Citations

Introduction There is emerging evidence supporting the use of the radial artery (RA) as a preferred secondary conduit for coronary artery bypass grafting (CABG) as it is associated with higher rates of graft patency at 5 years when compared with saphenous vein grafts (SVG). The modified Allen’s test (MAT) is traditionally regarded as the standard of care in the assessment of ulnar artery (UA) patency prior to RA harvesting. Unfortunately, due to high false-positive rates, a substantial number of pre-CABG patients are found to have an abnormal MAT despite normal UA patency, resulting in inappropriate exclusion from RA harvesting. The SVG is generally used in its place when this occurs, resulting in potentially lower rates of long-term graft patency. Methods and analysis The CAPITAL iRADIAL-CABG trial is currently enrolling participants 18 years of age or older undergoing CABG for whom the treating physician is considering the use of an RA conduit. Eligible patients will be randomised in a 1:1 fashion to MAT or smartphone-based photoplethysmography application assessment to assess collateral palmar circulation prior to RA harvesting. The primary outcome of the trial is the use of the RA as a conduit during CABG. The primary safety outcome is postoperative palmar ischaemia as determined by clinical assessment or requirement of vascular intervention. Secondary outcomes include vascular complications, early graft failure, need for rescue percutaneous coronary intervention during the index hospitalisation and a composite cardiovascular outcome of myocardial infarction, stroke and cardiovascular death prior to discharge from hospital. A total of 236 participants are planned to be recruited. Ethics and dissemination The study was approved by the Ottawa Heart Science Network Research Ethics Board (approval number 20180865-01H). The study results will be disseminated via conference presentations and peer-reviewed publications. Trial registration number NCT03810729.

Purpose: To describe a case of chronic myeloid leukemia with retinal leukemic infiltration identified by optical coherence tomography (OCT) and OCT angiography. Methods: Case report. Results: A 64-year-old man presented with bilateral painless blurred vision and three weeks of fatigue, unintentional weight loss, and complete hearing loss. Dilated fundus examination of both eyes showed peripheral intraretinal hemorrhages with white centers, vascular tortuosity, and peripheral nonperfusion. No macular lesions were identified by slit-lamp examination, fundus photography, fundus autofluorescence, or fluorescein angiography. Optical coherence tomography through the macula revealed multiple hyperreflective lesions throughout the inner retinal layers. Some of these lesions showed intrinsic flow by OCT angiography, but many lesions did not. The bone marrow biopsy confirmed chronic myeloid leukemia, and these intraretinal lesions were deemed to be leukemic infiltrates. The patient regained vision after systemic chemotherapy with resolution of the retinal infiltrates over time. Conclusion: Primary leukemic retinal involvement can be challenging to diagnose, especially when the macula appears normal clinically. Optical coherence tomography and OCT angiography are useful imaging modalities for the detection of retinal leukemic infiltration. Completing a thorough review of systems and initiating an urgent, systemic work-up are warranted in cases of retinal infiltration.

