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Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children’s Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

TPS366 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a <3 weeks gap since prior ibrutinib therapy. Primary objectives include CR or ORR and DOR compared to (matched) historical controls (closely matched if possible). 2nd objectives include tolerance/safety, PFS, and pop-PK sampling for CA-4948. Exploratory objectives; response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance. Treatment: CA-4948 at RP2D+ibrubinib at labelled doses; 21-day cycles to be repeated in the absence of toxicity or progression. Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Abstract Context. —Cytoplasmic yellow bodies are a common and frequent histologic finding in hyalinizing trabecular adenoma of the thyroid gland, a morphologically distinctive neoplasm, and are visible in fine-needle aspiration biopsy of the tumor. Objective. —To determine the prevalence and frequency of cytoplasmic yellow bodies in common thyroid tumors. Design. —Microscopic slides of random cases of papillary carcinoma (61 cases), follicular adenoma (27 cases), and Hürthle cell adenoma (12 cases) were searched for cytoplasmic yellow bodies. Setting and Patients. —Slides were from patients who had undergone surgery at Mayo Clinic, Rochester, Minn, and were obtained from the Mayo Clinic Tissue Registry. Main Outcome Measure. —Presence or absence of cytoplasmic yellow bodies. Results. —Cytoplasmic yellow bodies were found in papillary carcinoma (62%), follicular carcinoma (22%), and Hürthle cell adenoma (83%) but were very infrequent numerically in each tumor type. Conclusions. —Cytoplasmic yellow bodies may be present in papillary carcinoma and in follicular and Hürthle cell adenomas, but because they are uncommon in these tumors, they are unlikely to be found in fine-needle aspiration biopsy smears. Therefore, cytoplasmic yellow bodies are a useful cytomorphologic indicator of hyalinizing trabecular adenoma of the thyroid gland.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p< 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.

Background: Multiple myeloma (MM) occurs most commonly among the older population, with a median age of 69 years at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options for patients with hematologic malignancies, including MM. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated deep and durable responses in the pivotal phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory MM (RRMM; Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall response rate (ORR), complete response (CR) rate, median duration of response (DOR), and median progression-free survival (PFS) were 73%, 33%, 10.7 months, and 8.8 months, respectively, among all 128 patients treated across the target dose levels of 150-450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells. The safety profile of ide-cel was consistent with the mechanism of action of CAR T cell therapies, with the most common toxicities across all dose levels being cytopenia (97%) and cytokine release syndrome (84%). In the present analyses, the efficacy and safety of ide-cel in elderly patients in the KarMMa study were evaluated. Methods: Patients enrolled in the KarMMa trial (NCT03361748) were required to have ≥3 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to their last regimen per International Myeloma Working Group (IMWG) criteria. Patients received ide-cel at target doses of 150, 300, or 450 × 106 CAR+ T cells after 3 days of lymphodepletion with cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) followed by 2 days of rest. The primary endpoint was ORR, and the key secondary endpoint was CR rate. Additional secondary endpoints included DOR, PFS, and safety. Patients were classified into ≥65 years and ≥70 years subgroups for analysis. Responses were assessed according to IMWG guidelines, and DOR and PFS were analyzed using Kaplan-Meier methods. Results: Of the 128 patients treated with ide-cel, 45 (35%) were aged ≥65 years and 20 (16%) were aged ≥70 years. The median age within these age groups was 69 years (range, 65-78) and 73 years (range, 70-78), the median number of prior antimyeloma regimens was 6 and 5, and the median time since initial diagnosis was 6.7 years and 6.1 years, respectively. Baseline characteristics were generally similar between age groups with the exception of tumor burden. Response rates for both age groups were comparable with those of the overall ide-cel treated population, with ORRs of 84% to 90% and CR rates of 31% to 35% (Table). Likewise, median DOR among responders in both age groups (10.9 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. At the time of analysis, overall survival data were still immature. No new safety signals were observed in either of the older age groups compared with those in the overall ide-cel treated population (Table). Conclusions: These results demonstrate deep and durable responses with ide-cel treatment together with a manageable safety profile in triple-class exposed patients with RRMM aged ≥65 years and ≥70 years. Outcomes were comparable with those observed in the overall ide-cel treated population. These data suggest ide-cel is safe and effective in older patients and provide further evidence supporting ide-cel as a promising treatment option in RRMM. Figure 1 Disclosures Berdeja: Karyopharm: Consultancy; Kite Pharma: Consultancy; Cellularity: Research Funding; Acetylon: Research Funding; Genentech, Inc.: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Lilly: Research Funding; Janssen: Consultancy, Research Funding; EMD Sorono: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glenmark: Research Funding; Kesios: Research Funding; Legend: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; CURIS: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Poseida: Research Funding. Raje:Takeda: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Immuneel: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Research Funding; Amgen: Consultancy. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Lin:Gamida Cells: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rodriguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Manier:Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene/BMS: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Jenssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Consultancy; Takeda: Consultancy. Einsele:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Sanford:BMS: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Jagannath:Takeda: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

Introduction: Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study). Methods: We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle). Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway. Disclosures Savona: BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Takeda: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Griffiths:Celgene/BMS: Honoraria, Research Funding; Genentech Inc: Research Funding; Boston Biomedical: Honoraria; AbbVie Inc: Honoraria; Persimmune: Research Funding; Novartis: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Astex Pharmceuticals: Research Funding. Zeidan:CCITLA: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Incyte: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria. Patel:DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Keating:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Dao:Astex Pharmaceuticals, Inc.: Current Employment. Fazal:Jansen: Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Abbvie: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Jazz: Research Funding; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy. Roboz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Busque:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Wells:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Azab:Astex Pharmaceuticals, Inc.: Current Employment. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.

AbstractCancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.