Abstract: Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

Abstract: Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, 〈 20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, 〈 20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and 〈 20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

Abstract: 85 Background: While phase I trials are essential for the development of new anticancer drugs, there is a limited chance of benefitting for cancer patients participating in such trials. The information dialogue is therefore of substantial importance for providing a foundation to make a decision, and the support from relatives of potential value for the patient. This systematic review investigated patients’ prerequisites for deciding to participate in a phase I trial by summarizing the existing knowledge regarding patients’ decision-making when entering a phase I trial, and patients’ and their relatives’ perception of the information prior to enrollment. Methods: The review is based on the principles of Preferred Reporting Items for Systematic Reviews. A comprehensive systematic search was performed using the PubMed, Embase and PsycInfo databases and supplemented by a search for unpublished literature. Results: We identified 36 studies for inclusion in this review. When patients are offered participation in a phase I trial, information procedures as well as the patients’ individual approach influence the decision-making and the perception of the information provided. Across the studies exploring patients’ perception of information, there was a limited understanding of trial purpose and unrealistic expectations of benefit. The relatives’ perception of information remains unexplored. Evaluation of the included studies demonstrated a comprehensive risk of bias in the majority of studies. Conclusions: The information dialogue between physician and the patient concerning participation in a phase I trial seems to benefit from exact information taking account of the perspectives for each individual patient as well as the need for further discussion of trial. While relatives intuitively function as resources for patients entering a phase I trial, this topic is still not investigated.

Abstract: Background: Larotrectinib, a selective TRKi, is now FDA approved for pediatric and adult TRK-fusion solid tumors, regardless of tumor origin. Emergent TRK kinase mutations are a common mechanism of resistance to TRKis. LOXO-195, a selective TRKi, was developed to maintain potency against multiple TRK kinase domain mutations. Methods: Patients (pts) received LOXO-195 via a Phase I study (NCT03215511, n=20) or FDA expanded access single patient protocol (SPP, n=11). Eligible pts were ≥4-weeks old with a locally identified TRK fusion and had progressed or were intolerant to at least 1 priorTRKi. Parallel 3+3 dose escalations were pursued in adults and children, with intra-patient dose escalation permitted based on tolerance and pharmacokinetics. Pts aged & lt;12 received BSA-adjusted doses. Results: As of 03-DEC-2018, a total of 31 TRK-fusion pts (7 children, 24 adults) with 11 cancer types had been treated. Median duration on last prior TRKi was 9.5 months (range, 2-30). In the Phase 1, doses of 32 mg QD to 150mg BID were explored, and TEAEs (all grades/cause, in & gt;3 pts) were dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia, abdominal pain, fatigue, & lymphopenia (all 20%). Five Phase I pts (all adults) had DLTs: ataxia/dizziness (4), and ataxia/vomiting (1). For the SPPs: 1 pt dose-reduced and none discontinued for a TEAE. Cmax at doses ≥50 mg exceeded the predicted IC50 for TRK kinase mutations. Pretreatment tissue and/or plasma, as available, defined TRK kinase mutation status. Preliminary efficacy overall, and by TRK kinase mutation status, is shown in the Table. Discussion: LOXO-195 had preliminary efficacy in pts with resistance to prior TRKi mediated by TRK kinase mutations. The subset of pts who develop TRK-independent resistance are unlikely to benefit from LOXO-195. Dose selection is ongoing in both children and adults. Confirmed best overall response, all dose levels, investigator assessed per RECIST 1.1 (n=29≠)Patient CohortTotal Patients,nCR/PR, nStable Disease, nPD, nNon- evaluable, †nORRTRK Kinase Mutation20963245% (9/20)Solvent Front14742150% (7/14)Gatekeeper4111125% (1/4)xDFG2110050% (1/2)Identified bypass300210% (0/3)Other/ Unknown*61#31117% (1/6)Overall291096434% (10/29)≠ 2 pts still on study drug and awaiting 1st response assessment not included in Table.† 4 pts non-evaluable: 1 discontinued drug for unrelated new cancer diagnosis & lt;28 days after start of study drug and 3 withdrew within 14 days of study drug start.* Includes 1 pt with no identified TRK kinase resistance mutationor bypass alteration# and 5 pts who could not be tested.# Pt intolerant but not resistant to prior TRKi Citation Format: David Hyman, Shivaani Kummar, Anna Farago, Birgit Geoerger, Morten Mau-Sorensen, Matthew Taylor, Elena Garralda, Ramamoorthy Nagasubramanian, Michael Natheson, Lucy Song, Michael Capra, Mette Jorgensen, Alan Ho, Neerav Shukla, Steve Smith, Xin Huang, Brian Tuch, Nora Ku, Theodore W. Laetsch, Alexander Drilon, David Hong. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT127.

