PSVII-15 Effects of electrolyzed reduced water on intake, digestion and ruminal fermentation parameters in beef cattle

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 446-447
Author(s):  
Natasha L Bell ◽  
Daisy A Gonzalez ◽  
Kendrah DeLeon
Keyword(s):  
Transition Period ◽  
Rumen Fluid ◽  
Phase 1 ◽  
Analysis Data ◽  
Phase 2 ◽  
Ruminal Fermentation ◽  
Fermentation Parameters ◽  
Reduced Water ◽  
Electrolyzed Reduced Water

Abstract The effect of electrolyzed reduced water consumption by cattle is not well defined. The objective of this study was to evaluate the effect of electrolyzed reduced water on intake, in vitro true digestibility (IVTD), ORP and pH in four ruminally cannulated steers (4 Bos taurus; 317 kg BW). Steers were subjected to a two period (14 d), two treatment crossover design. Treatment included: 1) standard water (CON; pH = 7.0 ± 1.0) or 2) electrolyzed reduced water (ERW; pH = 9.0 ± 1.0). The project comprised of two studies where the effects of ERW were observed for steers consuming a roughage diet (phase 1) or concentrate diet (phase 2). During Phase 1, animals were provided bermudagrass hay ad libitum. A 14 d transition period followed phase 1 to allow transition of diets. In phase 2, animals were maintained on a concentrate diet. During each period, d 1–8 served as a treatment adaptation phase, d 9–13 allowed for measures of intake and digestion, and rumen fluid was collected at h 0, 2, 4, 8, and 12 after feeding on d 14 for VFA, pH and ORP analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). Intake, digestion, and ruminal fermentation parameters were not different for CON vs ERW steers (P ≥ 0.06). Analysis of VFA data have not been finalized and will be reported later. Results indicate that ERW has no effect on intake, digestion or ruminal fermentation parameters of steers consuming roughage or concentrate diets.

scholarly journals PSII-36 Effect of cyclic monensin feeding on intake and ruminal fermentation parameters in steers consuming low-quality forage

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 217-217
Author(s):  
Natasha L Bell ◽  
Kayla Hook ◽  
Kendrah De Leon ◽  
Alicia Hernandez
Keyword(s):  
Treatment Effect ◽  
Bos Taurus ◽  
Rumen Fluid ◽  
Animal Health ◽  
Analysis Data ◽  
Current Data ◽  
Period Effect ◽  
Ruminal Fermentation ◽  
Dried Distillers Grains ◽  
Fermentation Parameters

Abstract Effects of cyclic monensin feeding on utilization of low-quality forage (LQF; 4.9%CP) were evaluated using ruminally cannulated steers (12 Bos taurus; 260 kg BW). Steers were randomly assigned to one of three treatments: 1) CON (0 mg∙hd-1∙d-1 monensin; Rumensin® 90, Elanco Animal Health, Greenfield, IN), 2) MON (200 mg∙hd-1∙d-1 monensin) or 3) CYC (200 mg∙hd-1∙d-1 monensin for 14 d and 0 mg∙hd-1∙d-1 monensin for subsequent 14 d). Dried distillers grains (1 kg∙hd-1∙d-1) were fed for monensin inclusion. Each of the four periods were 28 days in length. Hay and ort samples were collected d 10–13 for determination of intake. Rumen fluid was collected with a suction strainer 0, 2, 4, 8, and 12 h after feeding on d 14 for pH analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). Periods were analyzed separately for all measures because of a period effect (P ≤ 0.01). A treatment effect was not observed for forage OM intake (P ≥ 0.10) or total OM intake (P ≥ 0.10). A treatment effect was observed in period 1 for forage NDF intake (P = 0.10) and total NDF intake (P = 0.10), but these effects were not observed in periods 2, 3 or 4 (P ≥ 0.18). A treatment effect (P = 0.02) was observed for pH in period 1, but was not evident in periods 2, 3, or 4 (P ≥ 0.17). An hour effect was observed for pH during all four periods (P ≤ 0.01). In addition to measures of intake and pH, measures were taken for digestion, VFA and microbial sequencing. These measures are currently being evaluated for later reporting. Current data suggest the effects of monensin change over time. Further evaluation of digestion, VFA, and the microbiome are required to determine a clear effect of cyclic monensin feeding.

