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Additional supporting information may be found online in the Supporting Information section at the end of the article.Fig S1 . The karyotype of 46,XY,add(7)(q22),dup(8) (q11.2q24).Supplementary Methods S1. Methods of whole exome sequencing, transcriptome sequencing, and pedigree analysis.

Purpose To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. Methods This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H 0 ), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H 0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. Results Two-year OS was 71% in arm A (95% CI: 55–87%) vs. 53% in arm B (95% CI: 36–71%); H 0 was rejected. Median OS was 49.1 vs. 24.1 months ( p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30–1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25–1.04) for progression, 0.43 (0.13–1.40) for locoregional failure, and 0.43 (0.17–1.05) for distant metastasis. Overall response was 81% vs. 69% ( p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 ( p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). Conclusion Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

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.