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Tucatinib is a potent HER2 (ErbB2) tyrosine kinase inhibitor, selective for HER2 vs. epidermal growth factor receptor (EGFR) and is active vs. brain metastases. Safety and efficacy of tucatinib combined with paclitaxel, pertuzumab, and trastuzumab are unknown and were tested in a planned 10 patient (pt) safety run-in of the I-SPY 2 trial. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts with tumors that were HER2+ by FISH were eligible for this treatment. Treatment included tucatinib (max dose 300 mg) BID for 12 weeks with weekly paclitaxel 80 mg/m2 and trastuzumab (2 mg/kg weekly following loading), and pertuzumab (420 mg every 3 weeks following loading), followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel and trastuzumab with pertuzumab for 12 weeks followed by AC every 2 weeks x 4. All pts undergo serial MR imaging and response at 3 & 12 weeks is combined with real time pCR data to estimate, and continuously update, the predicted pCR rate for each trial arm. The goal of the trial is to identify/graduate regimens with ≥85.% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint. This run-in arm was conducted to determine safety of combining tucatinib with paclitaxel/trastuzumab/pertuzumab, monitoring special adverse events of interest including LFT elevations and gastrointestinal toxicities.Methods: The I-SPY 2 methods have been previously published. Results: 20 pts were evaluable in tucatinib treatment arm. The control arm included 329 historical controls enrolled since April 2010. The initial tucatinib dose was 300 mg BID. After enrollment of the first 8 pts, there were 3 pts with grade 3 LFT elevations, 2 pts with grade 2/3 diarrhea, 1 pt with grade 2 neutropenia, and 1 pt with grade 3 nausea. After this safety review, the tucatinib dose was lowered to 250 mg BID. Among 5 additional pts enrolled, 3 developed grade 2/3 LFT abnormalities. The protocol was then modified to tucatinib 150 mg BID days 1-28 and then 250 mg BID days 29-84; 7 pts were treated. Safety data were reviewed after 20 pts were enrolled; the arm was then suspended due to similar LFT elevations regardless of tucatinib dose reduction or schedule. 7 of 20 pts (35%) had reversible Grade 3 or higher ALT/AST elevation (Table). No pt met criteria for Hy’s Law. In terms of efficacy, 12 of 14 evaluable pts had > 80% reduction of tumor volume by 12 weeks, measured by MRI assessment of functional tumor volume (FTV). Conclusion: The goal of the run-in arm was to determine the safety of adding tucatinib to the combination of paclitaxel/trastuzumab/pertuzumab. The addition of tucatinib resulted in unacceptable but reversible LFT elevations despite tucatinib dose reduction. Tucatinib containing therapy resulted in >80% decline in tumor volume at 12 weeks in 86% of pts. Tucatinib showed a high level of activity when combined with paclitaxel/trastuzumab/pertuzumab, but the combination is not feasible. Table: Number of pts with grade 2, 3, and 4 LFT elevations by treatment schedule (highest grade per patient per event, ALT or Treatment scheduleGrade 2 LFT elevationGrade 3 LFT elevationGrade 4 LFT elevationTucatinib 300 mg BID030Tucatinib 250 mg BID210Tucatinib 150 mg BID days 1-28 followed by 250 mg BID days 29 to 84112 Citation Format: David A Potter, Erin Roesch, Christina Yau, Ruixiao Lu, Denise Wolf, Susan Samson, Debra Stafford, Kathy S Albain, Claudine Isaacs, Meghana Trivedi, Douglas Yee, Judy Boughey, Alexandra Thomas, A. Jo Chien, Nola Hylton, Wen Li, Angela DeMichele, Jane Perlmutter, W. Fraser Symmans, Dawn L Hershman, Michelle Melisko, Laura J van 't Veer, Amy Wilson, Smita M Asare, Donald A Berry, Richard Schwab, Hope S Rugo, Laura J Esserman. Evaluation of Tucatinib + (Paclitaxel + Pertuzumab + Trastuzumab) followed by AC in high-risk HER2 positive (HER2+) stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-07.

Abstract Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-10-02.

ABSTRACT Introduction: Targeted regional optimization (TRO) describes partial resuscitative endovascular balloon occlusion of the aorta strategy that allows for controlled distal perfusion to balance hemostasis and tissue perfusion. This study characterized hemodynamics at specific targeted distal flow rates in a swine model of uncontrolled hemorrhage to determine if precise TRO by volume was possible. Methods: Anesthetized swine were subjected to liver laceration and randomized into TRO at distal flows of 300 mL/min (n = 8), 500 mL/min (n = 8), or 700 mL/min (n = 8). After 90 min, the animals received damage control packing and were monitored for 6 h. Hemodynamic parameters were measured continuously, and hematology and serologic labs obtained at predetermined intervals. Results: During TRO, the average percent deviation from the targeted flow was lower than 15.9% for all cohorts. Average renal flow rates were significantly different across all cohorts during TRO phase (P < 0.0001; TRO300 = 63.1 ± 1.2; TRO500 = 133.70 ± 1.93; TRO700 = 109.3 ± 2.0), with the TRO700 cohort having less renal flow than TRO500. The TRO500 and TRO700 average renal flow rates inverted during the intensive care unit phase (P < 0.0001; TRO300 = 86.20 ± 0.40; TRO500 = 148.50 ± 1.45; TRO700 = 181.1 ± 0.70). There was higher blood urea nitrogen, creatinine, and potassium in the TRO300 cohort at the end of the experiment, but no difference in lactate or pH between cohorts. Conclusion: This study demonstrated technical feasibility of TRO as a strategy to improve outcomes after prolonged periods of aortic occlusion and resuscitation in the setting of ongoing solid organ hemorrhage. A dose-dependent ischemic end-organ injury occurs beginning with partial aortic occlusion that progresses through the critical care phase, with exaggerated effect on renal function.

AbstractPreclinical data demonstrated that combining an anti–programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti–PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.

Abstract Abstract text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which 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/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible 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 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: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in &gt; 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. Figure 1 Figure 1. Disclosures Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. McCloskey: Pfizer: Consultancy; Takeda: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Geron: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Janssen: Research Funding; Onconova: Research Funding; Genentech: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; MedImmune: Research Funding; Jazz: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; Astellas: Consultancy; Astex: Research Funding; Jazz: Consultancy; Jasper: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Abstract Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab. Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation. The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities. 1Kapoor et al. Blood (2019) 134 (Supplement_1): 864. Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures O'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.