BACKGROUND:Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors. METHODS:Patients received oral KHK2455 at fixed doses of 0.3, 1, 3, 10, 30, and 100 mg once daily as run-in monotherapy for 28 days (cycle 0), and then in combination with 1 mg/kg intravenous mogamulizumab given weekly for cycle 1 and every 2 weeks from cycle 2 onward. RESULTS:Thirty-six patients were enrolled. One patient with an initial diagnosis of lower esophageal cancer (100-mg cohort) experienced grade 3 gastrointestinal necrosis, and did not receive mogamulizumab. Overall, KHK2455 + mogamulizumab was well tolerated, with manageable adverse events at all doses. KHK2455 + mogamulizumab demonstrated dose-dependent plasma concentration increases and suppression of IDO1 activity. One patient with advanced bevacizumab-resistant glioblastoma demonstrated a durable confirmed Response Evaluation Criteria in Solid Tumors, version 1.1, partial response, and nine patients achieved a durable disease stabilization of ≥6 months. On the basis of the preliminary antitumor response, the cohort expansion was not initiated. CONCLUSIONS:KHK2455 + mogamulizumab was safe and well tolerated with manageable toxicities, and resulted in dose-dependent suppression of IDO1 activity; signals of antitumor activity were observed.

Supplemental tables with the number of patients treated with number of cycles and the incidence of DLTs.

Representative image of complete response after treatment with pelabresib.

CONSORT diagram of patient disposition throughout study

PK/PD Analysis of the Relationship Between Maximum Relative Change in Gene Expression and Pelabresib Exposure Metrics.

Background: In sickle cell anemia (SCA), a point mutation in the β-globin gene results in abnormal hemoglobin prone to polymerization under hypoxic conditions. Erythrocytes become sickle-shaped and rigid, leading to painful vaso-occlusion, ischemic tissue damage, and endothelial dysfunction. Despite significant, life-threatening risks, allogeneic hematopoietic cell transplant (allo-HCT) is the only cure for SCA. Results of autologous HCT, using the addition of a non-sickling, post-transcriptional gene silencing or gene editing to increase fetal hemoglobin, are promising and suggest an alternative option for those who lack a suitable donor. Procuring hematopoietic stem and progenitor cells (HSPCs) is challenging in patients with SCA, as granulocyte colony-stimulating factor is contraindicated due to severe adverse effects. Peripheral blood mobilization with Plerixafor (Mozobil®, Genzyme) has recently been shown to be safe and effective in SCA. While mobilization with plerixafor allows collection of an HSPC product, many SCA patients require ≥2 cycles of multiday plerixafor doses and apheresis to collect sufficient quantities of HSCs for genetic manipulation. Reports suggest 30% of patients experience vaso-occlusive events (VOEs) of grade ≥3 during and after apheresis; therefore, a considerable unmet need exists for agents that augment stem cell (SC) yields and reduce apheresis time. MGTA-145 is an agonist of cell-surface chemokine receptor 2 (CXCR2) under development for the mobilization of CD34+ cells in combination with plerixafor. MGTA-145 binds to CXCR2, resulting in HSC release, which when given with plerixafor, increases mobilization of HSCs. Preclinical studies in animal models and clinical trials in healthy subjects and patients with multiple myeloma demonstrated that MGTA-145 with plerixafor results in more rapid and robust mobilization of CD34+ cells, including primitive HSC populations, compared to plerixafor alone. Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 1 or 2 doses of MGTA-145 combined with plerixafor for the mobilization of HSCs in individuals with SCA. Study Design and Methods: This phase 2, open-label, 2-part study (NCT05445128) will enroll approximately 10-14 adults ages 18-35 years with SCA, at 3 sites in the US. Participants must have a documented diagnosis of SCA, have a hydroxyurea washout period, and have adequate white blood cell counts and cardiopulmonary, renal, and liver function. Key exclusion criteria include history of VOE requiring a visit to a healthcare facility within 30 days of screening, poorly controlled healthcare conditions, including but not limited to cardiopulmonary or hepatorenal events ≤6 months prior to screening, and cerebrovascular accident or retinal infarct ≤2 years prior to screening. In the 1st cohort of Part A, subjects will receive a single 0.24 mg/kg subcutaneous dose of plerixafor followed by a single 0.03 mg/kg IV dose of MGTA-145, with apheresis occurring within approximately 30-45 minutes of MGTA-145 dosing. After a 1-week follow-up visit and an Independent Data Monitoring Committee (DMC) review, the 2nd cohort with additional subjects may be enrolled and given plerixafor and a 0.03 or 0.015 mg/kg or lower dose of MGTA-145 (FIGURE). Following a 1-week follow-up visit and a 2nd DMC review, patients will be enrolled in Part B and will receive, on 2 consecutive days, plerixafor and the same dose of MGTA-145 as the 2nd Part A cohort, followed by apheresis on each dosing day. The primary endpoint is total yield of CD34+ cells (CD34+ cells/kg). Safety outcomes include incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, Grade ≥3 TEAEs, treatment-emergent serious adverse events, and TEAEs leading to study drug discontinuation. Core exploratory endpoints include characterization of the phenotype and function of cells collected by apheresis and assessment of the gene-modifying potential of mobilized CD34+ cells. The results of this trial will establish if MGTA-145 with plerixafor will rapidly and safely mobilize robust numbers of high-quality SCs for HSCT in SCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883).Experimental Design:Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule.Results:The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease.Conclusions/Discussion:Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily.Significance:BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis.

