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Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC).Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%.Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events.The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual.

BackgroundImmune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies of alternatives to glucocorticoids are lacking. We examined whether interleukin-6 blockade by tocilizumab reduced ICI-induced colitis and arthritis.Patients and methodsPatients with solid cancer experiencing Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade >1 ICI-induced colitis/diarrhea (n=9), arthritis (n=9), or both (n=2) were recruited and treated with tocilizumab (8 mg/kg) every 4 weeks until worsening or unacceptable toxicity. Patients were not allowed to receive systemic glucocorticoids and other immunosuppressive drugs within the 14-day screening period. The primary endpoint was clinical improvement of colitis and arthritis, defined as ≥1 grade CTCAE reduction within 8 weeks. Secondary endpoints were improvements and glucocorticoid-free remission at week 24; safety; radiologic, endoscopic, and histological changes; and changes in plasma concentrations of C reactive protein, cytokines (IL-6, IL-8, and IL-17), and YKL-40.ResultsNineteen patients were available for efficacy analysis; one patient was excluded due to pancreatic insufficiency-induced diarrhea. Patients received treatment with pembrolizumab (n=10) or nivolumab (n=4) as monotherapy or ipilimumab and nivolumab (n=5) combined. Seven patients had been initially treated with glucocorticoids, and two of them also received infliximab. Ten patients continued ICI therapy during tocilizumab treatment. The primary endpoint was achieved in 15 of 19 (79%) patients. Additional one patient had ≥1 grade reduction at week 10, and another patient had stabilized symptoms. At week 24, ongoing improvement without glucocorticoids (n=12), including complete remission (n=10), was noted. Five patients had grades 3–4 treatment-related adverse events, which were manageable and reversible.ConclusionsTocilizumab showed promising clinical efficacy and a manageable safety profile in the treatment of ICI-induced colitis and arthritis. Our findings support the feasibility of randomized trials of immune-related adverse events.Trial registration numberNCT03601611.

545 Background: The treatment options for patients with biliary tract cancer (BTC) are limited. The aim of this study was to evaluate the clinical benefit of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with BTC. Methods: In this phase 2 study with a Simon’s 2-stage optimal design, patients with BTC refractory to at least one line of prior chemotherapy were randomized 1:1 to receive SBRT of 15 Gy combined with nivolumab or nivolumab/ipilimumab stratified by performance status. Signed informed consent was obtained from all patients. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of patients with stable disease, partial response (PR), or complete response according to RECIST 1.1. Decision on expansion independently for both arms was pending on CBR from the first stage. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between September 2018 and January 2022, 61 patients (19 SBRT/nivolumab and 42 SBRT/nivolumab/ipilimumab) received at least one treatment. Forty-eight patients (79%) had cholangiocarcinoma (intrahepatic 41, perihilar 2, distal 4, unspecified 1) and 13 patients (21%) had gallbladder cancer. No responses were observed in SBRT/nivolumab arm and this cohort was closed for inclusion after first stage based on CBR of 11% (95% confidence interval (CI) 1-33). SBRT/nivolumab/ipilimumab resulted in CBR of 31% (95% CI 18-47) and an overall response rate of 11.9% (95% CI 4.0-25.6). Of the five patients that achieved a PR, the median duration of response was 4.4 months (95% CI 0.0-9.2). A median PFS of 1.7 months (95% CI 1.6-1.7) and 1.7 months (95% CI 1.6-1.8), and a median OS of 4.7 months (95% CI 3.2-6.2) and 5.0 months (95% CI 2.1-7.9) were observed for patients receiving SBRT/nivolumab and SBRT/nivolumab/ipilimumab, respectively. Treatment-related adverse events grade 3 or higher occurred in 3 (16%) patients in the SBRT/nivolumab arm and 13 (31%) patients in the SBRT/nivolumab/ipilimumab arm. One patient died due to hepatitis in the combination arm. Conclusions: The combination of SBRT/nivolumab/ipilimumab demonstrated anti-tumor activity and acceptable toxicities in patients with advanced BTC. Further studies are warranted. Clinical trial information: NCT02866383 .

Background: Older patients with cancer are at risk of physical decline and impaired quality of life during oncological treatment. Exercise training has the potential to reduce these challenges. The study aim was to investigate the feasibility and effect of a multimodal exercise intervention in older patients with advanced cancer (stages III/IV). Patients and Methods: Eighty-four older adults (≥65 years) with advanced pancreatic, biliary tract, or non-small cell lung cancer who received systemic oncological treatment were randomized 1:1 to an intervention group or a control group. The intervention was a 12-week multimodal exercise-based program including supervised exercise twice weekly followed by a protein supplement, a home-based walking program, and nurse-led support and counseling. The primary endpoint was change in physical function (30-second chair stand test) at 13 weeks. Results: Median age of the participants was 72 years (interquartile range [IQR] 68–75). Median adherence to the exercise sessions was 69% (IQR 21–88) and 75% (IQR 33–100) for the walking program. At 13 weeks, there was a significant difference in change scores of 2.4 repetitions in the chair stand test, favoring the intervention group (p

PURPOSE To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC). METHODS Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383 ). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits. RESULTS Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival. CONCLUSION Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.

IntroductionImmunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and hypofractionated stereotactic body radiotherapy (SBRT) may work synergistically, and recent trials have supported this. We hypothesise that adding SBRT to CPI treatment can improve response rates in patients with mCRPC.Methods and analysisThe CheckPRO trial is an open-label, randomised, two-stage, phase II trial. We aim to enrol and randomise 80 evaluable patients with mCRPC who progressed following ≥2 lines of treatment. Enrolment started in November 2019 with 38 months expected enrolment period. The participants receive treatment for 52 weeks including four cycles of ipilimumab and nivolumab with or without concomitant SBRT (24 Gray in three fractions) to a single soft tissue or bone metastasis, followed by 10 cycles of nivolumab. Participants are followed until progression, death, or for 12 months after the end of treatment.Co-primary endpoints are the objective response rate and prostate-specific antigen (PSA) response rate. Secondary endpoints include safety, radiographic progression-free survival, clinical benefit rate, duration of response, PSA-progression-free survival beyond 12 weeks, quality of life and overall survival. Exploratory endpoints include translational analyses of tumour biopsies and consecutive blood samples. Biopsies from metastatic sites are collected at baseline, before the third treatment and at the end of treatment. Blood sampling for immune monitoring and circulating tumour DNA is performed consecutively at baseline and every radiographic assessment.Ethics and disseminationThis study follows the Helsinki Declaration and is approved by the Danish Ethics Committee System (journal no. H-19016100). All participants must receive written and oral information and provide a signed informed consent document prior to inclusion. The study results will be published in an international peer-review journal.Trial registration numberEudraCT number: 2018-003461-34. clinicaltrials.gov IDNCT05655715.

Background: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1. Objective: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients. Methods: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival. Results: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed. Conclusion: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Do-not-resuscitate (DNR) decision-making in severely ill patients presents many difficult medical, ethical, and legal challenges. The primary aim of this study was to explore cancer patients’ and health care professionals’ attitudes regarding DNR decision-making authority and timing of the decision. This study was a questionnaire survey among Danish cancer patients and their attending physicians and nurses in an oncology outpatient setting. Potential differences between patients’, physicians’, and nurses’ answers to the questionnaire were analyzed using Fisher’s exact test. Responses from 904 patients, 59 physicians, and 160 nurses were analyzed. The majority in all three groups agreed that DNR decisions should be made in collaboration between physician and patient. However, one-third of the patients answered that the patient alone should make the decision regarding DNR, which contrasts with the physicians’ and nurses’ attitudes, 0% and 6% pointing to the patient as sole decision-maker, respectively. In case of disagreement between patient and physician, a majority of both patients (66%) and physicians (86%) suggested themselves as the ultimate decision-maker. Additionally, 43% of patients but only 19% of physicians preferred the DNR discussion being brought up early in the course of the disease. With regard to the decisional role of patient vs. physician and the timing of the DNR discussion, we found a substantial discrepancy between the attitudes of cancer patients and physicians. This discrepancy calls for a greater awareness and discussion of this sensitive topic among both health care professionals and the public.

