PO Days Research Articles

Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with newly diagnosed multiple myeloma (NDMM) for whom transplant is not planned as initial therapy: A multicenter, randomized, phase III study (CEPHEUS).

TPS8056 Background: DARA is a human, anti-CD38 IgGκ monoclonal antibody that significantly reduced the risk of progression/death with a manageable safety profile across several phase 3 studies in relapsed/refractory MM and NDMM. DARA + VRd (D-VRd) demonstrated efficacy and tolerability in the safety run-in cohort of the ongoing phase 2 GRIFFIN study that included transplant-eligible NDMM pts. To determine whether D-VRd demonstrates efficacy and tolerability in NDMM pts for whom transplant is not intended as initial therapy, the phase 3 CEPHEUS study will evaluate the efficacy and safety of D-VRd vs VRd alone in this pt population. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd vs VRd alone in pts with NDMM for whom transplant is not intended as initial therapy. Approximately 360 pts will be stratified by ISS stage and age/transplant eligibility (age < 70 years and transplant-ineligible, or age < 70 years and refusal to transplant, or age ≥70 years) and will be randomized in a 1:1 ratio. All pts will receive eight 21-day cycles of VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO/IV Days 1, 2, 4, 5, 8, 9, 11, 12), followed by 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg PO/IV Days 1, 8, 15, 22) until progressive disease (PD). Patients in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks in Cycles 9+ until PD. All pts will receive preinfusion medications. Minimal residual disease (MRD)-negative rate at 10–5 sensitivity threshold by NGS is the primary endpoint. MRD will be evaluated at suspected complete response or better. Secondary endpoints include progression-free survival (PFS), MRD-negative rate at 1-year, durable MRD negativity, overall response rate, time to and duration of response, PFS on next line of therapy, overall survival, clinical efficacy in high-risk molecular subgroups, health-related quality of life, pharmacokinetics, immunogenicity, and safety. Clinical trial information: NCT03652064.

Smart start: Final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma.

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.

MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys

In female nonhuman primates, ovarian and extra-ovarian estradiol (E2) contribute components of negative and positive feedback regulation of pituitary gonadotropin, as well as sexually receptive behavior. Little is known, however, about accompanying changes in brain steroid hormone content, particularly at the level of the hypothalamus. As part of a larger study investigating ovarian and extra-ovarian E2 regulation of reproductive, sexual and metabolic function, 13 adult female marmosets housed with well-established male pairmates were ovariectomized (OVX) and immediately assigned to one of three treatment groups: E2 SC capsule replacement (E2, n=5, mimicking peri-ovulatory circulating E2 levels), vehicle (VEH, n=4, daily PO 1ml/kg Ensure®), and aromatase inhibition (LET, n=4, daily PO 1mg/kg letrozole). At necropsy 8-9 months following treatment onset, plasma samples were obtained and hemi-hypothalami were harvested. Tissues and samples were placed in liquid nitrogen and frozen at -80C until assayed by LC-MS/MS (steroid hormones) or RIA (gonadotropin). LET females exhibited elevated (p=0.05) post-OVX circulating CG levels (marmoset LH equivalent) compared to E2 females. Circulating E2 levels were similarly diminished (p=0.01) in VEH and LET female groups compared to E2 females, while circulating levels of DHEA were comparably elevated (p<0.001) in VEH and LET compared to E2 females. Increased DHEA likely reflects absence of E2-inhibition of adrenal androgen biosynthesis and development of a zona reticularis. Circulating levels of testosterone (T), androstenedione (A4), progesterone (P4) and 17-hydroxyP4 (17OHP) were comparable between all three female groups. Changes in hypothalamic steroids, however, differed from circulating levels. Hypothalamic E2 was diminished (p<0.001) only in LET compared to E2 and VEH females. In contrast, hypothalamic A4 was increased in both VEH (p=0.03) and LET (p=0.05) compared to E2 females, while hypothalamic DHEA was increased (p=0.04) only in VEH compared to E2 and LET females. Hypothalamic T, P4 and 17OHP were comparable across treatment groups, not surprisingly producing a diminished (p<0.001) E2:T ratio in LET versus E2 females. Taken together, these results suggest E2 inhibition of adrenal and hypothalamic androgen biosynthesis and reveal potential contribution of hypothalamic E2 and androgens to physiological and behavioral function, translationally relevant when E2 production or action is impaired, such as in women with polycystic ovary syndrome.

Laparoscopic segment 6 resection for alveolar echinoccus of the liver

Background: Alveolar echinocactus is a parasitic disease affecting the liver. It is located mostly at the right lobe of the liver. This disease can also be located at other organs like the lungs, brain, bone or adrenal gland. Curative resection is not always possible. Methods: We present here a case of liver alveolar echinococcus located at segment 6. Results: A 47 year old patient admitted to our clinic with complaints of abdominal discomfort and pain. At physical examination there was palpable mass at the right upper quadrant. Laboratory data revealed nothing abnormal. Computed tomography evaluation revealed a semi-solid mass located at segment 6. CT features were consistent with alveolar echinococcus mass. Since this disease is endemic in our region we didn't perform any biopsies. The patient underwent a laparoscopic non-anatomic resection of segment 6. We used harmonic scalpel and CUSA. Operation time was 185 minutes. Blood loss was approximately 300 cc. The patient discharged from the hospital at 5 po day. Conclusion: Laparoscopic resection is safe for alveolar echinoccoccus of the liver.

Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.

