ALBERT

Description: Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen-presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea. Methods: In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID. The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated. Results: In dose-escalation, sixteen patients were enrolled in four cohorts: 100 mg BID (n=4), 200 mg BID (n=3), 400 mg BID (n=5), and 600 mg BID (n=4). No dose-limiting toxicities were observed in any of these cohorts and the MTD was not reached. Treatment related adverse events (TRAEs) were reported in 9 (47.4%) patients and were all Grade 1-2 in severity. The most common (〉1 patient) were fatigue (15.8%), nausea (10.5%), and rash (10.5%) and no infections were reported. By flow cytometry, no consistent changes in circulating non-malignant or total T cell number or phenotype were observed. Pharmacodynamic analysis revealed ITK engagement by CPI-818 in all cohorts when CPI-818 is dosed BID. With increasing dose, the trough ITK occupancy in both blood and tissue increased. At doses of 200 mg and greater, trough occupancies were 〉75%. Near complete ITK inhibition (98%) was achieved at 600 mg BID and therefore, this dose was selected as the expansion cohort dose and higher doses were not explored. Reduction in serum cytokines including IL2 (six of eight patients), IFNg (eight of eight patients), and TNFa (eight of eight patients) was observed 24hr post-dose in patients treated with doses of 400 and 600mg, but not at lower doses. In dose escalation, a total of four PTCL patients were enrolled at doses of 200 mg BID or greater. A confirmed complete response was achieved in one PTCL-NOS patient in the 200mg BID cohort. Among 7 CTCL patients enrolled, a Nodal CR, improved mSWAT and slowing of Sézary cell expansion were seen (Figure 1). Given the safety profile, the PK/PD findings, and the early signs of efficacy, PTCL-NOS and CTCL cohorts were expanded at 600mg BID. To date, two patients with PTCL-NOS and one patient with CTCL have been recently enrolled in expansion cohorts. Conclusion: The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID. Disclosures Khodadoust: Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Feldman:Abbvie: Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Kim:miRagen: Research Funding; Elorac: Research Funding; Neumedicine: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Solingenix: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; Verastem: Research Funding; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Genetech/Roche: Research Funding. Kim:Mundipharma: Research Funding; Donga: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Horwitz:ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy. Buggy:Corvus Pharmaceuticals: Consultancy, Current Employment, Current equity holder in publicly-traded company. Hotson:Corvus Pharmaceuticals: Current Employment. Hill:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Munneke:Corvus Pharmaceuticals: Current Employment. Mahabhashyam:Corvus Pharmaceuticals: Current Employment. Miller:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Janc:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mobasher:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Description: Background: Characterization of T-cell receptor (TCR) diversity and dynamics is increasingly critical to understanding therapeutic immune responses targeting tumors. Current TCR profiling methods generally require invasive tissue biopsies that capture a single snapshot of immune activity or are limited by the sheer diversity of the circulating TCR repertoire. In theory, T-cells with the greatest turnover could best reflect pivotal immune dynamics from both circulating and tissue-derived compartments, including non-circulating tissue-resident memory T-cells (Trm). To noninvasively capture such responses in the blood, we developed and benchmarked a high-throughput TCR profiling approach using plasma, optimized for the fragmented nature of cfDNA and the non-templated nature of rearranged TCRs. We then applied this method for residual disease monitoring in mature T-cell lymphomas (TCL) without circulating disease and for characterizing immune dynamics after anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy of B-cell lymphomas with axicabtagene ciloleucel. Methods: We developed SABER (Sequence Affinity capture & analysis By Enumeration of cell-free Receptors) as a technique for TCR enrichment and analysis of fragmented rearrangements shed in cfDNA and applied this method using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). We used SABER to profile a total of 381 samples (300 cfDNA and 81 PBMC