scholarly journals PSI-2 Evaluation of feed by-products on in vitro DMD, methane production and ruminal fermentation parameters

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 289-290
Author(s):  
Sidonie P Robinson ◽  
Kim Ominski ◽  
Karin Wittenberg ◽  
Emma McGeough
Keyword(s):  
Rumen Fluid ◽  
Block Design ◽  
Ruminal Fermentation ◽  
Mitigation Potential ◽  
Ch4 Production ◽  
Randomized Complete Block Design ◽  
Fermentation Parameters ◽  
By Products ◽  
Corn Ddgs

Abstract In-vitro batch culture assessment was used to examine DMD, ruminal fermentation parameters and CH4 production associated with a range of by-products feeds including pea hulls, pea screenings, soybean, soybean meal, wheat bran, wheat screenings, wheat DDGS, wheat corn DDGS, corn DDGS, coarse hemp powder, hemp hulls, flax screenings, nexera canola, commodity canola, sunflower screenings, quinoa and dogwood in a randomized complete block design. By-products were obtained from various locations across Manitoba at 3 monthly timepoints to account for sample variability. By-products (0.5g DM) were weighed individually into jars and incubated at 39°C in jars containing buffered medium and rumen fluid for 48 hrs. Gas samples were collected at 3,6,9,12,18,24,36 and 48 hr and CH4, DM disappearance, pH, VFA and ammonia concentrations were measured. Data were analysed using the MIXED procedure of SAS including treatment as a fixed effect and run, block, month and location as random effects. Methane output was regressed on CP and NDF to determine the effect of these constituents. Treatment had a significant effect (P < 0.0001) on CH4 (ml/g DMD) produced, with dogwood having the lowest cumulative CH4 (11.13 ml/g DMD) compared to all other treatments. Methane (ml/g DMD) decreased (P < 0.0005) as pH decreased. An inverse relationship between protein and CH4 was apparent, which explained 31% (R2= 0.31) of the CH4 (ml/g DMD) produced. Further, NDF (%) had a significant effect (P < 0.0001) on CH4 and explained 25% (R2=0.25) of the CH4 (ml/g DMD) produced. Overall, by-products higher in crude protein and lower in NDF produced lower (P < 0.001) CH4 ml/g DMD. Although the addition of dogwood to cattle diets is novel, it does show potential CH4 mitigation potential using in vitro assessment.

PSXIII-6 Effects of cyclic monensin feeding on ruminally cannulated beef steers consuming low-quality forage

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 467-467
Author(s):  
Natasha L Bell ◽  
Daisy A Gonzalez ◽  
Kayla Hook
Keyword(s):  
Bos Taurus ◽  
Rumen Fluid ◽  
Animal Health ◽  
Analysis Data ◽  
Feeding Strategies ◽  
Beef Steers ◽  
Ruminal Fermentation ◽  
Dried Distillers Grains ◽  
Treatment Interaction ◽  
Fermentation Parameters

Abstract The loss of monensin efficacy when fed continuously requires further study for development of novel feeding strategies that may prolong its effectiveness. In the present study, effects of cyclic monensin feeding on utilization of low-quality forage (LQF; 4.9%CP) were evaluated using ruminally cannulated steers (12 Bos taurus; 260 kg BW). Steers were randomly assigned to one of three treatments: 1) CON (0 mg∙hd-1∙d-1 monensin; Rumensin® 90, Elanco Animal Health, Greenfield, IN), 2) MON (200 mg∙hd-1∙d-1 monensin) or 3) CYC (200 mg∙hd-1∙d-1 monensin for 14 d and 0 mg∙hd-1∙d-1 monensin for subsequent 14 d). Dried distillers grains (1 kg∙hd-1∙d-1) were fed for monensin inclusion. Each of four periods were 28 days in length. Hay, ort, and fecal samples were collected d 10–14 of each period for measures of digestion. Rumen fluid was collected with a suction strainer 0, 2, 4, 8, and 12 h after feeding on d 14 for VFA analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). A period × treatment interaction was not observed for any measure of digestion (DMD, OMD, NDFD; P ≥ 0.39). A period × treatment interaction (P < 0.01) was observed for acetate, propionate, and A:P. An hour effect was observed for all ruminal fermentation parameters (acetate, propionate, A:P ratio, total VFA; P ≤ 0.01). No treatment effects or interactions were observed for any ruminal fermentation parameters by period 4 (P ≥ 0.15), but an hour effect was observed for all parameters (P ≤ 0.03) in period 4. Exploration of novel feeding strategies results in knowledge beef cattle producers can apply in their operations. This data is particularly relevant in cow-calf operations where LQF is often consumed. Although cyclically feeding monensin was similar to continuous feeding, this research furthers our knowledge and understanding of monensin.

scholarly journals CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii46-ii46
Author(s):  
Andrew Lassman ◽  
Patrick Wen ◽  
Martin van den Bent ◽  
Scott Plotkin ◽  
Annemiek Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Nuclear Retention ◽  
Phase 2 Trial ◽  
Human Gbm

Abstract BACKGROUND Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins. METHODS We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate. RESULTS Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%). CONCLUSION Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).

PSXIII-8 Effects of different sources of Zn on in vitro ruminal fermentation and digestibility of a lactation diet

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 466-466
Author(s):  
Angela R Boyer ◽  
Yun Jiang ◽  
Alon Blakeney ◽  
Dennis Nuzback ◽  
Brooke Humphrey ◽  
...  
Keyword(s):  
Rumen Fluid ◽  
Random Effect ◽  
Rumen Fermentation ◽  
Gas Production ◽  
Ruminal Fermentation ◽  
Negative Effects ◽  
Minimum Concentration ◽  
High Metal Content ◽  
Different Sources

Abstract Vistore® minerals are hydroxychloride minerals that feature high metal content and improved bioavailability. This study was conducted to compare different sources of zinc (Zn) on in vitro rumen fermentation parameters. Three ruminally-cannulated Jersey heifers were adapted to a lactation diet for two weeks before used as donors. Three sources of Zn were tested at 20 ppm: No supplemental Zn (CON), ZnSO4, Vistore Zn, and another Zn hydroxychloride (Vistore-competitor). The concentration of Zn in this study was selected from a titration study (0 to 40 ppm ZnSO4) to identify the minimum concentration of ZnSo4 affecting rumen fermentation. The lactation diet (TMR) was dried and ground to 1mm and used as substrate. Rumen fluid was collected two hours after feeding. Substrate (0.5 g) was inoculated with 100 mL of 3:1 McDougall’s buffer: ruminal flued mixture at 39ºC for 24 h. Each treatment was run in triplicate and in three runs. Data were analyzed with R 3.0. The model included fixed effect of treatment and random effect of run. ZnSO4 reduced (P < 0.05) maximum gas production, DMD (54 vs. 55.9%) and cellulose (27.5 and 40.7%) digestibility. acetate to propionate ration (2.20 vs. 2.24) and NH3-N concentration (6.0 vs. 7.0 mg/dL), increased (P < 0.05) propionate % (27.2 vs 26.7%) compared to control. Vistore had higher pH than control (6.44 vs. 6.40, P = 0.02) but did not affect other parameters compared to CON. Vistore-competitor reduced total VFA production compared to control, ZnSO4, and Vistore (94 vs. 102, 106 and 107 mM, respectively, P = 0.01) but did not affect other parameters. In general, Vistore Zn maintained in vitro ruminal fermentation and digestibility, while ZnSO4 had negative effects on both fermentation and digestibility and Vistore-competitor reduced total VFAs. Results indicate hydroxychloride minerals may stabilize rumen parameters versus sulfate sources but different hydroxychloride sources appear to influence rumen parameters differently.

Effects of roughage type on particle separation, rumination, fiber mat characteristics, in situ degradation, and ruminal fermentation parameters in beef steers

2021 ◽  
Author(s):  
Catherine L Lockard ◽  
Caleb G Lockard ◽  
Wyatt N Smith ◽  
Kendall J Karr ◽  
Ben P Holland ◽  
...  
Keyword(s):  
Dry Matter ◽  
Rumen Fluid ◽  
Fluid Collection ◽  
Latin Square ◽  
Experimental Unit ◽  
Beef Steers ◽  
Ruminal Fermentation ◽  
In Situ Degradation ◽  
Fermentation Parameters

Abstract Six ruminally cannulated steers (average BW = 791 + 71 kg) were used in a replicated 3 × 3 Latin square experiment to determine the effects of roughage type on rumination, fiber mat characteristics, and rumen fermentation variables. Three roughages were included at 7% (DM basis) in a steam flaked corn-based diet; cotton burrs (CB), wheat silage (WS), or corn stalks (CS). Steers were fitted with a sensory collar to record rumination behaviors in 2-h intervals at the beginning of the experiment. Each 30-d period consisted of a 7-d of recovery, 14-d of diet adaptation, 7-d of rumination data collection (daily and bi-hourly average rumination), 1-d of rumen fluid collection, and 1-d of rumen evacuations. In situ degradation of individual roughages was determined for 4-d after period 3 evacuations. During rumen evacuations, ruminal contents were removed; the rumen fiber mat (RF) was separated from the liquid portion with a 2 mm sieve, weighed, and a subsample was dried. Data were analyzed using the MIXED procedure of SAS with steer as the experimental unit and roughage (CB, WS, and CS) as the main effect. Dry matter intake (DMI) was not different for CB and WS (P = 0.25) and greatest for steers consuming CS diet (P  < 0.01). Roughage type did not influence the weight of the RF dry matter (%; DM; P = 0.92), RF weight (P = 0.69), or RF:DMI ratio (P = 0.29). Daily rumination (min/d) did not differ among roughages (P = 0.40), but min of rumination/kg of DMI was greatest for CS (18.0 min), min/kg of NDF was greatest for WS (89.8 min; P = 0.02), and min/kg of peNDF was greatest for CS (132.4 min; P  < 0.01). Wheat silage had the greatest percentage of soluble DM and CB-R and CS-R (P  < 0.01) had the greatest ruminal degraded DM fraction. Rumen fiber mat did not differ for roughages, although rumination min/kg of DMI and peNDF was greatest for steers consuming CS and WS. In situ degradation determined that CB-R and CS-R had the greatest percentage of ruminal degraded DM. Based on the objective of the experiment, roughage type did not influence daily rumination or fiber mat characteristics.

scholarly journals PSVI-42 Effect of increasing concentrations of aflatoxins (AFB1) on rumen gas production (GP), dry matter (DM) disappearance and fermentation parameters using the in vitro ANKOM gas technique

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 194-195
Author(s):  
Jean-Philippe Marden ◽  
Virginie Marquis ◽  
Kheira Hadjeba Medjdoub ◽  
Marine Lacombe
Keyword(s):  
Feed Efficiency ◽  
Dry Matter ◽  
In Vitro Model ◽  
Rumen Fluid ◽  
Gas Production ◽  
Corn Silage ◽  
Vitro Model ◽  
Fermentation Parameters ◽  
Cheese Cloth

Abstract Aflatoxins are secondary metabolites produced by Aspergillus species known to be the most prevalent contaminants in feedstuffs. In ruminants, contaminated AFB1 feeds usually exhibit symptoms including reduced feed efficiency and milk production and decreased appetite. The objective of this study was to investigate the effects of different concentrations of AFB1 on rumen fermentation parameters by using the ANKOM gas production protocol. Rumen fluid was collected from a cannulated dry dairy cow, filtered with cheese-cloth and diluted (1:1) with a standard buffer. Triplicates of 75 mL flasks were fed 0,75g of feed (79% corn silage, 15% alfalfa and 6% concentrates) and inoculated with 0 (blank), 0,2, 0,5, 1 and 2 ppm of AFB1. Flasks were placed in a rotating incubation at 39°C for 96h and connected to ANKOM GP system. After 96h of incubation, the contents of each flask were centrifuged. Supernatants were analyzed for total VFA and AFB1 while precipitates were dried at 104°C for DM disappearance. The experimentation was repeated weekly 3 times and named wk1, 2 and 3. Statistical analysis was done by SPSS using a univariate model. Results showed no significant differences on GP max at 96h among AFB1 concentrations. Only wk 1 showed that higher AFB1 concentration (2 ppm) decreased significantly (P < 0,05) DM disappearance (- 8,2 pts) when compared to the blank. Total VFA contents (75,0 ± 1,6 mM) were not affected by AFB1. Wk 2 and 3 did not show any difference neither on DM disappearance nor on VFA (89,1 ± 1,6 mM; 110,2 ± 4,8 mM). It can be concluded that our in vitro model, GP did not reflect DM disappearance and it can be put forward that rumen fluid with low total VFA concentrations (≤ 75 mM) could be more sensible to AFB1 challenge.

A comparison of the suitability of different models for describing the gas production kinetics of whole-crop wheat

1998 ◽  
Vol 22 ◽  
pp. 215-216
Author(s):  
A. T. Adesogan ◽  
E. Owen ◽  
D. I. Givens
Keyword(s):  
Mathematical Model ◽  
Time Course ◽  
Rumen Fluid ◽  
Gas Production ◽  
Ruminal Fermentation ◽  
Production Kinetics ◽  
Fermentation Profile ◽  
Kinetics Of

Menkeet al. (1979), Beuvinket al. (1992) and Theodorouet al. (1994) developed techniques for measuring the time course of gas production of foods fermentedin vitrowith rumen fluid. These techniques require description of the fermentation profile with an appropriate mathematical model. Although several authors have used these techniques to study the ruminal fermentation of foods, little information is available on the suitability of the model chosen for describing the fermentation profile of the food under study. In this study, the models of Ørskov and McDonald (1979), Franceet al. (1993) and Beuvink and Kogut (1993) were fitted to thein vitrogas production profiles of 10 whole-crop wheat (WCW) forages (cv.Slepjner) to determine the model most suited to describing the data.

An ultrastructural analysis of cyst wall development in the metacestode ofHymenolepis diminuta(Cestoda)

Parasitology ◽  
1984 ◽  
Vol 89 (3) ◽  
pp. 537-566 ◽  
Author(s):  
K. Sylvia Richards ◽  
C. Arme
Keyword(s):  
Cyst Wall ◽  
Phase 1 ◽  
Basal Membrane ◽  
Hymenolepis Diminuta ◽  
Phase 2 ◽  
Phase 3 ◽  
Muscle System ◽  
Initial Development ◽  
Final Maturation

SUMMARYA series of development stages (I–XI) have been devised to describe the development of the cyst wall of the metacestode ofHymenolepis diminuta. The cyst wall possesses tegumentary, muscular, fibrous and inner cyst tissues, the developmental rates and differentiation patterns of which are not identical. The tegumentary tissue differentiates posteriorly. Its microvillus-bearing distal cytoplasm remains simple until scolex retraction, after which rapid increase in depth followed by vacuolation occurs and basal membrane infoldings surround Phase 3 fibrogenesis fibrils. Senescence, which also affects the tegumentary cytons, then ensues. The muscle system development is posteriad and maturation, completed before scolex retraction, is followed by myocyton senescence. Posteriorly differentiated fibroblasts commence Phase 1 fibrogenesis after scolex retraction and the primary fibrous zone is fully established within approximately 6 days. Phase 2 and 3 fibrogenesis develop centrifugally, the fibrils of Phase 2 surrounding the tegumentary cytons and myocytons prior to their senescence, and those of Phase 3 lying more peripherally. The inner cyst tissue, established posteriorly, differentiates anteriorly, centripetally and early, the penultimate stage commencing just before scolex retraction, about 6 days after which the final maturation junctional complexes start development. Neitherin vitroexcystment nor infectivity of the definitive host can be satisfactorily achieved before the initial development of the primary fibrous zone. This may play a skeletal role during excystment, and is shown to be unaffected by the digestive enzymes which cause loss of cytoplasmic integrity in the outer regions of the cyst.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

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