Background:Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the US. While complete response (CR) rates can be as high as 80% in patients (pts) undergoing initial induction chemotherapy, the majority of pts relapse. Pts who relapse or who fail to achieve CR after first cycle of induction therapy have a bleak prognosis. Selinexor inhibits the major nuclear transport protein exportin (XPO1), which is overexpressed in many cancers. Hematological neoplasms are particularly susceptible to inhibition of XPO1 and undergo apoptosis, while normal hematopoietic cells are largely spared. A Phase I study with selinexor monotherapy shows encouraging results in AML pts (NCT01607892). Selinexor's mechanism of action provides a novel approach and is a suitable agent for combination therapy with Ara-C and idarubicin. Methods: Pts with relapsed/refractory AML received Ara-C (100mg/m2, d1-7) and idarubicin (10mg/m2, d1, 3, 5) every 4 weeks.Two dose schedules of selinexor were administered in combination with chemotherapy: Cohort 1 received 40mg/m2 orally, twice weekly in 4 week cycles while cohort 2 received a selinexor flat dose of 60mg orally twice weekly for 3 weeks. The rationale for employing two dose levels of selinexor was to investigate differences in toxicity and efficacy and to determine the maximum tolerated dose/recommended phase II dose. The data cutoff date was July 28, 2016. Results: Forty-two pts were enrolled into the study between 09/2014 and 06/2016 in 3 German sites. Cohort 1 comprised 27 pats: 16 M, 11 F, median age 58 years (range 22-78), who had received a median of 2 prior treatment regimens (PTR) (range 1-5) including 10 pts (37%) with prior stem cell transplantation (SCT), 33% falling into the unfavourable cytogenetic risk group. Cohort 2 comprised 15 pts: 9 M, 6 F, median age 60 years (range 29-77), who had received a median of 1 PTR (range 1-2). Six patients (40%) had prior SCT and 40% falling into the unfavourable cytogenetic risk group; all 15 pts were evaluable for safety; 11 pts for efficacy (4 pts did not have a follow-up examination due to early death). Only one third of pts had late relapse (>12 months) in both cohorts. In cohort 1 all 27 pts received induction cycle 1 (IC 1) and one pt received a second induction cycle (IC 2). Two pts had consolidation therapy. For cohort 2 the values were 15, 0 and 2 respectively. The most frequent grade 3/4 toxicities attributable to selinexor for cohort 1 were vomiting (4%, for a median of 22 days), nausea (11%, for a median of 9 days) and diarrhea (52%, for a median of 6 days). For cohort 2 the respective values were vomiting (7%, one day), nausea (7%, 21 days) and diarrhea (40% median of 2 days). The median recovery time to neutrophils ≥ 0.5/nl and platelets ≥50/nl after IC 1 in pts who experienced a CR/CRi was 40 vs. 32 days and 37 vs. 29 days, for cohorts 1 and 2 respectively. One possibly drug related death occurred in cohort 1 (systemic inflammatory response syndrome) and one in cohort 2 (hemophagocytosis syndrome). In cohort 2 three cases (sepsis, pneumonia, asystole) resulted in fatal, although unrelated, outcomes. The overall response rate (ORR) for IC 1 in cohort 1 was 55.5% (22.2% CR, 33.3% CRi). 40% of these received SCT or donor lymphocyte infusions (DLIs), achieving a median relapse free survival (RFS) of 454 days and median overall survival (OS) of 465 days. Of the cohort 1 pts achieving CR/CRi after IC 1 and not being transplanted (N=9), three relapsed resulting in a median RFS of 241 days. Median OS for non-transplanted pts was 339 days. ORR in cohort 2 (N=11) was 54.5% (27.3% CR, 18.2% CRi; 9.1% morphologic leukemia-free state). Of cohort 2 pts that achieved CR/CRi after IC 1, none received SCT or DLI and no relapses had occurred as of the data cutoff date, resulting in a median RFS and OS of 96 days; the observation period is still on-going. As of the data cutoff date, 44.4% of all pts in cohort 1 (N=27) were alive with a median OS of 328 days and a median observation period of 330 days, and 90.9% of pts in cohort 2 (N=11) with a median OS and median observation period of 96 days. Conclusion: The prognosis of relapsed/refractory AML patients is remarkably poor. Our results suggest that combined treatment of Ara-C, idarubicin and selinexor might be an effective and tolerable treatment option and serve as a bridge to transplant. The lower selinexor dose shows better tolerability and should be further explored in this setting. Disclosures Fiedler: Gilead: Other: Travel reimbursement, Gilead; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement, Amgen, Patents & Royalties: Amgen, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Koltan: Research Funding; Teva: Other: Travel reimbursement Teva. Heuser:Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Novartis: Consultancy, Research Funding; Tetralogic: Research Funding; BerGenBio: Research Funding. Bokemeyer:Karyopharm: Research Funding.