BackgroundEfficacy of PO cobalamin (Cbl) supplementation in dogs with hereditary Cbl malabsorption (Imerslund‐Gräsbeck syndrome, IGS) is unknown.ObjectivesTo evaluate PO Cbl supplementation in Beagles with IGS previously treated parenterally. We hypothesized that 1 mg cyano‐Cbl daily PO would maintain clinical and metabolic remission.AnimalsThree client‐owned Beagles with IGS and 48 healthy control dogs.MethodsProspective study. Daily PO cyanocobalamin (cyano‐Cbl; 1 mg) supplementation was monitored for 13 (2 dogs) and 8 months (1 dog). Health status was assessed by owner observations. Methylmalonic acid (MMA)‐to‐creatinine concentrations were measured using an ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐TMS) method on urine samples collected monthly. Concurrent measurements of serum MMA concentration (n = 7; UPLC‐TMS) were available for 1 dog.ResultsAll dogs remained in excellent health during PO supplementation. Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2‐9; healthy dogs [n = 30], median, 2.9 mmol/mol creatinine; range, 1.3‐76.5). Urine MMA ranged from 38.9‐84.9 mmol/mol creatinine during the first 6 months in 1 dog already known to excrete comparable amounts when supplemented parenterally. Brief antibiotic treatment for an unrelated condition after 6 months resulted in low urine MMA (median, 2.8 mmol/mol creatinine; range, 1.9‐4.8) for the next 7 months. All concurrent serum MMA concentrations (median, 651 nmol/L; range, 399‐919) before and after month 6 were within the established reference interval (393‐1476 nmol/L; n = 48).Conclusions and Clinical ImportanceOne milligram of cyano‐Cbl daily PO appears efficacious for maintaining normal clinical status and normal cellular markers of Cbl metabolism in Beagles with IGS.

Fixed Dose Carfilzomib Triplets in Lenalidomide Refractory Myeloma

BackgroundMyeloma outcomes have improved due to the use of novel agents. However, patients who have failed bortezomib and lenalidomide represent a significant challenge. In New Zealand, myeloma patients are initially treated with CyBorD, transplant (if eligible) and VTD consolidation. Lenalidomide/dexamethasone is approved as third line therapy, or as second-line in patients with neuropathy. Compassionate access of carfilzomib became available in May 2016 for patients who have progressed after bortezomib and lenalidomide.MethodsPatients with myeloma treated with a carfilzomib triplet were identified from our database. After two initial doses of carfilzomib at 20mg/m2 patients were given a fixed dose of 60mg as a 30 minute infusion. Carfilzomib was given on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. To streamline administration, carfilzomib was infused via a Portacath in most patients. Patients received dexamethasone 20mg PO on days of carfilzomib (1, 2, 8, 9, 15 and 16), and cyclophosphamide 300mg/m2 PO Days 1, 8, and 15, thalidomide 100mg daily, lenalidomide 25mg Days 1-21 or venetoclax 800mg daily. Routine support care was valaciclovir, cotrimoxazole and allopurinol. Aspirin 100mg was given daily to reduce cardiovascular events. A baseline echocardiogram was obtained in all patients. Treatments were continued for 9 cycles, followed by maintenance (reducing carfilzomib to only Days 1 and 2 of a 28-day cycle, but continuing oral therapy) until treatment failure. Patients who progressed by IMWG criteria continued treatment if they continued to derive benefit. Patients were followed with monthly myeloma blood monitoring but did not routinely have bone marrow assessments to assess CR status. All statistical analysis was done using IBM SPSS version 20.ResultsBetween 18/5/16 and 21/5/18, 38 patients with RRMM were treated with a triplet containing carfilzomib, dexamethasone and cyclophosphamide( KCd n=33), lenalidomide (KRd n=3) thalidomide (KTd n=1), or venetoclax (KVd n=1). All patients except one, received at least 2 cycles of treatment and 19 currently continue therapy. The median number of cycles given is 10 (range 2-27). The median age at treatment initiation was 68yrs (range 51yrs to 91yrs); there were 17 patients >70yrs and three >80yrs. Patients had a median of 3 prior therapies and 18pts had received a ABMT, Prior treatment included bortezomib (100%), thalidomide (92%), lenalidomide (95%), and pomalidomide (18%). Carfilzomib triplets were generally well tolerated. One patient discontinued due to shortness of breath after two cycles. One patient had a non-STEMI cardiac event prior to routine use of aspirin, but continued on KCd. The best response was ≥CR 8% (n=3), ≥VGPR 32% (n=12), ≥PR 74% (n=28) ≥ MR 84% (n=32), four patients had SD and two progressed without benefit.Of the 38 patients, 21 have progressed with a median PFS of 9 ± 2.4 months. PFS was better in patients aged <70yrs, 53% at 18 months vs 0% for those aged >70 (median 4 months)(p=0.008). So far 15pts have died with a median OS of 18 ± 3 months. All deaths were in patients who had progressed. Outcomes were superior in those aged <70 yrs, OS 68% at 18 months (median OS not reached), versus those aged >70 yrs, OS 17% at 18 months (Median OS 11±6 months)(p=0.008) The median survival from relapse was poor at 2 months. However, of the 6 patients alive after progression, 3 received an anti-CD38 antibody as salvage and 3 remain on treatment with KCd, the longest continues on treatment at 15 months.SummaryFixed dose carfilzomib triplets are effective salvage therapy in myeloma patients who fail bortezomib and lenalidomide therapy. Treatment is well tolerated, even in elderly patients, albeit with inferior outcomes. [Display omitted] DisclosuresSimpson:Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Chan:Amgen: Honoraria; Karyopharm: Research Funding.

A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up

Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile.Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually.Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity.Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a “by-default-delayed” ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. [Display omitted] DisclosuresKorde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Pancreatic lithiasis and pancreatic pseudocyst in a 27-year-old woman – a case report

Introduction: Pancreatic cysts manifest as a common complication of acute and chronic pancreatitis. Drainage or resection of the pseudocysts is performed under specific indications, including stenosis of the common bile duct, infection of the cyst, compression of major vessels, compression of the stomach or duodenum or pancreaticopleural fistula. Methods: We report the rare case of a 27-year-old- female patient with a 2-year history of asymptomatic pancreatic pseudocyst and no clinical evidence of prior incidence of pancreatitis. Her medical history included diabetes mellitus type I, appendicectomy and C-section and there was no reference of alcohol abuse. Cyst was revealed randomly with Computed Tomography of the abdomen 2 years ago due to gynecological examination. She was admitted to our clinic due to constant pain located in the left upper abdomen radiating in the lumbar region for the last 7 days. A new Abdomen CT and MRCP was conducted, which revealed a large pancreatic pseudocyst with uneven margins, pancreatic duct dilatation, various pancreatic stones and several splenic infarcts. Results: Left-sided pancreatectomy and splenectomy was performed due to high suspicion of cystadenoma or cystadenocarcinoma. No post-operative complications were observed, and patient was discharged in good condition in 6th PO day. Conclusion: Pancreatic lithiasis appear more often to men than women, at the age of 40-60 years old, and in patients with acute-on-chronic pancreatitis. Implication of genetic factors should not be underestimated. Differential diagnosis must always include cystadenoma or cystadenocarcinoma to avoid serious preoperative misjudgment of draining rather than eradication of the cyst.

OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).

LBA4 Background: Olaparib is an oral PARP inhibitor with anti-tumor activity in HER2-negative mBC with a g BRCAm (NCT00494234). OlympiAD (NCT02000622) was a randomized, open-label, phase III study that assessed efficacy and safety of olaparib vs standard single agent chemotherapy treatment of physician’s choice (TPC) in pts with HER2-negative mBC and a g BRCAm. Methods: Pts aged ≥18 y with HER2-negative mBC (hormone receptor positive or triple negative [TN]) and a g BRCAm, who had received ≤2 chemotherapy lines for mBC, were randomized (2:1) to olaparib tablets (300 mg po bid) or TPC (21-day cycles of either capecitabine [2500 mg/m2 po days 1–14], vinorelbine [30 mg/m2 IV days 1 and 8] or eribulin [1.4 mg/m2IV days 1 and 8]). Treatment was continued until objective disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Results: 302 pts were randomized (median age 44 y; 50% TN; 71% prior chemotherapy for mBC; 28% prior platinum) of whom 205 received olaparib and 91 received TPC (6 TPC pts were not treated). At 77% data maturity, PFS by BICR was significantly longer in pts treated with olaparib vs TPC (HR 0.58; 95% CI 0.43, 0.80; P=0.0009; 7.0 vs 4.2 months, respectively). Time to second progression (investigator-assessed) was also longer in the olaparib arm (HR 0.57; 95% CI 0.40, 0.83). Objective response rate was 59.9 and 28.8% in olaparib and TPC arms, respectively. Grade ≥3 adverse events (AE) occurred in 36.6 and 50.5% of olaparib and TPC pts, with AEs leading to discontinuation in 4.9 and 7.7% of pts, respectively. Mean change from baseline in global health-related quality of life (HRQoL, EORTC-QLQ-C30) across all timepoints favored olaparib (difference vs TPC 7.5; 95% CI 2.48, 12.44; P=0.0035). Conclusions: Olaparib tablet monotherapy provided a statistically significant and clinically meaningful PFS benefit to HER2-negative mBC pts with a g BRCAm, compared to standard TPC. The safety profile of olaparib was consistent with prior studies. The efficacy benefit was seen beyond the first progression and HRQoL also improved. Clinical trial information: NCT02000622.

A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.

TPS9599 Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.

V1-04 RECONSTRUCTION OF BULBO-MEMBRANOUS URETHRAL STRENOSIS AFTER SURGERY FOR BENIGN PROSTATIC HYPERPLASIA WITH PRESERVATION OF CONTINENCE

You have accessJournal of UrologyReconstruction Lower Tract (I)1 Apr 2017V1-04 RECONSTRUCTION OF BULBO-MEMBRANOUS URETHRAL STRENOSIS AFTER SURGERY FOR BENIGN PROSTATIC HYPERPLASIA WITH PRESERVATION OF CONTINENCE Cristina Baeza, Reynaldo Gomez, Rodrigo Campos, and Laura Velarde Cristina BaezaCristina Baeza More articles by this author , Reynaldo GomezReynaldo Gomez More articles by this author , Rodrigo CamposRodrigo Campos More articles by this author , and Laura VelardeLaura Velarde More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.236AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bulbo-membranous urethral stenosis after surgery for benign prostate hyperplasia (BPH) are challenging because the internal sphincter has been removed and continence depends on the function of the external sphincter, which is located just at the site of the stenosis; any attempt for reconstruction may jeopardize continence. Anatomical studies have shown that the rhabdosphincter is separated from the membranous urethra by a sheath of connective tissue. We developed a novel technique performing a meticulous dissection of this sheath to separate the muscle from the urethral wall, thus performing an intra-sphincteric anastomosis without disturbing the sphincteric function METHODS A 67 year old patient underwent a transvesical simple prostatectomy for BPH. He developed an early bulbo-membranous stenosis managed initially with repeated dilation until he went into complete retention needing a suprapubic tube. The bulbar urethra is exposed through a vertical perineal incision with splitting of the bulbo-spongiosum muscle and then separated from the corpus cavernosum. Opening of the perineal membrane and splitting of the intercrural space in the midline, provides access to the dorsal aspect of the bulbo-membranous junction. The bulb is then mobilized to the left side, without detachment from the perineal body and the bulbar vessels are retracted. The sheath of the membranous urethra is now opened circumferentially at the bulbo-membranous junction, carefully reflecting the circular muscle fibers of the external sphincter until exposure of the urethral wall is obtained and the connecting tissue plane is identified. Gentle blunt proximal dissection along this plane allows separating the muscle away from the urethra towards the prostatic apex until healthy urethra is found to perform the bulbo-prostatic anastomosis, which is completed with a standard parachute technique. Finally the sphincteric muscle ring is anchored to the anastomosis with interrupted absorbable stitches RESULTS The patient was discharged on PO day 3 and the urethral catheter was removed at 3 weeks. He recovered normal continent micturition and is voiding symptoms free at 3 months of follow-up CONCLUSIONS Excision and bulbo-prostatic anastomosis with sphincter sparing for bulbo-membranous stenosis after BPH surgery is feasible and safe. Our technique allows repairing the urethra preserving continence and to our knowledge it has not been described before. A larger series and reproduction in other centers are needed to validate this technique © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e68-e69 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Cristina Baeza More articles by this author Reynaldo Gomez More articles by this author Rodrigo Campos More articles by this author Laura Velarde More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to Lenalidomide and Dexamethasone (LD) for the Treatment of Non-Transplant Eligible MM

Introduction : Cyclophosphamide, bortezomib and Dexamethasone (CyBorD) has become the standard frontline approach for the treatment of multiple myeloma (MM) in many centers across Canada. In the non-transplant eligible setting, recently a randomized controlled trial reported on the impact of Lenalidomide and Dexamethasone (LD), showing that this doublet-therapy is a feasible and efficacious combination. Based on the above-mentioned success of the LD combination, we aimed to compare the effect of CyBorD and LD for the treatment of non-transplant eligible MM (NTE) patients in the Alberta Myeloma and Dysproteinemia Program (AMDP). Patients and Methods : The primary objective was to assess ORR and PFS for NTE MM patients treated with CyBorD and LD. The recommended CyBorD regimen was as follows: bortezomib 1.3-1.5 mg/m2 SC or IV days 1, 8, 15 of a 28 day cycle (as of August, 2013 we adopted the a strategy whereby bortezomib can also be given on day 22), cyclophosphamide 300 mg/m2 PO days 1, 8, 15 and 22 and dexamethasone 20-40 mg PO days 1, 8, 15 and 22 with an aim to deliver a minimum of 9 cycles of treatment. LD was given at 25 mg days 1-21 of a 28-day cycle with Dexamethasone 20-40 mg PO days 1, 8, 15 and 22. Dose adjustments were at the discretion of the treating physician. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant and survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results: Ninety-one patients have received CyBorD and 56 have received LD. Clinical characteristics are shown in Table 1 . At the time of analysis, 64 and 32 patients in the CyBorD and LD are alive of which 10 and 11, respectively, have progressed, ORR and VGPR rates were 85.7% and 56% for patients treated with CyBorD, and 83.9% and 64% for LD respectively (p=0.3). Estimated median OS was 40 months for CyBorD compared to 66 months for LD (p=0.156). In addition, median PFS was longer for LD patients compared to CyBorD (26 months vs 16.4 months, p=0.018). The rate of treatment discontinuation was similar between both groups (8.7% vs 10%, p=0.3). In Conclusion: CyBorD and LD appeared to be effective treatment options for NTE myeloma patients with similar response rates. Recognizing the limitations of a retrospective series, it is interesting to note a longer PFS and a trend towards better PFS in the LD group, however, longer follow-up and prospective validation is still required. | Characteristic | CyBorD, n=91 | LD, n=56 | P value | | ---------------------------------------------------------------------------------------- | ------------------------------------------------- | ------------------------------------------------ | ------- | | Age (median) | 73.9 | 73.6 | 0.2 | | Gender Male Female | 57 (62.6%) 34 (37.4%) | 34 (60.7%) 22 (39.3%) | 0.8 | | B2microglobulin (µmol/L) | 4.9 | 4.89 | 0.4 | | Albumin (g/L) | 35 | 36 | 0.7 | | Stage I Stage II Stage III | 17.7% 35.4% 46.9% | 23.5% 37.2% 39.3% | 0.6 | | BMPC (%) | 32 | 37.5 | 0.6 | | Heavy chain: IgG IgA FLC only IgD IgM Biclonal | 50 10 18 1 1 3 | 26 17 9 0 1 0 | 0.068 | | Response rate ORR CR/nCR VGPR PR | 85.7% 23% 31.8% 30.7 | 83.9% 28% 37.5% 17.8% | 0.3 | * Ab : BMPC: Bone marrow plasma cell Table 1. Clinical Characteristics ![Figure 1.][1] Figure 1. Overall Survival according to treatment regimen ![Figure 2.][1] Figure 2. Progression-Free survival according to treatment regimen Disclosures Jimenez-Zepeda: Celgene: Honoraria; Amgen: Honoraria; JJ Celgene: Honoraria, Research Funding; Amgen: Honoraria. Sandhu: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Duggan: Celgene: Honoraria; Jansen: Honoraria. Neri: Celgene: Research Funding. Bahlis: Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Research Funding; Amgen: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. [1]: pending:yes

Rotational stability of 2 intraocular lenses with an identical design and different materials

To evaluate the rotational stability of nontoric intraocular lenses (IOLs) of the same design and different materials. Vienna Institute for Research in Ocular Surgery, Department of Ophthalmology, Hanusch Hospital, Vienna, Austria. Prospective randomized case series. This study included cataract patients with a corneal astigmatism of less than 1.75 diopters measured with the IOLMaster 500. Each patient received a hydrophilic IOL (Pod Ay 26P) in 1 eye and a hydrophobic IOL (Podeye) in the other eye. One hour and 3months postoperatively, retroillumination photographs were taken to assess rotational stability of the IOLs. In addition, autorefraction, subjective refraction, and Purkinje meter measurements were performed at the 3-month follow-up. Eighty eyes of 40 patients were included in this study. Three months postoperatively, the IOL rotation within the first 3months was 2.4 degrees±1.85 (SD) in the hydrophilic IOL group and 1.6±1.61 degrees in the hydrophobic IOL group. This difference was statistically significant (P=.016). The hydrophobic IOL was rotationally more stable than the hydrophilic IOL, although both IOLs provided good capsular bag stability.

Post-Splenectomy Portal Venous Thrombosis in Cirrhotic Patients: An Observational Clinical Trial

<i>Background:</i> Post-splenectomy portal venous thrombosis (PS-PVT) carries multiple threats to patients’ lives. Different variables were identified as risk factors for PS-PVT in cirrhotic patients. The aim of this study was to prospectively assess the incidence, risk factors, clinical presentation and treatment outcomes of PS-PVT in cirrhotic patients. <i>Patients and methods:</i> Sixty cirrhotic patients of Child class A submitted to open splenectomy were observed, both clinically and by Duplex ultrasound (US) examination, for the development of PS-PVT. <i>Results:</i> Overall, 17 patients (28.3%) developed PS-PVT at a median interval of 4.5 days (21 hours-7 days) post-splenectomy. Univariate analysis showed that lower preoperative platelet count (P&lt;0.0460) and white blood cell (WBC) count (P&lt;0.0001) and wider splenic vein diameter (SVD) (P&lt;0.0001) correlated with PS-PVT. Multivariate analysis identified lower preoperative WBC count [odds ratio (OR): 0.651, 95% confidence interval (CI): 0.245-0.893, P&lt;0.005] and wider SVD (OR: 2.383, 95% CI: 1.558-3.646., P&lt;0.001) as independent risk factors of PS-PVT. While 16 out of the 17 patients (94%) who had these 2 risk factors developed PS-PVT, only 1 out of the 43 patients (2.3%) who didn’t have the same risk factors developed thrombosis. All 17 patients had complete resolution of their thrombosis on anticoagulation therapy within 3-6 months without complications or mortality. <i>Conclusion:</i> PVT is a common complication of splenectomy in cirrhotic patients. Patients with low WBC count and wide SVD are highly susceptible to develop this complication mandating close observation from the 1^st PO day and immediate anticoagulation after diagnosis.

Safety and Efficacy of Filanesib in Combination with Pomalidomide and Dexamethasone in Refractory MM Patients. Phase Ib/II Pomdefil Clinical Trial Conducted By the Spanish MM Group

BackgroundFilanesib (ARRY-520) is a kinesin spindle protein inhibitor, with clinical activity in monotherapy in heavily pretreated MM patients (Lonial ASH 2013). We have previously demonstrated the preclinical synergy of this compound with pomalidomide and dexamethasone (Hernandez-García ASH 2015 & EHA 2016), the basis for the present trial.Material and MethodsMM patients relapsing after at least two prior lines of therapy including bortezomib and lenalidomide, who were refractory or intolerant to lenalidomide and refractory to the last line of therapy were treated until progression with 28-day cycles of filanesib iv on days 1, 2, 15 & 16, + pomalidomide po days 1-21 + dexamethasone at a fixed dose of 40 mg po days 1, 8, 15 & 22. Mandatory primary prophylaxis with G-CSF comprised two 7-days courses starting at day +3 and day +17. A Phase Ib was initially conducted to evaluate the maximum tolerated dose (MTD) of the combination, using a modified 3+3 dose-escalating algorithm and once the MTD was determined, the Phase II part of the trial was activated in order to evaluate the activity and further define the toxicity of the combination at this dose.ResultsThe phase Ib part of the trial included 14 patients with a median of 3.5 prior lines of treatment (range: 2-6); 11 (79%) were refractory to bortezomib; 13 (93%) refractory to lenalidomide, nine of them (64%) Len-refractory in the last line of therapy; 10 (71%) were double refractory to PI and lenalidomide; and 13 (93%) had received a prior ASCT.Out of these 14 patients, 7 were included in DL1 (pomalidomide 4 mg and filanesib 1 mg/m2) and the other 7 in DL2 (pomalidomide 4 mg and filanesib 1.25 mg/m2). None of the patients in DL1, experienced DLTs; and there was 1 DLT (G3 diarrhea lasting >7 days) in 1 out of the 6 evaluable patients in DL2.The most frequent treatment-related AEs were hematological: Anemia in 50% patients (36% G3 and 14% G4); neutropenia in 93% (21% G2, 21% G3 and 50% G4); and thrombocytopenia in 78% (50% G1/2, 14% G3 and 14% G4). Non hematological related AEs were mainly low grades, the most frequent-ones being diarrhea (28% G1/2 and 7% G3), asthenia in 36% (all of them G1/2) and infections. Most infections were upper respiratory tract and grades 1/2 (43%). Three patients presented with pneumonia (1 G2 and 2 G3), 1 patient each with sepsis and febrile neutropenia (both G3) and 1 patient died due to an Influenza A pneumonia. In order to maintain a good safety profile, although no formal MTD could be established based on DLTs, DL2 was defined as the recommended dose to proceed to the phase 2.As far as efficacy was concerned, 1 patient (7%) achieved VGPR and 6 (43%) PR for an overall response rate (ORR) of 50%; 1 additional patient (7%) achieved MR and the disease was stabilized in the remaining 6 patients (43%) (lasting for at least 3 cycles) accounting for a disease control rate (DCR) of 100%. Median time to response was 3 months. Remarkably, responses were not different in the nine patients refractory to lenalidomide in the last line of therapy (4 PR (44%) and 1 MR (11%)). After a median follow-up of 7 months, the median PFS was 7 months (CI95 3.3-10.6). Only 3 patients have died due to influenza A (n=1) and progressive disease (n=2).ConclusionThe recommended dose of the combination was defined as pomalidomide 4 mg + filanesib 1.25 mg/m2. The main toxicity was hematological but manageable; and the efficacy, with 50% overall response rate and 100% disease control rate in refractory patients, clinically confirms the synergy observed in the preclinical setting and supports the use of filanesib as a good partner for combination with pomalidomide and dexamethasone. Phase II is ongoing and updated results will be presented at the meeting. DisclosuresMartínez-López:Novartis: Honoraria, Speakers Bureau. De La Rubia:Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Ptaszynski:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Oriol:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. San-Miguel:BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; MSD: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Mateos:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Sustained High Rates of Complete Response and Minimal Residual Disease Negativity after 8 Cycles of Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R) in Patients with High-Risk Smoldering Multiple Myeloma: Updated Results of Clinical and Correlative Phase 2 Study

Background:High-risk smoldering multiple myeloma (HR-SMM) is a plasma cell dyscrasia which has a 5-year risk of progression to symptomatic multiple myeloma (MM) of approximately 75% based on current risk models. With the availability of novel therapies, early treatment may decrease the risk of progression and prolong survival as evidenced by the recent QuiRedex study results. More recently, studies have demonstrated that triplet regimens are superior to doublet in MM and whole exome sequencing in HR-SMM is indicative of treatment susceptible biology in early disease; supporting the use of effective combination therapy as early intervention. Expanding on our initial results using modern CRd-R therapy in HR-SMM patients (Korde et al. JAMA Onc 2015) we show unprecedented high rates of obtained and sustained complete response (CR) and minimal residual disease negativity (MRDneg CR) in an expanded cohort of patients with a median follow-up of ~3 years.Methods:Treatment-na•ve patients with HR-SMM (IMWG 2010 criteria; Mayo or PETHEMA models) were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective was best response (ORR), followed by secondary objectives of progression free survival (PFS) and response duration (DoR) which were assessed after every cycle of induction and every 90 days during maintenance. Correlative studies including assessment of minimal residual disease (MRD) by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) as defined by updated 2016 IMWG response criteria were performed after 8 cycles of induction and 1 and 2 years of maintenance LEN.Results:Eighteen patients meeting eligibility criteria were enrolled (data-lock 7/20/2016). Demographics and disease characteristics are shown in Table 1. Best ORR and >= VGPR rate (n=18) with CRd-R was 100% (Table 2). The proportion of patients who obtained stringent CR/CR after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 61%, 89%, and 89%, respectively. Of evaluable patients who achieved at least a CR, the proportion of patients who obtained MRD negativity (MRDneg CR) at the same time-points was 91%, 71%, and 75%, respectively. DoR and PFS at 36 months was 94% and overall survival with a median follow-up duration of 31 months was 100%. Toxicities Grade 3-4 occurring in >1 patient included lymphopenia (39%), neutropenia (28%), anemia (22%), diarrhea (17%), lung infection (17%), hypophosphatemia (11%), and thromboembolic event (11%). Significant serious adverse events included CHF which occurred in one patient.Conclusions:Early treatment of HR-SMM with modern CRd-R combination therapy with by-default-delayed HDM-ASCT resulted in unprecedented high rates of CR and MRDneg CR after 8 cycles of CRd. Following 2 years of additional LEN maintenance therapy, the CR and sustained MRDneg CR rates were 89% and 69%, respectively. Given the significant risk of progression to symptomatic MM and associated life limiting end-organ damage, early intervention for patients with HR-SMM with effective triplet-based therapies may be warranted. This first proof-of-principle study has thus far demonstrated exceptional clinical benefit. Therefore, this study will be re-opened to enrollment and long-term follow up results collected to expand on these promising results. Updated results will be presented at the Annual Meeting. [Display omitted] [Display omitted] DisclosuresKorde:Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:BMS: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria.

Preliminary Results of the Flugaza Trial: A Phase III Randomized, Open Label Study Comparing Azacytidine Versus Fludarabine and Cytarabine (FLUGA Scheme) in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction: Current recommendations for the treatment of AML in newly diagnosed elderly patients (≥ 65 years) include different therapeutic options (intensive or semi-intensive chemotherapy, low-dose chemotherapy, hypomethylating agents, and supportive care). Regardless of the selected treatment, the results are disappointing because of low overall survival (OS) rates and significant toxicity.Objectives: The primary objective of FLUGAZA trial is to compare the 1-year-OS in 350 patients aged ≥ 65 years diagnosed with AML assigned to azacytidine (n=175) or FLUGA (n=175) arms. Here we present the results of a pre-planned interim safety analysis for both outpatient treatment regimens.Methods Inclusion criteria: Patients diagnosed with de novo or secondary AML according to WHO classification (except for APL), previously untreated, age ≥ 65 years, ECOG <4. Randomization arms (1:1): azacytidine (AZA) (75 mg/m2 SC days 1-7) and FLUGA (fludarabine 40 mg/m2 PO days 2-6, cytarabine 75 mg/m2 SC days 2-6, filgrastim 5 µg/Kg SC days 1-3), cycles of 28 days. The treatment schedule consisted of 3 induction cycles (C1, C2, C3), 6 consolidation cycles and a maintenance treatment until relapse or progression. FLUGA was reduced in patients older than 75 years and filgrastim in the FLUGA arm was omitted when white blood cells (WBC) were > 25 x109/L. Concomitant use of hydroxyurea was allowed in the AZA arm if WBC was between 15 and 50 x109/L. In patients with more than 50 x109/L WBC assigned to the AZA arm, the first induction cycle was FLUGA.An interim analysis to assess myelotoxicity, early mortality and response rate was planned in the trial when the last of the first 100 randomized patients completed the first 3 induction cycles.Results: From October 2014 to April 2016, 162 patients were enrolled in 26 Spanish centers from the PETHEMA group. Of them, 22 patients were screen failure and 16 patients did not receive the assigned treatment. The first 100 patients treated were analyzed (58 patients were assigned to AZA arm and 42 to FLUGA arm). Baseline characteristics are shown in Table 1. Median age was 75 [65;90] years in AZA arm vs. 77 [65;88] years in FLUGA arm; 36 (62%) vs. 19 (45%) males. Five patients from AZA arm (n=58) received the first cycle of FLUGA because of WBC > 50 x109/L. Outcomes: overall response rate (CR+CRu+PR) based on the best response accumulated with 3 cycles of treatment was 62% in the AZA arm and 57% in the FLUGA arm. CR+CRu was achieved in 14 patients (24%) from AZA arm and 15 (36%) from FLUGA arm. Early mortality rate (8 weeks) was 14% in AZA and 22% in FLUGA arm. Toxicities: there were no differences in hospitalization and non-hematological ≥ G3 serious adverse events (SAEs) between both arms. Overall, 71 patients (71%), 61 out of 79 (77%) vs. 41 out of 64 (64%) patients, developed neutropenia (< 0.5 x x109/L) after C1, C2 and C3, respectively. Median duration of neutropenia in the AZA arm was 14 days (6;40), 21 days (4;95) and 18 days (1;45) after in C1, C2 and C3, respectively, vs. 15 days (4;33), 15 days (3;36) and 20 days (7;41) after C1, C2 and C3, respectively, in the FLUGA arm (no statistically significant differences). Eighty-one (81%), 55 out of 79 (70%) vs. 40 out of 64 (62%) patients, developed thrombocytopenia (< 50 x109/L) after C1, C2 and C3, respectively. Median duration of thrombocytopenia was 14 days (5;29) after C1, 18 days (4;88) after C2 and 14 days (7;25) after C3 in the AZA arm; vs. 16 (3;63), 20 (6;42) and 13 days (7;56) after C1, C2 and C3, respectively, in the FLUGA arm (NS).Conclusions: Outpatient treatment with AZA or FLUGA was feasible. Both treatment arms showed a similar rate of early mortality and relatively low CR/CRu rates. The study is currently enrolling patients until the planned accrual goal (350 patients) to assess the primary end-point (1-year OS). The study is registered at www.ClinicalTrials.gov as NCT02319135. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Sustained Minimal Residual Disease Negativity in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R): Updated Results of a Phase 2 Study

Background:State of the art treatment for patients with NDMM involves induction with triplet regimens utilizing newer therapies including combinations of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI) which improve progression-free survival (PFS) over doublet regimens. CFZ is a selective PI that inhibits the chymotrypsin-like activity of the 20S proteasome and has been approved in combination with LEN and DEX for the treatment of patients with relapsed or refractory MM who have received 1-3 lines of therapy. Furthermore, it has been associated with decreased neuropathy and increased clinical benefit over bortezomib-based combinations. This phase 2 study of 45 patients demonstrated that deep and durable responses with CRd-R can be achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing minimal residual disease negativity (MRDneg) at complete response (CR) and after 1 and 2 years of LEN maintenance. We also characterize depth of response by age and cytogenetic risk profile.Methods:Treatment-na•ve patients with MM were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective of the study was to estimate the rate of ³ Grade 3 peripheral neuropathy with secondary objectives of response (ORR), MRDneg, PFS, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, and 1 and 2 years of LEN maintenance.Results:Forty-five patients meeting eligibility criteria were enrolled (60% male; median age 60, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda). The proportion of patients who obtained a complete response (CR) with MRDneg after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 44%, 54% and 46%, respectively (Table 1). These deep responses of MRDneg CR were observed regardless of age group or cytogenetic-based risk profile (Table 2). ORR was 98% with a DoR at 48 months of 81%. PFS at 48 months was 82% and overall survival at 58 months was 86% with a median duration of follow-up of 31 months. Toxicities, in general, were manageable, with Grade 3-4 events occurring in >1 patient including lymphopenia (69%), neutropenia (27%), thrombocytopenia (20%) anemia (18%), hypophosphatemia (18%), leukopenia (16%), maculo-papular rash (13%), alanine aminotransferase elevation (11%), fatigue (9%), dyspnea (9%), hyponatremia 7%, thromboembolism (7%), lung infection (4%), hypoalbuminemia (4%). Serious adverse events included thromboembolism (13%), dyspnea (9%), anemia (7%), lung infection (4%), thrombocytopenia (4%), hyponatremia (4%), and pleural effusion (4%).Conclusions:Upfront treatment of NDMM with modern, highly efficacious CRd-R therapy with by-default-delayed HDM-ASCT led to high rates of sustained MRDneg CR (as defined by the updated 2016 IMWG response criteria) which is correlated with longer PFS and OS. Clinically important, these deep responses were observed regardless of the age of patients or cytogenetic risk. Our findings stress the importance of utilizing highly efficacious triplet-based regimens for the treatment of patients with NDMM regardless of age or cytogenetic risk. Updated results will be presented at the Annual Meeting. [Display omitted] [Display omitted] DisclosuresKorde:Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; Merck: Honoraria; BMS: Honoraria.