Abstract: Background: BRAF inhibitors have been approved in BRAF mutated malignant melanoma. However, in other BRAF mutated cancers, the effect of BRAF inhibition has been studied less extensively. BRAF mutated non-melanoma cancer patients (pts) were identified in a prospective genomic profiling study. The effect of targeted treatment was assessed by BRAF mutant allele fraction (AF) in circulating tumor DNA (ctDNA) and radiological response. Methods: Pts had tumor biopsies performed at enrolment and, if feasible, on or after treatment. Biopsies were subjected to whole exome sequencing, RNA sequencing and SNP array. Blood samples for ctDNA analysis were collected at baseline and longitudinally during treatment. Mutant BRAF fragments were quantified using droplet digital PCR (ddPCR) or by targeted next generation sequencing (NGS). Radiological response was evaluated according to RECIST 1.1. Results: Twenty-two BRAF mutated non-melanoma cancer pts (lung n=2, colorectal n=14, bile duct n=4, prostate n=1, pancreas n=1) were identified out of a total of 405 (5 %) pts enrolled in the Copenhagen Prospective Personalized Oncology (CoPPO) study. In all tumors we identified the BRAF V600E mutation except in one prostate cancer pt (BRAF K601E). Fifteen pts were treated with dabrafenib/trametinib (lung, bile duct), vemurafenib/panitumumab +/- irinotecan (colorectal) or vemurafenib (pancreas, prostate). Two pts were non-evaluable because one patient requested early termination and one has pending tumor evaluation. All pts had tumor reduction, except one patient with colon cancer. Six out of 13 (46%) pts achieved partial response (lung n=2, bile duct n=1, colorectal n= 3) and 7/13 (44%) had stable disease (prostate n=1, bile duct n=1, colorectal n= 5) as best response according to RECIST 1.1. Median progression-free survival was 20 weeks. Eighteen pts analysed by ddPCR or NGS at baseline had detectable mutant BRAF in the plasma obtained before initiation of therapy. Eight of the 18 pts had ctDNA assessed during treatment and all presented with a reduction in mutant BRAF AF corresponding to a reduction in tumor volume. Moreover, in 5/8 pts, time of best radiological response coincided with the lowest detectable BRAF mutant AF. Analysis of on- and post treatment biopsies and matched ctDNA samples are pending to identify putative mechanisms of resistance and will be reported at the meeting. Conclusion: Targeted therapy seems active in BRAF mutated non-melanoma cancer pts and treatment response is evaluable by monitoring mutant BRAF in ctDNA during therapy. Citation Format: Lise Barlebo Ahlborn, Ida Viller Tuxen, Olga Oestrup, Ane Yde Schmidt, Cecilia Brunhoff Håkansson, Finn Celius Nielsen, Ulrik Lassen, Christina Westmose Yde, Morten Mau-Sorensen. BRAF mutant allele fraction in circulating tumor DNA as marker of treatment response in BRAF mutated non malignant melanoma cancers identified in the Copenhagen Prospective Personalized Oncology study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2017-5393

Abstract: We evaluated the clinical benefit of tumor molecular profiling to select treatment in the phase I setting. Experimental Design: Patients with advanced solid cancers and exhausted treatment options referred to a phase I unit were included in a prospective, single-center, single-arm open-label study (NCT02290522). Tumor biopsies were obtained for comprehensive genomic analysis including whole-exome sequencing and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression-free survival (PFS). Results: From May 2013 to January 2017, a total of 591 patients were enrolled, with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. A total of 101 patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15 of 101 patients (0% complete response, 15% partial response), with a median PFS of 12 weeks (95% confidence interval, 9.9–14.4). Conclusions: Our study supports the feasibility of genomic profiling to select patients in the phase I setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption. See related commentary by Ratain, p. 1136

Abstract: Purpose: Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand–receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment. Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258–66. ©2014 AACR.