Background: Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. While complete response rates can be as high as 80% in patients undergoing initial induction chemotherapy, the majority of AML patients will relapse. Refractory or relapsed patients have a bleak prognosis. As there is currently no standard regimen for these patients, a great clinical need exists for new treatment options. Selinexor, an oral first-in-class Selective Inhibitor of Nuclear Export (SINE), inhibits XPO1 mediated nuclear export inducing cytotoxicity in cells with genomic damage. Preclinical data with Ara-C and selinexor significantly prolonged the survival of leukemic mice. A phase I clinical study demonstrated encouraging results in AML patients. The role of selinexor as mono-therapy or in combination is currently under investigation in phase II trials of AML. Aims: This phase II trial investigates the efficacy & tolerability of Ara-C and Idarubicin in combination with selinexor in patients with relapsed or refractory AML. Methods: Patients with relapsed/refractory AML were treated with Ara-C (100 mg/m2, continuous infusion, day 1-7), idarubicin (10 mg/m2, day 1, 3, 5) every 4 weeks. Selinexor was administered twice weekly orally starting on day 2 (40 mg/m2). A small cohort of patients received selinexor after registration and before first induction cycle for correlative studies. The primary endpoint was percentage of patients achieving a complete remission or complete remission without normalization of peripheral blood counts (CRi). Secondary endpoints were partial remission rate, percentage of patients undergoing subsequent allogeneic stem cell transplantion, early death rate, overall survival (OS), event-free survival and toxicity. Results: As of June-16-2015, 21 patients with AML have been enrolled at 3 sites in Germany (NCT02249091) after obtaining informed consent of which 20 had received ≥ 1 induction cycle and were evaluable for efficacy and toxicity. Median age was 60 (range 34-78) years. Seven patients had a complex and 6 a normal karyotype (unknown in 7 cases). On average, patients had received 3.5 (range 1-6) prior therapies. 2 patients had primary refractory disease and 11 patients an early relapse and 7 patients a late relapse. 7 patients had prior allogeneic transplantation. Overall response rate was 60% (25% of patients achieved CR, 25% of patients achieved CRi, 10% of patients achieved PR). Sixty percent of patients received or were planned for stem cell transplantion or donor lymphocyte infusion. The most frequent non-hematologic AES were vomiting, diarrhoea, nausea, fatigue, anorexia and neutropenic fever. One treatment-related death occurred. The patient developed subarachnoid haemorrhage during thrombocytopenia grade 4 and died. Summary / Conclusion: The prognosis of relapsed/refractory AML patients is remarkably poor. Our findings suggest that Ara-C and Idarubicin in combination with selinexor resulted in a remarkable response rate and is a promising regimen in this particularly unfavourable cohort of patients without unexpected toxicities enabling the majority of them to proceed to first or second allogeneic stem cell transplantation. Disclosures Fiedler: Teva, Amgen, Astellas: Other: Travel Grant; Pfizer, Amgen, Kolltan: Research Funding; Karyopharm: Research Funding. Off Label Use: Selinexor has been used in combination with AraC and idarubicin in relapsed/refractory AML patients.. Chromik:Karyopharm: Research Funding. Theile:GSO Hamburg: Employment. Kranich:GSO Global: Employment. Heuser:Karyopharm: Research Funding.