Abstract Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis resulting from aberrant megakaryopoiesis and expression of pro-inflammatory cytokines. These processes, heavily influenced by bromodomain and extraterminal domain (BET) protein-mediated gene regulation, lead to myeloproliferation and cytopenias. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in the ongoing MANIFEST Phase 2 study (NCT02158858). Methods: In arm 1 of MANIFEST, pelabresib is administered as monotherapy to pts with MF who are intolerant/refractory to, or ineligible for RUX; in arm 2, as an 'add-on' to RUX in pts with MF who have suboptimal/lost response; and in arm 3 as combination therapy with RUX in JAKi treatment-naïve pts with MF. To evaluate the effects of pelabresib on BM biology, analyses were conducted using BM biopsy samples obtained pre-treatment and at 24 weeks post-treatment during the MANIFEST trial. Central pathology review of reticulin staining was conducted to evaluate BM fibrosis (BMF) grading and immunohistochemistry staining for changes in erythroids (ERY) and megakaryocytes (MK), respectively. Independent digital images of stained BM slides were also evaluated with a semi-quantitative cell-specific detection algorithm for reticulin density, percentage CD71+ ERY, mean number of CD61+ MK and mean distance between nuclei for CD61+ MK. Results: Exploratory analyses across the three treatment arms showed BM improvements after 24 weeks of treatment. Paired comparison by digital analysis of baseline and 24-week treatment BM biopsies from 29 pts showed reduction (range 67%-15.5%) in reticulin intersections per field in 45% (13/29) pts. Furthermore, digital analysis of CD71+ ERY and CD61+ MK from paired biopsies showed increased ERY progenitors in 50% (16/32) pts, decreased MK density in 57% (15/26) pts and decreased MK clustering in 46% (12/26) pts at 24 weeks. Decreased MK clustering correlated with decreased density of CD61+ MK in 75% pts (9/12). Correlative analysis between observed clinical responses and bone marrow improvements are ongoing and will be available for presentation at the conference. We previously reported (Talpaz M, et al. ASH 2020; Abstract 2163) that in pts with MF, pelabresib can reduce spleen volume, improve symptoms, improve bone marrow fibrosis, demonstrate increase in hemoglobin levels, and reduce transfusion burden. Updated 24-week data reflecting a higher number of evaluable pts and new long-term data at 48 weeks across the MANIFEST trial, will be presented. Conclusions: Treatment with pelabresib as monotherapy or in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in increased ERY progenitors, decreased MK density and reduction of BM fibrosis, as assessed by digital pathology. These data suggest possible disease-modifying potential for pelabresib by improving BM histology and function, leading to potential clinical benefits. Disclosures Verstovsek: Roche: Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Mascarenhas: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Prelude: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz: Celgene: Consultancy; Imago: Consultancy; Takeda: Other: Grant/research support ; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: La Jolla Pharma: Consultancy; Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; CTI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AOP: Consultancy. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rampal: Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Memorial Sloan Kettering: Current Employment; Kartos: Consultancy. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Taverna: Constellation Pharmaceuticals: Current Employment. Cui: Constellation Pharmaceuticals: Current Employment. Zavidij: Constellation Pharmaceuticals: Current Employment. Chen: Constellation Pharmaceuticals: Current Employment. Colak: Constellation Pharmaceuticals: Current Employment. Efuni: Constellation Pharmaceuticals: Current Employment. Keller: Constellation Pharmaceuticals: Current Employment. Trojer: Constellation Pharmaceuticals: Current Employment. Harrison: Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Nuclear factor-κB (NF-κB), a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. Pelabresib (CPI-0610) is a first-in-class, oral, small-molecule inhibitor of the tandem amino-terminal bromodomains (BD1 and BD2) of bromodomain and extraterminal domain (BET) proteins, which regulate gene expression pathways. In preclinical studies, pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability, and preliminary efficacy results from the first-in-human Phase 1, multicenter, open-label, dose-escalation study of pelabresib in patients (pts) with relapsed or refractory lymphomas (NCT01949883).

BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker. RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose. CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies. ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract. Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1368.

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan to kynurenine, suppressing T cell effector activity and increasing T regulatory cell activity. IDO1 expression is induced in some cancer cells and has been associated with suppression of effector T cell responses toward tumors. In nonclinical studies, IDO1 inhibition combined with other clinically established immune modulating agents (eg, anti-CTLA-4 or anti-PD-1 antibodies) showed a significant improvement in tumor growth suppression. KHK2455 is a long acting and selective IDO1 inhibitor under development as a new approach to enhance anti-tumor immunity. KHK2455 is being combined with different anti-cancer therapies to explore its ability to enhance anti-tumor immunity and overcome tumor immune evasion. Avelumab is a PD-L1 checkpoint inhibitor approved for treatment of urothelial carcinoma. This study represents an opportunity to assess the complementary action of KHK2455 IDO1 inhibition and avelumab checkpoint inhibition in the treatment of urothelial carcinoma. Methods: Study 2455-002 is a two-part, multicenter, open-label Phase 1 study of KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma (including bladder, urethra, ureters, and renal pelvis), who are checkpoint inhibitor naїve and previously treated with platinum-based therapy. Part 1 (dose-escalation) has a 3+3 design to evaluate safety and tolerability and identify the maximum tolerated dose (MTD). Dose de-escalation based on dose limiting toxicities is permitted. Part 2 (cohort expansion) further explores the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity for the combination regimen at the MTD or highest tested dose. All subjects will receive oral KHK2455 at their assigned dose and avelumab IV. The primary study endpoints are safety and tolerability, and the secondary endpoints are efficacy (based on RECIST v1.1 criteria), pharmacokinetics, and immunogenicity. Exploratory endpoints include examination of pre and post treatment biopsies for intratumoral suppression of IDO1 activity to correlate peripheral and intratumoral suppression, along with pre and post treatment serum markers including, but not limited to, immune mediators and related cytokines. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for continuous variables and frequency distributions and percentages for discrete variables will be utilized. Approximately 44 subjects are planned for enrollment (12 subjects in Part 1 and 32 subjects in Part 2). Clinical trial information: NCT03915405 (sponsor: Kyowa Kirin Pharmaceutical Development, Inc.) Citation Format: Pratibha Desai, Santosh Rao, Yuta Ikawa, Barbara Kapelan, Sergey Efuni, Robert Latek, Takashi Sato, Denis Healy, Yousef Zakharia. An open-label, phase 1 study of IDO inhibitor KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT238.

[This corrects the article DOI: 10.1093/crocol/otaa049.].

Background IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sezary syndrome. Methods In this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated. Results Thirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1). Conclusions KHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination. Acknowledgements Medical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA. Trial Registration NCT02867007 (www.clinicaltrials.gov) Ethics Approval This study was approved by Ethics Committees at all participating study institutions.

3040 Background: IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. Unlike other inhibitors, KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Moga is a monoclonal antibody with enhanced ADCC activity that has shown synergy with KHK2455 in preclinical models. Methods: Pts with advanced solid tumors received escalating doses of KHK2455 alone (0.3, 1, 3, and 10 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV Moga for 4 weeks (Cycle 1) and then on Days 1 and 15 (from Cycle 2) in a standard 3+3 Phase I design. Dose escalation was based on safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production). Results: 21 pts were enrolled in cohorts that received KHK2455 at 0.3, 1, 3, and 10 mg dose levels. No DLTs were observed. The most frequent adverse events (≥5%) included maculopapular rash, thrush, dysphagia, thrombotic event, and tachycardia, none of which were considered related to KHK2455. One case of rash (Gr 3) was considered related to Moga but not a DLT. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated in plasma samples (67% and 66% inhibition in Kyn concentrations and Kyn:Trp ratio, respectively, compared to baseline) and ex vivo stimulation assays ( > 95% inhibition in Kyn production) at 10 mg KHK2455, confirming target modulation. Four patients (n = 3 head and neck; n = 1 ovarian) from all dosing groups have achieved durable RECIST disease stabilization for more than 6 months, and one (salivary gland carcinoma) for more than 14 months. Conclusions: KHK2455 in combination with Moga is safe and well tolerated at all doses tested, suppresses Kyn production in a dose-dependent and sustained manner, and demonstrates early signals of antitumor activity. These data support the continued development of this promising combination. Clinical trial information: NCT02867007.