Zoonotic trypanosomes in South East Asia: Attempts to control Trypanosoma lewisi using human and animal trypanocidal drugs

Beside typical human trypanosomes responsible of sleeping sickness in Africa and Chagas disease in Latin America, there is a growing number of reported atypical human infections due to Trypanosoma evansi, a livestock parasite, or Trypanosoma lewisi, a rat parasite, especially in Asia. Drugs available for the treatment of T. brucei ssp. in humans are obviously of choice for the control of T. evansi because it is derived from T. brucei. However, concerning T. lewisi, there is an urgent need to determine the efficacy of trypanocidal drugs for the treatment in humans. In a recent study, pentamidine and fexinidazole were shown to have the best efficacy against one stock of T. lewisi in rats.In the present study suramin, pentamidine, eflornitine, nifurtimox, benznidazole and fexinidazole, were evaluated at low and high doses, in single day administration to normal rats experimentally infected with a stock of T. lewisi recently isolated in Thailand. Because none of these treatments was efficient, a trial was made with the most promising trypanocide identified in a previous study, fexinidazole 100mg/kg, in 5 daily administrations. Results observed were unclear. To confirm the efficacy of fexinidazole, a mixed infection protocol was set up in cyclophosphamide immunosuppressed rats. Animals were infected successively by T. lewisi and T. evansi, and received 10 daily PO administrations of 200mg/kg fexinidazole. Drastic effects were observed against T. evansi which was cleared from the rat's blood within 24 to 48h; however, the treatment did not affect T. lewisi which remained in high number in the blood until the end of the experiment. This mixed infection/treatment protocol clearly demonstrated the efficacy of fexinidazole against T. evansi and its inefficacy against T. lewisi. Since animal trypanocides were also recently shown to be inefficient, other protocols as well as other T. lewisi stocks should be investigated in further studies.

Abstract CT011: Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozolomide or irinotecan in patients with advanced malignancies

Abstract Background: Talazoparib is the most potent PARP inhibitor in clinical development (IC50 = 0.57 nMol/L). When talazoparib is combined with DNA damaging agents a synergistic effect mediated through enhanced PARP inhibition and PARP trapping is seen. Here we report first in human combination studies of talazoparib with temozolomide (TEM) or irinotecan (IRI) with biomarker correlates of response. Methods: A phase I dose escalation study evaluated escalating doses of talazoparib (? 0.5 mg PO QD) with either TEM (? 25 mg/m2 PO days 1-5) (Arm A) or IRI (? 25 mg/m2 IV q2 weeks) (Arm B) every 28 days in patients with advanced malignancies. In both arms the dose of talazoparib was escalated first up to the single agent maximum tolerated dose (MTD) of 1.0 mg before the dose of chemotherapy was increased. The primary endpoint was the determination of the maximum tolerated dose (MTD), and secondary endpoints included pharmacokinetics, tumor response, and biomarkers. DLTs were assessed during the 1st cycle of each dose level. RECIST version 1.1 assessment was done every 8 weeks. Prior TEM or IRI was permitted. A subset of patients had tumor assessment using next generation sequencing (NGS) to identify genomic aberrations distinct from BRCA mutations. Results: 41 patients received escalating doses (0.5-1.0 mg) of talazoparib and either TEM or IRI: 19 patients in Arm A and 22 in Arm B. Median age was 57 (21-77), all PS were 0 or 1 and the median number of prior chemotherapy regimens was 6 (1-15). The MTD for each arm was talazoparib 1.0 mg and 37.5 mg/m2 for either TEM or IRI. Confirmed partial responses (PR) were seen in 4/7 (57%) germline BRCA wild-type platinum-resistant ovarian cancer patients, and PRs were seen in one patient each with Ewing's Sarcoma, cervical adenocarcinoma, small cell lung cancer and triple negative breast cancer. There was a correlation between response and the presence of deleterious somatic mutations in non-BRCA DNA repair genes (e.g. PALB2, RAD51D, MSH2). In the ovarian patients, Homologous Recombination Deficiency (HRD) scores ?42 was correlated with response. The most common grade 3/4 AE's (?5%) related to the treatment combination talazoparib + TEM were neutropenia (28%), anemia (33%) and thrombocytopenia (33%), and for the combination talazoparib + IRI were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant PK interactions were seen between talazoparib and either TEM or IRI. Conclusions: The combination of talazoparib with either TEM or IRI is generally well tolerated in patients with heavily pre-treated advanced malignancies. Regardless of histology, there was a correlation with the presence of specific genomic alterations (not confined to DNA repair) and a PR by RECIST. These data support further evaluation of talazoparib in combination with TEM or IRI in tumors to evaluate efficacy and safety with a focus on relevant somatic mutations, pathway predictors and/or response/resistance biomarkers. Citation Format: Zev A. Wainberg, J. Randolph Hecht, Gottfried E. Konecny, Jonathan W. Goldman, Saeed Sadeghi, Bartosz Chmielowski, Arun Singh, Richard S. Finn, Diego Martinez, Lisa Yonemoto, John Glaspy, Dennis J. Slamon. Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozolomide or irinotecan in patients with advanced malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT011.