samples) from 75 lymphoma patients and 18 healthy controls. After mapping sequencing reads (hg38) to identify candidate rearrangements within TCR loci, unique cfDNA fragments were resolved by a novel strategy to define consensus of unique molecular identifiers clustered by Levenshtein distances, followed by CDR3-anchoring for enumeration of final receptor clonotypes. SABER thus leverages information from fragmented TCRs, a critical requirement for cfDNA, to make V gene, CDR3, and J gene assignments after deduplication-mediated error-correction. We benchmarked SABER against established amplicon-based TCR-β targeted sequencing (LymphoTrack, Invivoscribe) and repertoire analysis methods (MiXCR; Bolotin et al, 2015 Nature Methods) when considering both cfDNA and PBMC samples from healthy adults and TCL patients. We assessed SABER performance for tracking clonal molecular disease in patients with mature TCLs from both cellular and cell-free circulating compartments (n=9). Malignant TCL clonotypes were identified in tumor specimens using clonoSEQ (Adaptive Biotechnologies). Finally, we evaluated TCR repertoire dynamics over time in 66 DLBCL patients after CAR19 T-cell therapy. Results: SABER demonstrated superior recovery of TCR clonotypes from cfDNA compared to both amplicon sequencing (LymphoTrack, Invivoscribe) and hybrid-capture methods when enumerating receptors using MiXCR (Fig. 1A). When applied to blood samples from TCL patients, SABER identified the malignant clonal TCR-β rearrangement in 8/9 (88.9%) cases, with significantly improved detection in cfDNA (p=0.015, Fig. 1B). Specifically, tumoral TCR clonotype was detectable only in cfDNA in 6 cases (75%), cfDNA-enriched in 1 case (12.5%), and detectable only in PBMCs in 1 case (12.5%). We applied SABER to monitor TCR repertoire dynamics in cfDNA after CAR T-cell therapy of patients with relapsed/refractory DLBCL and observed increased T-cell turnover and repertoire expansion (greater total TCR-β clonotypes) (Fig. 1C). As early as 1-week after CAR19 infusion, TCR repertoire size was significantly correlated both with cellular CAR19 T-cell levels by flow cytometry (p=0.008) as well as with retroviral CAR19 levels in cfDNA (p=2.20e-07) suggesting faithful monitoring of CAR T-cell activity (Fig. 1D). TCR repertoire size one month after infusion was significantly associated with longer progression-free survival (HR 0.246, 95% CI 0.080-0.754, p=0.014). Conclusions: SABER has a favorable profile for cfDNA TCR repertoire capture when compared to existing methods and could thus have potential broad applicability to diverse disease contexts. Given the higher abundance of lymphoma-derived TCRs in cfDNA than intact circulating leukocytes, SABER holds promise for monitoring minimal residual disease in T-cell lymphomas. This approach also holds promise for monitoring T-cell repertoire changes including after CAR T-cell therapy and for predicting therapeutic responses. Disclosures Kurtz: Genentech: Consultancy; Foresight Diagnostics: Other: Ownership; Roche: Consultancy. Kim:Corvus: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company; Apricity Health: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Diehn:Varian Medical Systems: Research Funding; Illumina: Research Funding; Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy. Khodadoust:Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding.

Description: Background MAVORIC was a phase 3, open-label, multi-center, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab compared with vorinostat in patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) (NCT01728805). Mogamulizumab-associated rash was the second most common TEAE of any cause or grade in the mogamulizumab treatment arm and the most common TEAE leading to treatment discontinuation, resulting in a discontinuation rate of 7% (13/184). Grade 1-2 and 3 drug rashes occurred in 20% (36/184) and 4% (8/184) of mogamulizumab-treated patients, respectively. The objectives of this analysis were to describe histopathological and other characteristics of drug rash in patients who received mogamulizumab in MAVORIC. Methods In MAVORIC, 372 patients were randomized 1:1 to receive either intravenous mogamulizumab at 1.0 mg/kg once weekly for Cycle 1 (28 days) and then on days 1 and 15 of subsequent cycles or oral vorinostat at 400 mg daily. Confirmed overall response rate (ORR; complete response + partial response) was based on a global composite response involving all four disease compartments and verified at two consecutive visits. Guidance to investigators was provided in the protocol for evaluation and management of new drug rash on mogamulizumab treatment. Patients