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Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized, placebo-controlled, phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS]: 38.6 vs 15.6 months in MRD- vs MRD+ patients, HR 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median 18.8 vs 11.6 months, HR 0.65) or at the 14-month landmark (median 16.8 vs 10.6 months, HR 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single timepoint MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant endpoint during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status.

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

A harmonic vortex beam is a typical vector beam with a helical wavefront at harmonic frequencies (e.g., second and third harmonics). It provides an additional degree of freedom beyond spin- and orbital-angular momentum, which may greatly increase the capacity for communicating and encoding information. However, conventional harmonic vortex beam generators suffer from complex designs and a low nonlinear conversion efficiency. Here, we propose and experimentally demonstrate the generation of a large second-harmonic (SH) vortex beam with quasi-nonlinear spin–orbit interaction (SOI). High-quality SH vortex beams with large topological charges up to 28 are realized experimentally. This indicated that the quasi-angular-momentum of a plasmonic spiral phase plate at the excitation wavelength (topological charge, q) could be imprinted on the harmonic signals from the attached WS2 monolayer. The generated harmonic vortex beam has a topological charge of ln=2nq (n is the harmonic order). The results may open new avenues for generating harmonic optical vortices for optical communications and enables novel multi-functional hybrid metasurface devices to manipulate harmonic beams.

This research focuses on the bias and type I error control issues when the marginal structural models (MSMs) are applied to evaluate the causal survival benefits of active intervention versus control in randomized clinical trials (RCTs) with treatment switching after disease progression. When MSMs are applied in the RCT setting, the question of interest, model specifications, strategies for type I error control, bias reduction, etc. differ somewhat from those for observational studies. This manuscript discusses the approaches used to accommodate these differences. Through Monte Carlo simulations and a case study, our research demonstrates that, with sufficient attention paid to issues applicable to RCTs in particular, MSMs may perform better than the inverse probability of censoring weighting (IPCW) method in analyzing the survival endpoint in RCTs with treatment switching because more information is used by the MSM.

Metalenses can potentially reduce the size and complexity of existing cameras, displays, and other optical devices, owing to their capability of flexible manipulation of the polarization, amplitude, and phase of light. However, metalenses capable of maintaining polarization and broadband wavefront shaping under arbitrarily polarized excitation have not been studied. In this study, we present the first demonstration of a biomimetic moth-eye-shaped metalens for polarization-maintaining, broadband and angle-insensitive focusing under an arbitrarily polarized excitation in the mid-infrared waveband (3.1–8.0 µm). Modulation and focusing efficiencies of 92% and 90%, respectively, were achieved. Moreover, a bifocal moth-eye-shaped metalens operating at normal and oblique incidences was realized. Compared to previously reported metalenses, the one proposed in this study exhibited a better focusing under oblique incidence, ensuring light transmission as effectively as a traditional lens. This study paves the way for the development of polarization-maintaining, broadband, and angle-insensitive microscale optical devices and imaging systems.

Background High-flow nasal cannula (HFNC) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. However, evidence to support the use of HFNC in chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure after extubation is limited. This study was conducted to test if HFNC is non-inferior to non-invasive ventilation (NIV) in preventing post-extubation treatment failure in COPD patients previously intubated for hypercapnic respiratory failure. Methods COPD patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to HFNC or NIV at extubation at two large tertiary academic teaching hospitals. The primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (NIV for patients in the NFNC group or vice versa). Results Ninety-six patients were randomly assigned to the HFNC group or NIV group. After secondary exclusion, 44 patients in the HFNC group and 42 patients in the NIV group were included in the analysis. The treatment failure rate in the HFNC group was 22.7% and 28.6% in the NIV group—risk difference of − 5.8% (95% CI, − 23.8–12.4%, p = 0.535), which was significantly lower than the non-inferior margin of 9%. Analysis of the causes of treatment failure showed that treatment intolerance in the HFNC group was significantly lower than that in the NIV group, with a risk difference of − 50.0% (95% CI, − 74.6 to − 12.9%, p = 0.015). One hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation (p p = 0.006). The comfort score and incidence of nasal and facial skin breakdown of the HFNC group was also significantly better than that of the NIV group [7 (6–8) vs 5 (4–7), P p = 0.027], respectively. Conclusion Among COPD patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of HFNC after extubation did not result in increased rates of treatment failure compared with NIV. HFNC also had better tolerance and comfort than NIV. Trial registration chictr.org (ChiCTR1800018530). Registered on 22 September 2018, http://www.chictr.org.cn/usercenter.aspx

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD− vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD− status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD− status vs those converting from MRD− to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD−. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single–time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD− status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD− status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.

BackgroundSUMOylation is a post-translational modification that serves as an important modulator of immune responses via its role in constraining the type I interferon (IFN-1) response. TAK-981 is a small molecule that inhibits SUMOylation and increases IFN-1-dependent innate immune responses with the potential to enhance adaptive immunity. Here, we report dose-escalation data from a TAK-981 Phase 1/2 clinical study (NCT03648372), the first clinical data for a SUMOylation inhibitor.MethodsAdults with advanced/metastatic solid tumors or relapsed/refractory lymphomas received TAK-981 IV twice-weekly (BIW; days 1, 4, 8, 11) or once-weekly (QW; days 1, 8) in 21-day cycles. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, plus available pharmacokinetic/pharmacodynamic (PK/PD) data. Phase 1 objectives were to determine TAK-981 safety/tolerability and establish the recommended phase 2 dose (RP2D).ResultsSeventy-six patients received TAK-981 at 10 dose levels (3–40 mg BIW; 60–120 mg QW/BIW). Median age was 61 years (range, 38–79); 42 (55.3%) patients were female. Four dose-limiting toxicities were seen in 62 evaluable patients (transient grade 3 ALT/AST elevation, 60 mg BIW; grade 3 pneumonitis, 90 mg BIW; grade 3 stomatitis and grade 3 cognitive disturbance, 120 mg BIW). Per BLRM, 120 mg BIW was determined to be the maximum tolerated dose. At data cut-off, median treatment duration was 2 cycles (range, 1–12); 13 (17.1%) patients were ongoing. table 1 summarizes TAK-981 safety. The most common (≥20%) treatment-emergent adverse events (TEAEs) were fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), decreased appetite (22.4%). Common (≥5%) grade ≥3 TEAEs were hypokalemia (9.2%), anemia (7.9%), lymphocyte count decreased (6.6%), abdominal pain (5.3%). Grade 2 cytokine release syndrome was reported in 4 (5.2%) patients; symptoms resolved within 12–24 hours with supportive oxygen and/or IV fluids. One partial response was observed at 40 mg TAK-981 BIW in a patient with relapsed/refractory HER2-negative, hormone receptor-positive breast cancer. TAK-981 exhibited linear PK, with approximately dose-proportional exposure and a mean terminal half-life of 3.8–10.8 hours at ≥60 mg. Evidence of dose-dependent target engagement (figure 1), and PD (figures 2–4) in blood were observed. The single-agent TAK-981 RP2D was 90 mg BIW.Abstract 476 Table 1Summary of TAK-981 safety profileAbstract 476 Figure 1PD in patients receiving TAK-981 on the BIW schedule: target engagement.Blood samples were collected on Cycle 1 Day 1 pre-dose and at multiple timepoints after TAK-981 administration. Target engagement in T cells was detected by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formed during the inhibition of the SUMO-activating enzyme by TAK-981; Cycle 1 Day 1 signal increased at 1 hour post-end-of-infusion compared to the background level observed pre-dose.Abstract 476 Figure 2PD in patients receiving TAK-981 on the BIW schedule: SUMOylation.SUMOylation in T cells, detected by flow cytometry with an antibody recognizing SUMO2/3, decreased at 1 hour post-end-of-infusion on Cycle 1 Day 1 compared to pre-dose, indicating that fewer SUMO2/3 chains are formed when the SUMO-activating enzyme is inhibited.Abstract 476 Figure 3PD in patients receiving TAK-981 on the BIW schedule: upregulation of CXCL10 expression.Upregulation of mRNA levels of CXCL10, an IFN-I-regulated gene, in peripheral blood. Gene expression was measured using Nanostring nCounter at Cycle 1 Day 1 pre-dose and at several timepoints post-dose. Data for maximum increase at 8 or 24 hours, relative to pre-dose, is shown.Abstract 476 Figure 4PD in patients receiving TAK-981 on the BIW schedule: NK cell activation.NK cell activation in peripheral blood measured by flow cytometry. Percentage of CD69-positive NK cells at Cycle 1 Day 1 pre-dose and at 24 hours post-end-of-infusion is shown by patient for each dose.ConclusionsThe data generated in this study support continued TAK-981 development for treatment of solid tumors and lymphoma. The Phase 2 study expansion is ongoing in patients with advanced/metastatic non-small-cell lung, cervical, and colorectal cancer, and in relapsed/refractory non-Hodgkin lymphoma.Trial RegistrationClinical Trial identification: ClinicalTrials.gov. Identifier: NCT03648372Ethics ApprovalThe study was approved by the Institutional Review Board or Institutional Ethics Committee of all participating institutions

Nonlinear photonic crystals are capable of highly efficient nonlinear wavefront manipulation, providing a promising platform for compact and large-scale integrated nonlinear devices. However, the current nonlinear encoding methods for nonlinear photonic crystals inherently require a number of disordered and complex microstructures, which are quite challenging in a real fabrication process. Herein we propose and experimentally demonstrate a nonlinear detour phase method for nonlinear wavefront manipulation in nonlinear photonic crystals. With the proposed method, the designed nonlinear detour phase hologram only requires a set of basic building blocks with simple shapes, which are easy to fabricate by using the femtosecond laser writing technique. The second-harmonic hologram is demonstrated by designing the nonlinear detour phase patterns, and the quasi-phase-matching scheme in the second-harmonic holographic imaging process is also discussed. This study conceptually extends the conventional detour phase method into the nonlinear regime, offering new possibilities for compact nonlinear micro-devices with multi-functions.

Acute lung injury (ALI) is a serious respiratory syndrome characterized with uncontrolled inflammatory response. Oxyberberine has strong potential for clinical usage since it showed strong anti-inflammatory, antifungal, and antiarrhythmic effects in various diseases. In the present study, we evaluated whether oxyberberine can inhibit lipopolysaccharide- (LPS-) induced ALI in vivo and further evaluated the possible involvement of mitophagy in vitro by using A549 cells, a human lung epithelial cell line. Our in vivo study shows that oxyberberine significantly inhibited LPS-induced lung pathological injury and lung edema, as indicated by the changes in lung wet/dry ratio and total protein levels in the BALF in mice. Moreover, oxyberberine inhibited inflammation, as indicated by the changes of neutrophil accumulation and production of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 in both the lung and bronchoalveolar lavage fluid (BALF) in ALI mice. Our in vitro study shows that LPS significantly decreased the protein level of mitochondrial proteins, including cytochrome c oxidase subunit IV (COX IV), p62, and mitofusin-2 (Mfn2) in A549 cells. In addition, LPS induced significant Parkin1 translocation from cytoplasm to mitochondria. These changes were significantly inhibited by oxyberberine. Notably, the inhibitory effect of oxyberberine was almost totally lost in the presence of lysosome fusion inhibitor bafilomycin A1 (Baf), a mitophagy inhibitor. In conclusion, the present study demonstrated that oxyberberine alleviated LPS-induced inflammation in ALI via inhibition of Parkin-mediated mitophagy.

2506 Background: SUMOylation is a post-translational modification with a role in limiting type 1 interferon (IFN-1)-dependent immune responses. Subasumstat is a small-molecule inhibitor of SUMOylation with the potential to increase antitumor immunity and overcome tumor resistance to checkpoint inhibitors (CPI) by inducing IFN-1 signaling. Preclinical data suggest that subasumstat enhances antigen cross-presentation, promoting T cell dependent antitumor responses; subasumstat plus an anti-PD-1 CPI has shown synergistic tumor growth inhibition and activation of CD8+ T cells and natural killer cells in syngeneic mouse models. We report data from the dose escalation part of a phase 1b study of subasumstat with pembrolizumab in pts with relapsed/refractory, CPI-exposed, non-squamous non-small-cell lung cancer (NSCLC) or microsatellite-stable colorectal cancer (MSS-CRC). Methods: Pts received escalating doses (40, 60, 90, and 120 mg) of subasumstat IV in 3 dosing schedules: days 1 and 8 (QW), days 1, 4, 8, and 11 (BIW), or days 1, 8, and 15 (90 mg only) of 21-day cycles, plus pembrolizumab 200 mg IV on day 1 of each cycle for 2 years or until disease progression or unacceptable toxicity. Dose escalation was guided by Bayesian optimal interval design. Phase 1b primary objectives were safety, tolerability, and the recommended phase 2 dose of subasumstat with pembrolizumab. Results: As of October 13, 2021, 43 (35 MSS-CRC; 8 NSCLC) pts had received ≥1 dose of subasumstat (22 BIW [40–120 mg]; 15 QW [90 –120 mg]; 6 on days 1, 8, 15 [90 mg)]. Median number of treatment cycles was 3; 28 (65%) pts had discontinued treatment, 21 (49%) due to progressive disease. Median age was 58 years (range 34–77); 56% of pts were male. One pt had a dose-limiting toxicity of grade 3 angioedema at 120 mg BIW. The maximum tolerated dose was not identified. Treatment-emergent adverse events (TEAEs) occurred in 38 (88%) pts; subasumstat-related TEAEs occurred in 34 (79%) pts, and included chills in 20 (47%), pyrexia in 16 (37%), fatigue in 9 (21%), anemia in 6 (14%), and stomatitis in 5 pts (12%; 3 [50%] in the 120 mg BIW cohort). Grade ≥3 TEAEs occurred in 24 (56%) pts; subasumstat-related grade ≥3 TEAEs reported in 10 (23%) pts included anemia, pyrexia, and increased aspartate aminotransferase (2 [5%] pts each). Pharmacokinetic activity of subasumstat was linear and decreased in a tri-phasic manner. Subasumstat exerted pharmacodynamic activity including target engagement, SUMOylation inhibition and increased IFN-1 signaling. Partial responses were observed at ≥40 mg dose levels in pts with NSCLC and MSS-CRC. Conclusions: Subasumstat plus pembrolizumab showed a favorable safety profile and promising anti-tumor activity in pre-treated NSCLC and MSS-CRC pts. Updated data will be presented at the meeting. Subasumstat plus pembrolizumab is currently in phase 2 clinical development (NCT04381650). Clinical trial information: NCT04381650.

Recently, multi-functional nonlinear wavefront control has attracted extensive attention. In particular, nonlinear holography can carry information and has potential for application in information encoding and computing. However, it is quite challenging because it puts forward higher requirements with nonlinear conversion efficiency and wavefront control performance. Here, we propose and experimentally demonstrate chirality-selected second-harmonic (SH) holography based on a Au–WS2 nonlinear optical interface. It is realized using nonlinear geometry phase control with a sub-wavelength resolution. Furthermore, binary amplitude manipulation is introduced by replacing specific rectangular nanoholes with square nanoholes. This indicates that the average intensity of holograms is increased by 39% and the hologram variation coefficient is decreased by 44% in comparison with that in pure geometry phase control. In addition, the SH signal from the monolayer WS2 with a large second-order susceptibility is further enhanced by the strong local-field in Au nanoholes, leading to a high SH conversion efficiency of 10−6. Therefore, it offers an important stepping stone towards multi-functional SH holography, which may have potential for application in nonlinear information encoding and processing.

Context: Ponatinib (PON) is active against native BCR-ABL1 and all identified single-resistance mutations, including T315I. In the PACE study, heavily pretreated patients with Ph+ ALL treated with PON had nondurable responses because of new compound mutations (Cortes 2013, 2018). Sequential use of tyrosine kinase inhibitors (TKIs) can select for T315I and compound BCR-ABL1 mutants. Use of first-line PON in Ph+ ALL may decrease likelihood of these mutations. A Phase 2 study of PON with chemotherapy in newly diagnosed Ph+ ALL reported improved long-term outcomes (5-year event-free survival, 67%; overall survival, 71%) versus a second-generation TKI (Sasaki 2016). Objective: Compare efficacy and safety of first-line PON versus imatinib with reduced-intensity chemotherapy in patients with newly diagnosed Ph+ or BCR-ABL1–positive ALL (p190/p210 transcript type). Methods: PhALLCON (NCT03589326) is a Phase 3, open-label, parallel-assignment, randomized study. Patients remain on treatment until they complete study, relapse from complete remission (CR), have progressive disease, have unacceptable toxicity, withdraw consent, proceed to hematopoietic stem cell transplant (HSCT), or sponsor terminates study. The study started August 2018 and will be conducted in up to 35 countries. Currently, 115 sites are active globally. Accrual is ongoing, with 134 patients enrolled. The trial will enroll ≈230–320 patients (≥18 years) with ECOG performance status ≤2. Patients will be randomized 2:1 to PON 30 mg/d or imatinib 600 mg/d orally, with reduced-intensity chemotherapy in induction (Cycles 1–3), consolidation (Cycles 4–9), and maintenance (Cycles 10–20). Primary endpoint is measurable residual disease (MRD)-negative (BCR-ABL1/ABL1 ≤0.01%) CR at end of induction (≈3 months). The key secondary endpoint is event-free survival, defined as dates of randomization until death (any cause), failure to achieve MRD-negative CR by end of induction, or relapse from CR. Other secondary endpoints include CR/incomplete blood count recovery rates, molecular response rates, MRD-negative CR duration, primary induction failure, overall response rate, CR duration, time to treatment failure, MR4.5 duration after induction, overall survival, and safety, including arterial occlusive/venous thromboembolic events. Other analyses include a subgroup analysis of patients with/without HSCT and an exploratory analysis by mutation status. PhALLCON is sponsored by Takeda Development Center Americas, Inc.

Summary This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty‐eight patients were enrolled across the 3 drug‐drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least‐squares mean area under the plasma concentration‐time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91‐1.31) and was 1.11 (0.86‐1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least‐squares mean ratio of 0.26 [90%CI 0.18‐0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least‐squares mean ratio of 0.46 [90%CI 0.29‐0.73]) in the presence of rifampin. The clinical drug‐drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P‐glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

Background The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide–dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. Methods Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd). Results At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%). Conclusions This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. Trial registration ClinicalTrials.gov, NCT01564537 Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0501-4) contains supplementary material, which is available to authorized users.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; >4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (>5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time ( Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation

To investigate the benefits and risks of stress ulcer prevention (SUP) using proton pump inhibitors (PPI) for critical patients.The clinical data of adult critically ill patients admitted to the intensive care unit (ICU) of Northern Jiangsu People's Hospital from January 2016 to December 2018 were retrospectively analyzed. All patients who were treated with PPI for SUP within the first 48 hours after ICU admission were enrolled in the SUP group. Those who not received PPI were enrolled in the control group. A one-to-one propensity score matching (PSM) was performed to control for potential biases. The gender, age, underlying diseases, main diagnosis of ICU, drug use before ICU admission, sequential organ failure score (SOFA) at ICU admission, risk factors of stress ulcer (SU) and PPI usage were recorded. The end point was the incidence of gastrointestinal bleeding, hospital acquired pneumonia, Clostridium difficile infection and 30-day mortality. Kaplan-Meier survival curves were plotted, and survival analysis was performed using the log-rank test.1 972 critical patients (788 in the SUP group and 1 184 in the control group) were enrolled, and each group enrolled 358 patients after PSM. Prior to PSM, compared with the control group, the SUP group had older patients, more underlying diseases, higher proportion of acute coronary syndrome (ACS), acute cerebrovascular disease, acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and poisoning in main diagnosis of ICU, more serious illness, and more risk factors of SU, indicating that ICU physicians were more likely to prescribe SUP for these patients. The incidence of gastrointestinal bleeding in the SUP group was significantly lower than that in the control group [1.8% (14/788) vs. 3.7% (44/1 184), P0.05], while the incidence of hospital acquired pneumonia and 30-day mortality were significantly higher than those in the control group [6.6% (52/788) vs. 3.5% (42/1 184), 17.9% (141/788) vs. 13.1% (155/1 184), both P0.01]. There was no significant difference in the incidence of Clostridium difficile infection between the SUP group and the control group [2.9% (23/788) vs. 1.8% (21/1 184), P0.05]. After the propensity scores for age, underlying diseases, severity of illness and SU risk factors were matched, there was no significant difference in the incidence of gastrointestinal bleeding or 30-day mortality between the SUP group and the control group [2.2% (8/358) vs. 3.4% (12/358), 15.9% (57/358) vs. 13.7% (49/358), both P0.05], but the incidence of hospital acquired pneumonia in the SUP group was still significantly higher than that in the control group [6.7% (24/358) vs. 3.1% (11/358), P0.05]. Kaplan-Meier survival curve analysis showed that the 30-day cumulative survival rate of the SUP group was significantly lower than that of the control group before the PSM (log-rank test: χFor critical patients, the use of PPI for SUP could not significantly reduce the incidence of gastrointestinal bleeding and mortality, but increase the risk of hospital acquired pneumonia.

TPS2667 Background: SUMOylation, a posttranslational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in regulating type I interferon (IFN-I)-dependent innate response and functions to constrain the innate immune response, which can impair tumor immune surveillance. TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme subunit 2 (SAE2). Inhibition of SAE2 by TAK-981 disrupts SUMOylation, thereby allowing innate immune system activation. In ex vivo assays, TAK-981 increased phagocytic activity of monocyte-derived macrophages, increased natural killer cell cytotoxicity, and induced markers of dendritic cell activation and maturation via IFN-I signaling. In syngeneic mouse models, TAK-981 resulted in antitumor activity, including complete remissions, and a sustained, protective antitumor immune response. Methods: This first-in-human study of single-agent TAK-981 comprises two parts. Phase 1 primary objectives are to determine safety and tolerability, and to select a recommended phase 2 dose (RP2D); secondary objectives are to assess preliminary antitumor activity, characterize pharmacokinetics (PK), and explore pharmacodynamic (PD) biomarkers. This phase will enroll ̃70 pts with untreatable locally advanced or metastatic solid tumors or RR lymphoma. The phase 2 primary objective is to evaluate preliminary efficacy at the RP2D in ̃132 pts with non-squamous non-small cell lung cancer, cervical cancer, microsatellite-stable colorectal cancer, or CD20+ RR diffuse large B-cell lymphoma or follicular lymphoma. Pts receive TAK-981 via a 1-hour intravenous infusion on days 1, 4, 8, and 11 in 21-day cycles until unacceptable toxicity, pt withdrawal, or death. Dose escalation is proceeding from 3 mg, guided by an adaptive 3+3 design combined with Bayesian logistic regression modelling with overdose control, plus consideration of other safety, clinical, PK, and PD data. The RP2D will be based on the maximum tolerated dose (MTD) or on a biologically effective dose (BED) that is ≤MTD. The BED is defined as a dose at which there is evidence of drug-target engagement and inhibition of SUMOylation, plus: induction of cytokines/chemokines and/or IFN-I signature in tumor or blood; evidence of increased T cell infiltration in tumor; or antitumor activity. PK/PD modeling in the BED range is ongoing and will be used in RP2D determination. Clinical trial information: NCT03648372.

The nonlinear Talbot effect is a near-field nonlinear diffraction phenomenon in which the self-imaging of periodic objects is formed by the second harmonics of the incident laser beam. We demonstrate the first, to the best of our knowledge, example of nonlinear Talbot self-healing, i.e., the capability of creating defect-free images from faulty nonlinear optical structures. In particular, we employ the tightly focused femtosecond infrared optical pulses to fabricate LiNbO3 nonlinear photonic crystals and show that the defects in the form of the missing points of two-dimensional square and hexagonal periodic structures are restored in the second harmonic images at the first nonlinear Talbot plane. The observed nonlinear Talbot self-healing opens up new possibilities for defect-tolerant optical lithography and printing.

8527 Background: Maintenance therapy delays disease progression in non-ASCT NDMM patients. However, in practice, currently used maintenance therapies may be limited to fixed duration due to toxicity and route of administration; additional options are needed. Methods: 706 non-ASCT NDMM patients who received 6–12 months of standard-of-care induction therapy and achieved at least a partial response (≥PR) were randomized 3:2, double-blind, to the oral proteasome inhibitor (PI) ixazomib (n = 425; 3 mg, cycles 1–4, then, if tolerated, 4 mg, cycle 5 onwards) vs placebo (n = 281) on days 1, 8, and 15 of 28-day cycles for ≤2 yrs. Patients were stratified by prior PI exposure (yes vs no), pre-induction International Staging System (ISS) disease stage (I/II vs III), age ( < 75 vs ≥75 yrs), and post-induction best response (complete or very good partial response [CR/VGPR] vs PR). Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics were well balanced. Overall median age was 73 yrs, 38% of patients were aged ≥75 yrs, 35% were ISS stage III, and 22%/40%/38% had CR/VGPR/PR post induction. Overall, 82% of patients received a PI and 33% an immunomodulatory drug as part of their induction regimen. At a median follow-up of 21.1 months, median PFS was 17.4 months with ixazomib vs 9.4 months with placebo (hazard ratio [HR] 0.659, 95% confidence interval [CI] 0.542–0.801, p < 0.001). Significant (p < 0.001) PFS benefit was seen in patients who achieved CR/VGPR post induction (Table). Overall survival data are not yet mature (19% of events); follow-up is ongoing. Treatment-emergent adverse events (TEAEs) were mostly grade 1–2 (37% vs 23% of patients had grade ≥3 TEAEs with ixazomib vs placebo). Common TEAEs for ixazomib vs placebo included nausea (27% vs 8%), vomiting (24% vs 4%), and diarrhea (23% vs 12%); 5% vs 6% of patients had new primary malignancies. No cumulative toxicities were observed. Conclusions: Ixazomib maintenance therapy in non-ASCT NDMM patients showed a clinically meaningful 34% reduction in the risk of progression or death, with a well-tolerated safety profile. Ixazomib is the first oral PI maintenance option for non-ASCT NDMM patients. Clinical trial information: NCT02312258 . [Table: see text]

We extend the functionality of nonlinear photonic crystals by fabricating a structure combining a few individual optical transformations in second harmonic generation. In particular, we employed all-optical spontaneous polarization reversal in ferroelectrics to create nonlinear holograms with curved fork-like spatial modulation of nonlinearity for the generation of second harmonic optical vortices. The curved fork-like structure represents a combination of a standard vortex harmonic generator (fork structure) and an axicon, thereby allowing us to realize the second harmonic “perfect vortices” whose diameter remains constant independently of their topological charge.

We present an indirect and non-destructive optical method for domain statistic characterization in disordered nonlinear crystals, having a spatially random distribution of ferroelectric domains with homogeneous refractive index. This method, based on a combination of numerical simulations and experimental measurements, analyses the wavelengthdependent second harmonic spatial distribution. We apply this technique to the characterization of two different random media, with drastically different statistical distributions of ferroelectric domains.

© 2018 [Optical Society of America]. Users may use, reuse, and build upon the article, or use the article for text or data mining, so long as such uses are for non-commercial purposes and appropriate attribution is maintained. All other rights are reserved. We present an indirect, non-destructive optical method for domain statistic characterization in disordered nonlinear crystals having homogeneous refractive index and spatially random distribution of ferroelectric domains. This method relies on the analysis of the wave-dependent spatial distribution of the second harmonic, in the plane perpendicular to the optical axis in combination with numerical simulations. We apply this technique to the characterization of two different media, Calcium Barium Niobate and Strontium Barium Niobate, with drastically different statistical distributions of ferroelectric domains.

Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1 center dot 8 mg/kg intravenously once every 3 weeks) in 60 patients (aged >= 18 years) with CD30-positive relapsed/refractory HL, a history of >= 1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi-agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4 center dot 6 months and median duration of CR was 6 center dot 1 months. After a median follow-up of 6 center dot 9 and 16 center dot 6 months, median PFS and OS were 4 center dot 8 months (95% confidence interval, 3 center dot 0-5 center dot 3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (>= 10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high-risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.

Summary This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.

We demonstrate an indirect non-destructive optical method for the characterization of ferroelectric domain size and distribution based on the analysis of the generated second harmonic spatial distribution. This method is based on a combination of experimental measurements and numerical simulations and allows obtaining information of domain statistics in disordered structures via the analysis of wavelength dependence of the angular second harmonic diffraction pattern.

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4-mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4-mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28-day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic-evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least-squares mean ratios (capsule B versus capsule A) were 1.16 for Cmax (90% confidence interval [CI], 0.84-1.61) and 1.04 for AUC0-216 (90%CI, 0.91-1.18). The most frequently reported grade 3 drug-related adverse events were fatigue (15%) and nausea (10%); there were no grade 4 drug-related adverse events. These results support the combined analysis of data from studies that used either formulation of ixazomib during development.

Details of all sitesâ ethics committee approvals. (DOC 44 kb)

Supplementary methods. Hou C16010 China Continuation study J Hematol Oncol. (DOCX 38 kb)

Supplementary results. Hou C16010 China Continuation study J Hematol Oncol. (DOCX 40 kb)

Background TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate. SUMOylation has a key role in restraining Type I interferon (IFN) responses (Decque, Nature Immunology 2016; Seeler, Nat Rev Cancer 2017). In-vivo preclinical studies have demonstrated that inhibition of SUMOylation by TAK-981 promotes innate and adaptive antitumor immune responses dependent on induction of Type I IFN signaling. This includes modulating the activity of innate effector cells. In macrophages, TAK-981 induced polarization towards the M1 phenotype, upregulated Fcγ receptors, and enhanced phagocytosis and antibody-dependent cellular phagocytosis (ADCP) in an ex-vivo assay. In natural killer (NK) cells, TAK-981 promoted upregulation of the activation marker CD69 and the degranulation marker CD107, increased the number of IFNγ+ NK cells in tumors, and enhanced cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) in an ex-vivo assay. This enhancement of ADCP and ADCC supports the combination of TAK-981 with IgG1 therapeutic monoclonal antibodies. In-vivo studies have demonstrated synergistic antitumor activity with TAK-981 combined with rituximab in severe combined immunodeficient mice (lacking lymphocytes but retaining a functional innate immune system) bearing human diffuse large B-cell lymphoma xenografts. Specifically, in OCI-Ly-10 and TMD8 tumor models, the combination reproducibly resulted in complete regression (CR) of all treated tumors at doses at which no CRs were achieved with either single agent. In the PHTX-166L patient-derived xenograft model, tumor growth delay and 1 CR were achieved at doses that showed only very modest tumor growth delay with single agents. Methods This is an open-label, multicenter, non-randomized, phase 1b/2 study investigating the safety and efficacy of TAK-981 in combination with rituximab in adult patients with CD20-positive r/r NHL. The study comprises Phase 1b (dose escalation) and Phase 2 (2 treatment arms: indolent [iNHL] and aggressive [aNHL] NHL). Eligible patients must have CD20-positive r/r NHL (excluding mantle cell lymphoma in Phase 2) and have failed ≥2 prior lines of therapy; one prior line of therapy must have included a CD20-directed antibody. TAK-981 will be administered intravenously (IV) on Days 1 and 8 in 21-day cycles. The starting dose will be informed by the ongoing first-in-human TAK-981-1002 Phase 1 trial (NCT03648372). Rituximab will be administered IV weekly at 375 mg/m2 x 3 doses followed by 375 mg/m2 on Day 1 of subsequent 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity. Phase 1b will enroll ~34 patients to identify the maximum tolerated dose and/or pharmacologically active dose of the combination. Dose escalation will be guided by an adaptive Bayesian logistic regression model that implements escalation with overdose control. Phase 2 will enroll ~56 patients in 2 parallel arms (iNHL/aNHL). Efficacy of the combination will be assessed by the investigator per Lugano 2014 response criteria. The primary endpoint for Phase 2 is overall response rate (ORR). The design is based on Simon's 2-stage design, in which the null hypothesis for each arm (true ORR is 20%) will be tested against a one-sided alternative. In the first stage, 12 patients will be accrued in each arm. If there are ≤2 responses in the 12 patients in either arm, the arm(s) will be stopped. Otherwise, 13 additional patients will be accrued per arm. The null hypothesis will be rejected for an arm if ≥8 responses are observed in the 25 patients on that arm. This design yields a type I error rate of 0.1 and 80% power when the true ORR is 40%. Tumor biopsies will be collected to determine SUMO pathway inhibition by immunohistochemistry and the induction of innate and/or adaptive immune response by measuring levels of IFN-regulated gene transcripts and the activation state of tumor-infiltrating lymphocytes and myeloid cells, including NK cells and macrophages. Innate and/or adaptive immune response and IFN signalling activation will also be assessed in peripheral blood by immunoprofiling, gene expression analysis, and measurement of cytokine and/or chemokine secretion. Enrollment is planned to open in October 2019. Disclosures Assouline: Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Mehta:Seattle Genetics: Research Funding, Speakers Bureau; Astex: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Spectrum: Consultancy, Speakers Bureau; Imbrium therapeutics: Consultancy; Roche-Genentech: Research Funding; miRagen: Research Funding; Kyowa-Kirin: Consultancy, Speakers Bureau; Astra-Zeneca: Speakers Bureau; Sanofi: Consultancy; Affimed: Research Funding; Forty Seven Inc: Research Funding; Juno/Celgene: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Takeda: Research Funding; Rhizen: Research Funding; ADC therapeutics: Research Funding; Pharmacyclics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Caimi:Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Patel:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Huszar:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Other: Shareholder. Berger:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Friedlander:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gomez-Pinillos:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Proscurshim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. OffLabel Disclosure: TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate.