48.4). 70% of patients experienced acute G4 neutropenia, 24% G4 leukopenia, 24% G3 paresthesia, 4% G3 cardiac arrythmia, 4% underwent death after chemotherapy. Late toxicity was represented by 24% dyspnea G3.ConclusionsAHR combined with chemotherapy is feasible with no severe side-effects, and it appears highly acceptable by patients.Trial registrationThis study is registered with the EudractCT registration 2008-006525-14. Registered on 9 December 2008.

Stratified monotherapy approach according to MGMT methylation status in elderly patients with glioblastoma.

2050 Background: The elderly patients with glioblastoma have an extremely poor prognosis. As they often have some degree of age-related vulnerability, it is especially important to minimize a risk of treatment-related adverse events by optimizing treatment intensity for this population. We conducted phaseⅡ clinical trial to investigate the efficacy of stratified monotherapy approach according to O6-methylguanine-DNA methyltransferase (MGMT) methylation status in elderly patients with glioblastoma. Methods: Patients aged 70 years or older with Karnofsky performance status (KPS) of at least 60 were eligible for this study. MGMT methylation status was quantitatively assessed by pyrosequencing based on the average methylation ratio of 16 CpG sites in the MGMT gene promoter. The patients with highly methylated MGMT promoter defined as an average methylation ratio with 30% or higher were treated with temozolomide (TMZ) monotherapy (standard 5/28 regimen), while the others with low or intermediate levels of MGMT promoter methylation were treated with radiation therapy (40Gy/15fr) alone. Results: Between April 2013 and December 2017, 70 patients were enrolled in this study. Median age was 78 years (70-91) and median KPS was 60 (60-100). Of 70 patients, 19 patients with highly methylated MGMT promoter received TMZ monotherapy, while the remaining 51 patients were treated with radiation therapy. Median progression-free survival (PFS) and median overall survival (OS) were 7.5 and 17.4 months in the TMZ group, respectively. Median PFS and median OS were 4.6 and 10.4 months in the radiotherapy group, respectively. Conclusions: For elderly glioblastoma patients with highly methylated MGMT promoter, TMZ monotherapy could be a treatment option. Clinical trial information: UMIN000012172.

The SUNEVO (GETNE-1408) trial to evaluate the activity and safety of thecombination of sunitinib with evofosfamide (TH-302) in patients with G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve forsystemic treatment: A phase II study of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumors (GETNE).

4105 Background: Angiogenesis plays an important role in tumorigenesis and progression of pNETs. Evofosfamide (EVO) is a DNA alkylator prodrug that selectively activates under hypoxia. Sunitinib as monotherapy shows a wide range of responses (9-24%) in similar populations. We hypothesized that sunitinib-induced hypoxia might increase the cytotoxic activity of EVO in patients with metastatic pNETS and naïve for systemic treatment other than somatostatin analogues (SSA). Methods: This is a phase-II, single-arm, and multicenter trial of EVO (340mg/m2 on days 8, 15 and 22 every 4 weeks) and sunitinib (37.5mg/day continuously). Primary endpoint was Objective Response Rate (ORR) by RECIST v1.1 assessed every 8 weeks. A Simon two-stage optimal design was used, considering a minimum of 3 responses in the first 18 pts in order to start with the second stage (power = 0.80, alpha = 0.05). Results: Between May/2015 and May/2018, 17 pts were included (median age was 62.4 y.o). Prior SSA was reported in 7 (41.2%) pts and 8 (47.1%) had a Ki-67 &gt; 10%. There were 2 responders (11.8%; n = 1 complete and n = 1 partial response); stable disease was observed in 76.5%. Median (range) PFS and duration of response were 10.4 months (m) (2.9-17.9m) and, respectively 24.4m (13.7-35.2m), respectively. Grade 3 or 4 adverse events occurred in 11 (64.7%) pts, being neutropenia (33.3%), fatigue (16.7%), thrombocytopenia (11.1%), hand-foot syndrome (5.6%), and pancreatitis (5.6%) the most frequent. Toxicity led to treatment discontinuation in 5 (38.5%) pts. Dose reductions were reported in 20% (sunitinib) and 100 % (EVO) of pts. Conclusions: Combination of sunitinib and EVO failed to demonstrate activity in terms of tumor shrinkage as only two patients achieved response, therefore, second stage was not proceeded. While cross trial comparisons are difficult, response rate of 12% with the combination was disappointing. Concerns over toxicity arose; translational analysis are undergoing. Clinical trial information: NCT02402062.

Feasibility and toxicity of neoadjuvant nivolumab with or without ipilimumab prior to extensive (salvage) surgery in patients with advanced head and neck cancer (the IMCISION trial, NCT03003637).

2575 Background: surgery w/wo adjuvant radiotherapy (RT) for (recurrent) advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% 5-year OS, indicating the need for novel treatment options. In recurrent metastatic HNSCC nivolumab nearly tripled the 2-year OS. Aiming at improving clinical outcome in advanced HNSCC in a curative setting, we tested the feasibility of nivolumab ± ipilimumab neoadjuvant to (salvage) surgery w/wo RT. Methods: investigator-initiated phase-IB/II trial to assess feasibility of neoadjuvant nivolumab monotherapy (240 mg in week 1&amp;3: arm-A) or in combination with ipilimumab (1 mg/kg in week 1: arm-B) before surgery (≤ week 5) w/wo RT for advanced HNSCC. Results: 12 patients were included (3+3 design, both arms) in phase-IB of this study; 7/12 (58%) patients had pre-existent moderate-to-severe comorbidities (ACE-27). All patients were HPV negative. All patients received surgery as planned (25-33 days after start of immunotherapy) with no unexpected wound healing problems. In both groups, 4 patients (67%) experienced immune-related toxicity: grade 1-2 (n = 4) and grade 3-4 (n = 1; colitis) in arm-A; grade 1-2 (n = 5) and grade 3-4 (n = 2; colitis and elevated liver enzymes) in arm B. Immune-related toxicity was managed with prednisone (n = 2) and infliximab (n = 1). There was 1/6 (12.5%) pathological response in arm-A (1 near complete response, nCR) and 3/6 (50%) in arm-B (1x partial response and 2x nCR). No patients with nCR had a recurrence at follow-up (median 10 months). Preliminary data (mutational load will be added) show increased H7-B3 gene expression in non-responders before treatment, and increased endothelial cell and NK cell gene expression in responders post-treatment. Overall, in these 12 patients, neoadjuvant ipilimumab + nivolumab resulted in a significant increase in immune-related gene expression when compared to nivolumab only, irrespective of treatment response. Conclusions: neoadjuvant ipilimumab + nivolumab can safely be administered prior to major surgery for advanced HNSCC. Efficacy is promising and will be further evaluated in the phase-II trial continuation. Clinical trial information: NCT03003637.

Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer—The ETOP NICOLAS trial

ObjectivesChemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial. Material and methodsNICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached. Results and conclusionAs of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period.The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.

951d – Tradipitant, a Novel Nk-1 Receptor Antagonist, Significantly Improved Nausea and Other Symptoms of Gastroparesis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase Ii Trial

951d – Tradipitant, a Novel Nk-1 Receptor Antagonist, Significantly Improved Nausea and Other Symptoms of Gastroparesis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase Ii Trial

Consolidation with 90Y ibritumomab tiuxetan radioimmunotherapy in mantle cell lymphoma patients ineligible for high dose therapy: results of the phase II multicentre Polish Lymphoma Research Group trial, after 8-year long follow-up

Polish Lymphoma Research Group performed a phase-II trial to test whether 90Y ibritumomab tiuxetan radioimmunotherapy (Y90) may constitute an alternative consolidation for mantle cell lymphoma patients unfit for high-dose therapy. Forty-six patients were consolidated with Y90 following response to the 1st (n = 34) or 2nd line (n = 12) (immuno)chemotherapy. Majority of the patients had advanced disease (stage IV and presence of B-symptoms in 85% and 70%, respectively) and high MIPI (5.8, range 4–7). Consolidation with Y90 increased the complete remission (CR) rate obtained by the 1st line therapy from 41% to 91% and allowed for median PFS of 3.3 and OS of 6.5 years. In the first relapse, CR rate increased from 16% to 75%, while median PFS and OS totaled 2.2 and 6.5 years, respectively. At 8 years, 30% of patients, consolidated in the 1st line CR were alive, without relapse. Toxicity associated with Y90 is manageable, more severe after fludarabine-based regimens.