with an initial Grade 1 drug rash were allowed to continue treatment with use of topical steroids as needed. For patients with Grade ≥2 drug rash, mogamulizumab was temporarily stopped, and treatment of the drug rash with topical steroids was advised. Use of systemic steroids was prohibited during the study. Treatment could resume if the drug rash resolved to Grade ≤1 within 2 weeks. Biopsies were evaluated by an on-site pathologist, and a central blinded review was also conducted. Results This analysis included 44 patients who were treated with mogamulizumab and experienced drug rash during MAVORIC. Pathologically, central review assessed rashes as granulomatous, histiocytic spongiotic, lichenoid, eosinophilic, psoriasiform, or a combination of these patterns with no clear predominant histological pattern. Among the 44 patients with drug rash, 59.1% (26/44) were ≥65 years of age, and more patients with SS [56.8 (25/44)] than MF [43.2% (19/44]) experienced drug rash. Median (Q1, Q3) exposure among patients with drug rash was 344 days (162, 652) in patients with SS and 185 days (85, 463) in patients with MF. Mogamulizumab did not result in any cases of anaphylaxis or SJS/toxic epidermal necrolysis (TEN). Concomitant or immediate prior CTCL therapies that may make patients prone to drug rash were examined, and no trend toward increased incidence of drug rash was observed with any particular agent or class. The proportion of SS responders with drug rash was significantly higher than responders without rash (P=0.02; Figure 1); the proportion of MF responders with drug rash did not differ from responders without rash (P=0.21). Overall, the median (Q1, Q3) time to onset of drug rash was 106 days (36, 254). Initial drug rash occurred after response to mogamulizumab in 70% (14/20) of patients who experienced both. Thirty-five patients (80%) in the drug rash cohort resumed treatment with mogamulizumab upon resolution of initial drug rash per-protocol. After these patients resumed treatment, the median (Q1, Q3) duration of exposure to mogamulizumab was 183 days (58, 332). Conclusions Mogamulizumab-associated rashes displayed heterogeneous histopathology without one predominant feature; therefore, close correlation of suspected drug rash with clinical features is advised to differentiate it from disease progression. A trend toward higher rate of drug rash was observed in patients with SS, the group more likely to respond to mogamulizumab. Therefore, drug rash may be attributable to increased exposure, but rash may also involve underlying disease characteristics or treatment-induced immune alterations; further investigations are warranted. Nevertheless, the observation that 80% of patients on trial were able to continue mogamulizumab for 〉6 months following resolution of their initial rash suggests that appropriate evaluation, identification, and management of these reactions may prevent premature discontinuation. Disclosures Musiek: Kyowa Kirin: Honoraria; Helsinn: Honoraria; miRagen: Other: Investigator; Elorac: Other: Investigator; Soligenix: Other: Investigator. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Bagot:Helsinn/Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huen:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Other: Travel expense reimbursement, Research Funding; miRagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Research Funding; Rhizen: Consultancy, Research Funding. Fisher:Dana-Farber Cancer Institute: Current Employment; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Haun:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Karger, Inc.: Patents & Royalties: Textbook royalties. Vermeer:Kyowa Kirin: Consultancy, Research Funding; Takeda: Research Funding; PIQUR: Research Funding; Innate Pharma: Consultancy. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Herr:Kyowa Kirin, Inc.: Current Employment. Kim:Elorac: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin Pharma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; miRagen: Research Funding; Merck: Research Funding; Solingenix: Research Funding; Trillium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Description: Background The MAVORIC study, a phase 3, open-label, multi-center, randomized controlled trial, compared the safety and efficacy of mogamulizumab with vorinostat in patients with mycosis fungoides (MF) or Sézary syndrome (SS) that relapsed/was refractory after ≥1 systemic therapy. Among patients treated with mogamulizumab, the confirmed global overall response rate (ORR; partial [PR] or complete response [CR]) was 28% (52/186), with a median duration of response of 14.1 months. The benefits of mogamulizumab treatment can be further characterized by assessing ORR and duration of response, both clinically important aspects of treatment success, together in a combined measure. For example, ORR4 describes a response lasting at least 4 months and was the primary endpoint in a phase 3 trial of brentuximab vedotin in patients with MF. The objective of this analysis was to assess the clinical and demographic characteristics of MAVORIC cohorts who have ORRs of different durations following treatment with mogamulizumab. Methods This post hoc analysis of MAVORIC, based on a secondary data analysis as of March 19, 2018, divided patients into 4 cohorts based on minimum duration of response (≥4, ≥6, ≥8, and ≥12 months; ORR4, 6, 8, and 12, respectively). Linear regression analysis (odds ratios [ORs] for ORR12 response) was performed for gender, baseline Eastern Cooperative Oncology Group (ECOG) Performance Status, disease type, disease stage (IB-IV), blood involvement, baseline CCR4 expression, age, time from diagnosis, mSWAT, and LDH. Stepwise multivariate analysis was carried out on the same factors. Blood samples at multiple time points after blood CR were collected from 2 SS patients in the ORR12 cohort at a single site, and the frequency of malignant TCR was monitored with the clonoSEQ next generation sequencing platform (Adaptive Biotechnologies; Weng 2013). Samples were assessed at baseline and every 3-6 months to monitor molecular minimal residual disease (MRD). Results Response rates by disease compartment for patients treated for ≥12 months with vorinostat and mogamulizumab are shown in the Table. Among patients randomized to mogamulizumab (n=186), ORRs lasting ≥4, ≥6, ≥8, and ≥12 months were seen in 25.3%, 21.0%, 16.1%, and 10.8%, respectively. Responses in blood and skin lasting ≥6 months (ORR6) were seen in 49.2% and 27.4% of mogamulizumab-treated patients, respectively, compared with 5.6% and 7.5% of vorinostat-treated patients. When baseline characteristics of patients achieving ORR12 were compared with all other patients treated with mogamulizumab via linear regression analysis, ORR12 patients were more likely to have SS (P=0.016, OR 0.29), stage IVA1 disease (P=0.0002, OR 11.13), and any blood involvement (P=0.03, OR 0.19). There was no correlation between skin CCR4 level at baseline and likelihood of attaining ORR12. When ORR12 patients were compared with patients who achieved shorter responses (ie, ORR2 patients who did not reach ORR12), long-term responders were more likely to have stage IVA1 disease (P=0.006, OR 7.3). Stepwise multivariate analyses confirmed diagnosis of SS as a significant predictor of long-term response. In 2 patients in the ORR12 cohort from a single center (best response global CR), the molecular MRD was monitored after clinical clearance of blood Sézary cells by routine flow cytometry. A 71-year-old man with SS demonstrated CR in blood after 1 mogamulizumab cycle and in skin at cycle 3. At last follow-up, the frequency of malignant TCR sequence in blood remained barely detectable at

Description: Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging Fcγ receptors. Here we report updates from the first-in-human study of TTI-621 (NCT02663518) in hematologic malignancies. Methods Study Part 1 tested increasing weekly intravenous doses of TTI-621 based on 3+3 escalation. The maximum tolerated dose was initially determined to be 0.2 mg/kg based on dose limiting toxicity (DLT) of thrombocytopenia [Grade (Gr) 4 of any duration]. Expanded testing followed in patients (pts) with hematologic malignancies, including leukemia, lymphoma, and multiple myeloma. In Part 2, most pts received 0.2 mg/kg. However, based on investigator discretion, a subset of pts received escalating doses up to 0.5 mg/kg. In Part 3, pts with T-cell lymphomas received stepwise dose escalations from 0.2 to 0.5 mg/kg over the first 5−8 weeks. In over 200 pts tested in Parts 1−3, thrombocytopenia did not increase with dose, typically recovered within 2−4 days, and was not associated with clinical sequelae. Part 4 was then undertaken to optimize TTI-621 dosing and is currently escalating doses in a 3+3 manner through pre-planned dose levels (0.5, 0.7, 1, and 1.4 mg/kg) in pts with cutaneous T-cell lymphoma (CTCL). The DLT criteria was modified to require Gr 4 thrombocytopenia lasting 〉72 hours. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) per CTCAE v 4.03. Blood samples are obtained for pharmacokinetics (PK) and for pharmacodynamic (PD) assessments of receptor occupancy (RO) on normal peripheral T cells. Disease assessments are performed per Olsen's criteria. Results In Parts 1−3 (n=214), the most common related AEs were infusion-related reaction (IRR, 43%; 3% Gr ≥3), thrombocytopenia (30%; 22% Gr ≥3), chills (21%; 0% Gr ≥3), and fatigue (15%; 1% Gr ≥3). Objective responses to single agent TTI-621 were achieved in 14/71 (20%) NHL pts including CTCL (n=42, 1 CR, 7 PRs), PTCL (n=22, 2 CRs, 2 PRs) and DLBCL (n=7, 1 CR, 1 PR). In Part 4, as of July 10, 2020, 15 pts (9M/6F, median age 67 years) have enrolled into 4 dose cohorts (0.5−1.4 mg/kg). CTCL subtypes include mycosis fungoides (MF, n=10) and Sézary syndrome (n=5) with advanced (≥IIB) disease in 9 (60%) pts who received a median of 3 (range 1−12) prior systemic therapies. Related AEs have occurred in 11 (73%) pts including IRR (n=10) and thrombocytopenia (n=3); Gr ≥3 AEs have occurred in 4 (27%) pts including thrombocytopenia (n=3), IRRs (n=2), and exfoliative dermatitis (n=1). Thrombocytopenia generally occurred on dosing days, recovered in 2-4 days, and has not worsened with increasing doses. IRRs typically occurred during initial infusions. The Gr 3 IRR events occurred in 2 pts in the 1 and 1.4 mg/kg cohorts; low Gr IRRs have occurred across doses in 8 pts. IRRs typically resolved without recurrence and low Gr events often resolved allowing for completion of infusions. For initial infusions, the Gr 3 IRRs prompted increasing infusion times from 1 hour up to 4 hours and discretional use of steroid pre-medication. The exfoliative dermatitis occurred Day 80 and led to treatment discontinuation in 1 pt with MF whose underlying disease confounded the etiology. PK results reveal dose dependent increases in exposure; PD studies indicate ~60% RO at end of infusion up to 1 mg/kg. Antitumor activity to date includes 1 PR and 1 skin CR in 6 evaluable pts in the 1 mg/kg cohort; 2 responding pts bridged to allogeneic transplantation. The mean % change in mSWAT scores were -0.4%, -27%, and -37% for 0.5, 0.7 and 1 mg/kg cohorts, respectively. 1.4 mg/kg cohort results will be presented at the meeting. Conclusions In Parts 1−3, TTI-621 doses of 0.05 to 0.5 mg/kg were well-tolerated and demonstrated single agent activity in multiple hematologic malignancies. Preliminary data from Part 4 dose optimization indicate that weekly infusions of TTI-621 up to 1.4 mg/kg are well-tolerated without dose limiting or cumulative thrombocytopenia. Antitumor activity was seen at 1 mg/kg; dose escalation is continuing at 2 mg/kg. Disclosures Horwitz: Janssen: Consultancy; Verastem: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; ASTEX: Consultancy; Portola: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Myeloid Therapeutics: Consultancy; Vividion Therapeutics: Consultancy; Infinity/Verastem: Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Affirmed: Consultancy; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Sawas:Flatiron Health: Current Employment; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company. Feldman:AstraZeneca: Consultancy; Viracta: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Janssen: Speakers Bureau; Bayer: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Portola: Research Funding. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Flinn:Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Agios: Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Curio Science: Consultancy; Constellation Pharmaceuticals: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Johnson & Johnson: Other; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Percival:Pfizer: Research Funding; Trillium: Research Funding; Nohla Therapeutics: Research Funding; Biosight: Research Funding; Oscotec: Research Funding; Cardiff Oncology: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Debiopharm Group: Research Funding. Savage:Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; BeiGene: Other: Steering Committee. Akilov:Mallinckrodt: Consultancy; Medivir: Consultancy; Seattle Genetics, Inc.: Consultancy; Kyowa Hakko Kirin: Consultancy; Soligenix: Honoraria; Pfizer: Research Funding; Actelion: Consultancy, Research Funding; Trillium Therapeutics Inc.: Consultancy, Research Funding. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Denovo: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Kim:Kyowa-Kirin Pharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen: Research Funding; Trillium: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Research Funding. Lin:Trillium Therapeutics Inc.: Current Employment. Catalano:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Molloy:Trillium Therapeutics Inc.: Current Employment. Large:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Ansell:Affimed: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding.