Standard Of Care Regimens Research Articles

A Network Meta-Analysis (NMA) to Evaluate Comparative Effectiveness of Frontline Treatments for Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (TIE)

A Network Meta-Analysis (NMA) to Evaluate Comparative Effectiveness of Frontline Treatments for Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (TIE)

1188PD - Margetuximab (M) + pembrolizumab (P) for treatment of patients (pts) with HER2+ gastroesophageal adenocarcinoma (GEA) post-trastuzumab (T): Survival analysis

1188PD - Margetuximab (M) + pembrolizumab (P) for treatment of patients (pts) with HER2+ gastroesophageal adenocarcinoma (GEA) post-trastuzumab (T): Survival analysis

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV

BackgroundTwo drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.MethodsWe conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.ResultsA total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.ConclusionsTreatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.)

Phase I/II, open-label, 2-arm study to evaluate safety, tolerability, and clinical activity of GSK2857916 in combination with 2 standard-of-care (SoC) regimens in relapsed/refractory multiple myeloma: (DREAMM 6).

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.

Visualizing real-world outcomes through the lens of a molecular tumor board: Persona-typing pancreatic cancers for clinical decision support.

e18100 Background: Despite the molecular diversity of pancreatic adenocarcinoma, standard therapy options remain largely molecularly-untailored except in the context of DNA damage response alterations such as BRCA mutations, NTRK fusions, or microsatellite instability. Methods: To broaden the utility of molecular profiling, we analyzed real-world outcomes and established 12 molecularly-driven clusters, or “persona types” (PTs), across a cohort of 1280 pancreatic cancers with CLIA-grade genomic/proteomic data (commercially available NGS/IHC panels). Patients were consented into Perthera’s precision oncology platform via referrals from advocacy programs and hospital partnerships for case review by a molecular tumor board (MTB). Persona types were generated using unsupervised k-means clustering of molecularly-tailored therapy recommendations formulated by the MTB. Progression-free survival was documented across all lines of therapy. Results: Personas based on multi-omic profiles and expert-driven recommendations were representative of molecular phenotypes reported in previous studies (e.g. DNA damage response deficiencies, BRAF mutations, other non-KRAS-drivers, SWI/SNF alterations, squamous-associated genes, cell cycle regulators, etc.). To streamline the exploration of real-world outcomes, we developed an interactive dashboard that enables users to compare PFS survival curves across Personas for various therapies such as gemcitabine/nab-paclitaxel, FOLFIRINOX, other standard regimens, immunotherapy, PARP inhibitors, RAF/MEK/ERK inhibitors, and more. Persona types associated with increased/decreased sensitivity to several classes of agents were identified (e.g. PD-1/L1 inhibitors in a persona enriched for cell cycle dysregulation, PARP inhibitors in a persona enriched for BRCA mutations). Conclusions: Empowering oncologists with personalized insights into real-world outcomes may promote investigator-initiated trials and augment clinical decision support, particularly when choosing between standard of care regimens or when exploring potential clinical trial options.

Topical skin therapies in subjects undergoing full facial rejuvenation.

Cosmeceutical therapies including face washes, moisturizers, chemical peels and antioxidant formulations are intended to improve the esthetic appearance of skin. The use of these products as adjuncts to full facial rejuvenation with hyaluronic acid filler and abobotulinumtoxinA may improve cosmetic and socio-esthetic outcomes. To characterize the effect of skin care products in subjects undergoing full facial rejuvenation with abobotulinumtoxinA and hyaluronic acid in improving facial skin appearance, patient satisfaction, and projected first impressions. Twenty subjects were recruited and divided into two treatment groups. Subjects in Group A followed a standard skin care regimen, whereas subjects in Group B received a more robust skin care regimen including chemical peels and antioxidant formulations. All subjects underwent facial rejuvenation treatments with hyaluronic acid at Visit 2 and with abobotulinumtoxinA at Visit 7. Patient esthetic improvement, satisfaction, self-esteem, and first impression were evaluated via the Fitzpatrick Wrinkle Assessment Scale, Global Aesthetic Improvement Scale, Skin Quality Assessment, Heatherton & Polivy State Self-Esteem Scale, Subject Satisfaction Scale, and the First Impressions Questionnaire. Both treatment groups experienced significant improvements in the Skin Quality Assessment, Fitzpatrick Wrinkle Assessment Scale, Heatherton and Polivy State Self-Esteem Scale, and First Impressions Questionnaire. The cosmeceutical therapies used in this study in combination with abobotulinumtoxinA and hyaluronic acid filler improved subjects' skin quality, self-esteem, and projected first impressions. Larger studies are needed to determine the most efficacious combination of topical skin therapies with facial rejuvenation therapy.

Excision repair cross-complementing group-1 (ERCC1) gene induction in peripheral blood mononuclear cells as a marker of outcome in patients with colorectal cancer treated with oxaliplatin.

542 Background: Oxaliplatin is a third generation platinum agent that confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the standard of care regimens for patients with colorectal cancer (CRC). Tissue resistance to oxaliplatin appears to be multifactorial, with the nucleotide excision repair (NER) pathway playing a major role. We have previously demonstrated that Excision Repair Cross-Complementing group-1 (ERCC1), can be induced in colorectal cell lines on exposure to Oxaliplatin and high levels confer resistance to apoptosis. We aim to further this knowledge by analyzing gene expression in vivo, using PBMC as a surrogate, to assess ERCC1 as a biomarker of sensitivity to Oxaliplatin therapy. Methods: Patients with CRC who received oxaliplatin were consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC. Results: Fifty-four patients were enrolled on study, 25 (46.3%) had mCRC. Twenty-four patients were included in final analysis based on clinical data. Thirteen (52%) had an increase in ERCC expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. However, in these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with Oxaliplatin. This induction can serve as a potential marker of resistance to oxaliplatin based chemotherapy in mCRC as evidenced by the significant difference in PFS. Further analyses of the influence of ERCC1 polymorphisms on outcomes is underway.

Enhancing cytotoxic chemotherapy response through targeted BET bromodomain inhibition in preclinical pancreatic cancer models

Background and Hypothesis: 
 Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and the standard of care regimen, nab-paclitaxel (NPT) plus gemcitabine (Gem), leads to a dismal 8.5 months median survival. Targeted inhibition of Bromodomain and Extra-Terminal (BET) protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance cytotoxic chemotherapy response in PDAC. 
 Experimental Design: 
 In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice. 
 Results: 
 Inhibition in cell proliferation in human PDAC cells at 1 µM concentration in NPT+Gem, iBET-762, and NPT+Gem+iBet762 was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa cells. iBET-762 decreased oncogenic proteins c-Myc, [Symbol]-catenin, Vimentin, and P-AKT while apoptosis related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitors proteins P21 & P27 were increased. In a peritoneal dissemination model, median animal survival compared to control (21 days) was increased after therapy with NPT+Gem (33 days, a 57% increase), iBet-762 (30 days, a 43% increase) and NPT+Gem+iBET-762 (44 days, a 110% increase). Effect of iBET-762 in combination with chemotherapy on local tumor growth is currently underway. 
 Conclusion and Potential Impact: 
 These findings suggest that the effects of standard chemotherapy can be enhanced through specific inhibition of BET proteins activity, and supports the clinical application of iBET-762 in combination with standard chemotherapy in PDAC patients.

Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): Analysis of Pollux and Castor

Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): Analysis of Pollux and Castor

Efficacy of Daratumumab in Combination with Standard of Care Regimens in Lenalidomide-Exposed or -Refractory Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Analysis of the Castor, Pollux, and MMY1001 Studies

Efficacy of Daratumumab in Combination with Standard of Care Regimens in Lenalidomide-Exposed or -Refractory Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Analysis of the Castor, Pollux, and MMY1001 Studies

Three-Year Follow up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma (RRMM)

Introduction: Daratumumab is a human, CD38-targeted, IgGκ monoclonal antibody with both direct on-tumor and immunomodulatory mechanisms of action. In the phase 3 POLLUX study, D-Rd reduced the risk of disease progression or death by 63% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P 3 years of median follow-up. Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to receive Rd (lenalidomide 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone 40 mg per week) ± daratumumab (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, then Q4W until disease progression). High risk cytogenetic abnormalities included t(4;14), t(14;16), and del17p. At the time of suspected CR and at 3 and 6 months after confirmed CR (and every 12 months thereafter if CR was maintained), bone marrow aspirates were assessed for MRD using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as maintenance of MRD negativity at the 10-5 threshold for ≥6 or ≥12 months. PFS on subsequent line of therapy (PFS2), an exploratory endpoint, was defined as time from randomization to progression after next line of subsequent therapy or death. Results: A total of 569 pts were randomized (D-Rd, n = 286; Rd, n = 283). At a median follow-up of 39.5 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median, not reached [NR] vs 17.5 months; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.35-0.55; P The median duration of treatment was 34.3 months in the D-Rd arm versus 16.0 months in the Rd arm. The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd versus Rd are described in Table 2. No differences were observed for D-Rd versus Rd in discontinuations due to TEAEs (14% of pts in each treatment group) or incidences of second primary malignancies (7% of pts in each treatment group). Updated data including PFS2 will be presented at the meeting. Conclusion: After >3 years of median follow-up, D-Rd continued to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in RRMM pts. The higher rate of sustained MRD negativity with D-Rd compared with Rd suggests that continued D-Rd treatment drives these deep responses and delays progression. No new safety signals were observed following a median of 34 months of D-Rd exposure. Disclosures Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. White:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Ho:Takeda: Honoraria, Other: Travel to meeting; Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Other: Travel to meeting. Moreau:Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Krevvata:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

ABSTRACT Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

Transitions in palliative care: conceptual diversification and the integration of palliative care into standard oncology care.

Palliative care acknowledges the historical origin of the hospice developed in the UK during the 20th century. Palliative care initially focused primarily on end-of-life care provided at hospices, but then changed to at-home care, leading to the formation of a support system provided by the palliative care team. The palliative care team further coordinated with acute care hospitals and became involved in earlier stages of care as well, such as providing symptomatic relief in conjunction with cancer treatment. On this backdrop, the concept of palliative care itself also evolved over time. In recent years, attempts at early-stage palliative care from the initial stages of treatment are being studied with respect to cases with complications such as advanced cancer. Early-stage palliative care has been reported to improve patient quality of life (QOL), improve depression, reduce the burden on the family, and possibly improve survival prognosis for some advanced cancers. Currently, efforts to integrate palliative care into standard oncology care regimens by providing specialist palliative care and cancer treatment as a single unit are anticipated to enter more widespread practice. Such a care approach differs from conventional palliative care, which is started around the time when the end of conventional cancer treatment, and consists of applying specialist palliative care from the stage where cancer treatments are administered to address with multiple problems. Many breast cancer patients have severe problems such as esthetic outcome, sexuality and psycho-social effects associated with breast cancer itself and treatment. And it effects their QOL for a long time not only during therapy but also having done therapy or recurrence. Therefore, it may be effectiveness for patients to integrate of palliative care into standard oncology care in breast cancer, but the effect of it for only breast cancer patients has not been reported on yet. In this paper, after reviewing the concepts and historical evolution of palliative care, we describe the integration of palliative care into standard oncology care that has been making progress recently.

Subcutaneous daratumumab (DARA) in patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Part 2 update of the open-label, multicenter, dose escalation phase 1b study (PAVO).

8013Background: Intravenous (IV) administration of DARA 16 mg/kg is approved as monotherapy and in combination with standard of care regimens for RRMM. The phase 1b PAVO study (NCT02519452) demonst...

Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE)

Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE)

EPA + DHA supplementation reduces PMN activation in microenvironment of chronic venous leg ulcers: A randomized, double-blind, controlled study.

Sustained high levels of activated polymorphonuclear leukocytes (PMNs) and PMN-derived proteases in the microenvironment of chronic venous leg ulcers (CVLUs) are linked to chronic inflammation and delayed healing. Uncontrolled PMN activity eventually destroys newly developed tissue and degrades critical growth factors. The bioactive components of fish oil (n-3 eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have strong inflammation-resolving actions and have been shown to assuage PMN activity, but have not been tested in CVLU patients. This randomized controlled study compared the effectiveness of oral EPA + DHA therapy to a placebo for reducing PMN activation in CVLU microenvironments. At Days 0, 28, and 56, markers of PMNs (CD15) and activated PMNs (CD66b), and levels of PMN-derived proteases human neutrophil elastase and matrix metalloproteinase-8 were measured in CVLU fluid from patients receiving standard compression therapy and (1) EPA + DHA therapy (n = 16) or (2) placebo (n = 19). By Day 56, the EPA + DHA Group had a significantly lower percentage of CD66b+ cells in CVLU fluid compared to Day 0 (p = 0.02) and to Day 28 (p = 0.05). Importantly, there were downward trends in levels of both matrix metalloproteinase-8 and human neutrophil elastase over time in the EPA + DHA Group, which also demonstrated greater reductions in wound area by Day 28 (57% reduction) and Day 56 (76% reduction) than the Control Group (35% and 59%, respectively). Moreover, reductions in wound area had significant negative relationships with CD15+ cells in wound fluid at Days 28 (p = 0.008) and 56 (p < 0.001), and CD66b+ cells at Days 28 (p = 0.04) and 56 (p = 0.009). The collective findings provide supplemental evidence that high levels of activated PMNs in CVLU microenvironments inhibit healing, and suggest that EPA + DHA oral therapy may modulate PMN activity and facilitate healing of CVLUs when added to standard care regimens.

Abstract 4183: A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of lung cancer

Abstract M3814 is a potent and selective inhibitor of DNA-PK, one of the key cellular regulators of DNA damage induced by ionizing radiation or certain cytostatics used in the treatment malignant disease. One of these drugs, Etoposide, induces double strand breaks (DSB) in cellular DNA. DSBs are most difficult to repair and, if left unrepaired, can lead to induction of cell cycle arrest and/or apoptosis and ultimately cell death. DNA-PK plays a critical role in the repair of DSB via the non-homologous end-joining pathway. M3814 was tested for activity in combination with Etoposide in a panel of 98 cancer cell lines derived from lung cancer. A broad potentiation effect of DNA-PK inhibitor was observed in most cancer cell lines. As a rule, cell lines sensitive to Etoposide demonstrated increased sensitivity to the combination. M3814 did not show significant effect on cancer cell growth/viability in combination with Cisplatin compared to Cisplatin alone at concentrations that effectively inhibit DNA-PK activity. At the same time, M3814 did not negatively affect the antitumor activity of Cisplatin. The therapeutic effect of M3814 in combination with the standard of care (SoC) regimen of Etoposide and Cisplatin was tested in the human small cell lung cancer xenograft model, NCI-H520. Triple combination of M3814, Etoposide and Cisplatin resulted in increased efficacy compared to SoC treatment arm. Since myeloid and lymphoid suppression is one of the dose limiting toxicities of the SoC regimen in patients, the effect of the triple combination on myeloid and lymphoid blood cells was investigated in immunocompetent mice. Whereas the SoC treatment showed reduction of the myeloid and lymphoid compartments, the addition of M3814 did not additionally reduce these cells neither in the treatment nor the recovery phase. Our results warrant further investigations to explore the potential of the combination in the clinical setting. Citation Format: Christian Sirrenberg, Astrid Zimmermann, Thomas Grombacher, Lyubomir T. Vassilev, Lars Damstrup, Frank T. Zenke, Andree Blaukat. A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4183. doi:10.1158/1538-7445.AM2017-4183

Abstract 567: CD38 blockade overcomes the immune resistance to anti-PD-L1 therapy by boosting CD8 T cell response

Abstract Although strategies incorporating immune checkpoint inhibition, e.g. PD-1/PD-L1 blockade, are achieving unprecedented successes and increasingly becoming incorporated into standard of care regimens for cancer patients, high rates of resistance still limit the potential efficacy. Therapeutic improvement requires a thorough understanding of the biological process of resistance. To date there have been few studies reporting mechanisms of resistance to PD-L1 blockade. We have explored the resistance mechanisms to functional PD-L1 loss in preclinical lung cancer models by using pharmacological and genetic approaches (PD-L1 blocking antibody treatment or CRISPR/Cas9-mediated deletion of PD-L1 on tumor cells). The molecular and immune profiles of the tumor microenvironment were evaluated in mutant K-ras/p53 (KP) GEM lung cancer models and multiple immunocompetent syngeneic models (both KP and Lewis lung cancer). Additionally, to determine the applicability of the results to patients with lung cancer, we analyzed 259 patient tumor specimens with IHC staining and evaluated the immune markers in TCGA datasets (adenocarcinoma and squamous) and the MD Anderson PROSPECT dataset. We observed that lung tumors gained resistance to anti-PD-L1 antibody treatment over time, and that the up-regulation of CD38 on tumor cells accounted for the treatment resistance. We also observed the same resistance mechanism caused by CD38 up-regulation in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors generated with the CRISPR/Cas9 system. Manipulation of CD38 on a panel of lung cancer cell lines, demonstrated that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability in vitro and in vivo. Furthermore, to test whether CD38 blockade might be therapeutically efficacious to counter anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 in lung cancer animal models and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Bioinformatic analyses of the patient tumor databases revealed a strong correlation between CD38 expression and an immune suppressive inflammatory signature. Finally, in 259 lung cancer specimens, 18.5% of cases exhibited positive staining for CD38 on tumor cells. Based upon our studies, we conclude that the up-regulation of CD38 on tumor cells is a major mechanism of resistance to anti-PD-L1 therapy, and that CD38 is a novel immune checkpoint that inhibits CD8+ T cell function. The blockade of CD38 and PD-L1 is a rational combination to prevent immune resistance and increase the response rate for lung cancer patients. Citation Format: Limo Chen, Lixia Diao, Yongbin Yang, Xiaohui Yi, Jaime Rodriguez, Youhong Fan, Leticia Rodriguez, Jared Fradette, Christin Ungewiss, Jonothan Roybal, Jingfen Zhu, Jing Wang, Lauren Byers, Stephen Ullrich, Ignacio Wistuba, John Heymach, Xiao-Feng Qin, Don Gibbons. CD38 blockade overcomes the immune resistance to anti-PD-L1 therapy by boosting CD8 T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 567. doi:10.1158/1538-7445.AM2017-567

Abstract 1423: Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer

Abstract Platins are one of the most widely used classes of chemotherapeutic drugs. Although used as part of first-line standard of care regimens for advanced non-small cell lung cancer (NSCLC), their effectiveness remains limited, with a 5-year survival rate of 18%. Therefore, combination therapy to overcome resistance and improve survival is needed. Pevonedistat (TAK-924/MLN4924) is an investigational first-in-class Nedd8-activating enzyme (NAE) inhibitor that blocks activation of the cullin family of E3 ubiquitin ligases by preventing cullin conjugation with Nedd8, a ubiquitin-like protein. In vitro, pevonedistat is synergistic with carboplatin in a cell viability assay in 6 out of 20 NSCLC cell lines either with or without paclitaxel. In vivo studies using patient-derived xenograft (PDX) models showed a combination effect in a carboplatin-insensitive but not carboplatin-sensitive model. To evaluate the mechanism of the synergy between pevonedistat and platinum, RNAi of 320 DNA-damage response genes was performed in 4 cell lines in vitro. Depletion of genes involved in TC-NER (transcription-coupled nucleotide excision repair) and ICR (interstrand crosslink repair) reduced the synergy between pevonedistat and platinum, with the contribution of each pathway varying by cell line. Since TC-NER and ICR are also involved in the repair of DNA damage by platins, the results suggest that delaying completion of platin induced DNA repair by pevonedistat results in enhanced cell death. Pevonedistat may impede TC-NER by inhibition of neddylation of the E3 ubiquitin ligase CUL4-RBX1-DDB1-ERCC8, thereby possibly providing a direct reversal of resistance to platins. Citation Format: Xiaozhen Liu, David Bouck, Khristofer Garcia, Jonathan Blank, Hugues Bernard, Allison Berger, Mike Kuranda, Erik Koenig, Eric Lightcap. Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1423. doi:10.1158/1538-7445.AM2017-1423

Abstract P4-02-02: Increased tumor perfusion following treatment with trastuzumab as measured by contrast-enhanced ultrasound

Abstract Introduction: The primary purpose of this study is to determine if the order of dosing in standard-of-care (SOC) combination therapy for HER2+ breast cancer has an effect on the perfusion characteristics within the tumor. Improving the intratumoral delivery of cytotoxic systemic therapy is a significant challenge in advancing cancer treatment. Knowledge of the vascular changes following SOC treatments could enable optimizing their order and timing, potentially leading to significantly improved response. Currently, one SOC regimen for HER2+ breast cancer treatment is doxorubicin administered for 3-4 cycles prior to trastuzumab. Our goal is to quantitatively map the changes in perfusion in response to different combinations of trastuzumab plus doxorubicin treatment through imaging in a murine model of HER2+ breast cancer. Experimental Design: BT474 breast cancer cells (1×107) were subcutaneously implanted into mice (n = 12) and randomly assigned into three treatment groups: two doses of trastuzumab (10 mg/kg) followed by doxorubicin (1.5 mg/kg), doxorubicin prior to trastuzumab (same total drug dosage as group 1), and saline. After tumors reached ~225 mm3, animals were imaged with contrast-enhanced ultrasound (CEUS) (VisualSonics Vevo 770, Definity microbubbles) before treatment (day 0), and on days 1, 3, 4, and 7. Treatment occurred on days 0, 3 and 4. Percent change (from baseline, day 0 scans) of the CEUS signal intensity quantified from the functional vasculature (surrogate for vessel perfusion) following contrast injection were measured for each animal for each day. Tumors were extracted on day 7, and sectioned, paraffin-embedded, and stained with CD31, alpha-SMA and H&amp;E. Results: Tumors treated with trastuzumab initially exhibited a significant increase in CEUS signal intensity (from the functional vasculature) on day 1 compared to tumors initially treated with doxorubicin (p &amp;lt; 0.01). Additionally, compared to the control tumors, tumors treated with trastuzumab prior to doxorubicin revealed a significant increase in perfusion (change in signal intensity of functional vasculature) of contrast agent on days 3 (p = 0.01), 4 (p = 0.001) and day 7 (p &amp;lt; 0.01). There were no significant differences in the doxorubicin treated first group and the controls on any of the days (p &amp;gt; 0.25). Qualitative differences were noted between control and treated groups for alpha-SMA, no apparent differences were noted in microvessel density. Conclusion: Trastuzumab significantly improves a tumor's vascular perfusion in this HER2+ breast cancer model. Doxorubicin dosing prior to treatment with trastuzumab may potentially be hindering the intratumoral delivery of the subsequently delivered, targeted therapy. Improving the tumor's functional vasculature by altering the order of dosing of these combination therapies by giving trastuzumab prior to cytotoxic therapy has potential to enhance both the delivery and the effectiveness of these combination therapies. These data indicate a potential pathway to optimize therapeutic efficacy for individual HER2+ breast cancer patients. Citation Format: Sorace AG, Barnes SL, Quarles CC, McIntyre JO, Yankeelov TE. Increased tumor perfusion following treatment with trastuzumab as measured by contrast-enhanced ultrasound [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-02.