Study Drug Exposure Research Articles

Serious infection risk of tofacitinib compared to biologics in patients with rheumatoid arthritis treated in routine clinical care

Recently, serious infections related to the use of tofacitinib (TOF) for treatment of rheumatoid arthritis (RA) have raised considerable interest. This study aimed to compare the risk for serious infections in patients with RA upon receiving TOF versus biologic disease-modifying antirheumatic drugs (bDMARDs) by age at treatment initiation. We identified adult RA patients exposed to TOF or bDMARDs using data collected by the Swiss registry for inflammatory rheumatic diseases (SCQM) from 2015 to 2018. The event of interest was the first non-fatal serious infection (SI) during drug exposure. Missing or incomplete SI dates were imputed as either the lower (left) or upper (right) limit of the known occurrence interval. The ratio of SI hazards (HR) of TOF versus bDMARDs was estimated as a function of age using covariate-adjusted Cox regression applied to each type of imputed time-to-SI. A total of 1687 patients provided time at risk for a first SI during study participation and drug exposure for 2238 different treatment courses, 345 for TOF and 1893 for bDMARDs. We identified 44 (left imputation) or 43 (right imputation), respectively, first SIs (12/12 on TOF versus 32/31 on bDMARDs). Left and right imputation produced similar results. For patients aged ≥ 69 years, the treatment HR started to be increased (lower limit of 95% confidence intervals (LLCIs) > 1). By the age of 76, the difference between TOF and bDMARDs started to be clinically relevant (LLCIs > 1.25). For patients aged < 65 years, the data were insufficient to draw conclusions. Our results suggest that we should expect an increased risk for SIs in older patients treated with TOF compared to bDMARDs supporting a cautious use of TOF in these patients.

#5500 THE IMPACT OF CHRONIC KIDNEY DISEASE-ASSOCIATED PRURITUS RELIEF ON SKINDEX-10 DISEASE AND SOCIAL FUNCTIONING DOMAINS

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) is a serious condition that greatly impacts patients’ quality of life (QoL). Moderate-severe pruritus affects up to 47% of patients undergoing haemodialysis (HD) [1]. The aim of this analysis was to assess the impact of itch relief on the disease and social functioning domains of the Skindex-10 questionnaire in a post hoc analysis of the difelikefalin (DFK) Phase 3 studies in patients with CKD-aP undergoing HD. Method Patients with moderate-to-severe CKD-aP (mean Worst Itch Numerical Rating Scale [WI-NRS] score ≥4 [KALM-1] or ≥5 [Study 3105 and KALM-2]) undergoing HD were enrolled and randomised 1:1 to receive intravenous DFK 0.5 µg/kg or placebo (KALM-1 and -2) or open-label DFK (Study 3105) 3 times/week for 12 weeks. Data from all patients who completed the studies were included in the present analysis irrespective of study drug exposure; data were pooled for patients receiving DFK and placebo from the KALM studies. The 12-week change from baseline in the Skindex-10 questionnaire subdomains were assessed for disease (Q1–3) and social functioning (Q7–10). Change from baseline in the mood/emotional distress domain has previously been reported (Q4–6) [2]. Results Skindex-10 scores were available for 914 patients (KALM studies: n = 720; Study 3105: n = 194). At Week 12, patients with a clinically relevant (WI-NRS ≥3-point) change (decrease) in itch (KALM: n = 305; 3105: n = 143) reported a relative mean (± standard error) corresponding improvement of 59.7%±2.0 (KALM) and 65.9%±2.6 (3105) from baseline in the disease domain of Skindex-10, compared with 18.4%±2.3 and 30.7%±4.4 of patients with &amp;lt;3-point WI-NRS improvement (KALM: n = 415 [Figure A]; 3105: n = 51 [Figure B]). In addition, a much greater improvement in QoL was reported for the social functioning domain for patients with ≥3-point WI-NRS improvement, compared with patients with &amp;lt;3-point improvement (66.2%±3.5 vs 11%±7.6 in the KALM studies; 75.5%±4.0 vs 49.4%±8.5 in Study 3105). Overall, the patients with ≥3-point WI-NRS change reported relative mean improvement from baseline ranging from 64%±2.3 to 70.2%±2.6 across the total Skindex-10 scale compared with 15.1%±4.8 to 35.4%±5.5 of patients with &amp;lt;3-point improvement at Week 12 across all studies. Conclusion In this post hoc analysis, patients with CKD-aP undergoing HD who reported a clinically meaningful reduction in itch intensity also achieved a substantially greater improvement in both the disease and social functioning domains of Skindex-10, as well as overall itch-related QoL.

A phase Ib/II study of GFH018 in combination with toripalimab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC).

6026 Background: The transformed growth factor beta (TGF-β) signaling pathway is dysregulated in carcinogenesis. In NPC patients, upregulation of TGF-β pathway is correlated with disease stage or phenotype due to Epstein-Barr virus (EBV) infection. GFH018, a novel TGF-βRI inhibitor, can inhibit tumor growth through inhibiting the activity of TGF-βRI kinase to block the signal transduction of TGF-β and modulate the tumor immune microenvironment. Preclinical studies showed that GFH018 in combination with PD-1/PD-L1 monoclonal antibody can significantly inhibit tumor growth synergistically. Here we report the preliminary results of combining GFH018 and Toripalimab treating R/M NPC patients (pts). Methods: This is a phase Ib/II study to evaluate the safety and efficacy of the combination of GFH018 and Toripalimab in pts with advanced solid tumors. Patients with RM NPC were enrolled to receive GFH018 80mg twice a day (BID) 14-day-on/14-day-off in combination with Toripalimab 3mg/kg every two weeks. Tumor assessment was performed every 8 weeks per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. Results: As of 31 Dec 2022, 32 pts with R/M NPC who had progressed on at least one prior line therapy were enrolled. Sixteen (50%) had received ≥3 lines of prior therapies, and 19 (59.4%) had previously received immune checkpoint inhibitors (ICIs) and platinum-based chemotherapies. The median duration of study drug exposure was 7 weeks. Twenty-five pts (78.1%) experienced treatment-related adverse events (TRAEs) of any grades, and 11 pts (34.4%) had ≥ Grade 3. The most common TRAEs (occurring in ≥ 3 pts) were anaemia (n = 6, 18.8%), hyponatraemia (n = 6, 18.8%), rash (n = 6, 18.8%), fatigue (n = 4, 12.5%), white blood cell count decreased (n = 4, 12.5%), aspartate aminotransferase increased (n = 3, 9.4%), back pain (n = 3, 9.4%), decreased appetite (n = 3, 9.4%), hypokalaemia (n = 3, 9.4%), and hypothyroidism (n = 3, 9.4%). As of 18 Jan 2023, among the 27 pts with post-baseline tumor assessments, 8 achieved partial response (PR), and 5 stable disease (SD); the overall response rate (ORR) was 29.6%, and disease control rate (DCR) was 48.1%. Six PR and 2 SD were observed among the 12 pts without prior treatment of ICIs; the ORR was 50%, and DCR was 66.7%. Four pts discontinued treatment without any post-baseline tumor assessments due to AEs or withdrawal of consent, and 1 patient is premature for tumor assessment. Conclusions: GFH018 combined Toripalimab was well tolerated and demonstrated preliminary efficacy in pts with R/M NPC. Specifically, in pts who had not previously received ICIs, promising antitumor activity was observed supporting further investigation to this group of pts. Clinical trial information: NCT04914286 .

Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin

Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding. This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups. From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively). Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

BackgroundPeripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC.Methods200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol.DiscussionMOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC.Trial Registration: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Targeting Thrombophilia in Sickle Cell Disease with Isoquercetin: Results of a Fixed Dose, Single Center, Phase II Randomized Clinical Trial

Introduction: Sickle cell disease (SCD) is characterized by elevated markers of hemostatic activation and thrombophilia manifesting as arterial stroke and venous thromboembolism (VTE). Anticoagulation for VTE in SCD is associated with an increased risk for bleeding. In cancer patients at high risk for VTE, the flavonoid Isoquercetin (IQ) lowered D-dimer and soluble P-selectin possibly by inhibiting plasma protein disulfide isomerase. In a murine model of SCD, IQ with Hydroxyurea (HU) reduced platelet accumulation and fibrin deposition following laser-induced injury. Given these results, we tested the hypothesis that IQ would be relatively safe and reduce thrombo-inflammatory biomarkers in steady state SCD patients. Methods: We conducted a phase II randomized, double blind, placebo-controlled study at the NIH Clinical Center. Eligible patients had SCD, were 60 days remote from an acute VOC or blood transfusion and were on a stable dose of HU. Study subjects (n=46) were randomly allocated to receive either Isoquercetin 1000 mg daily (n= 23) or placebo (n= 23) for 28 days and were monitored at the beginning and at completion of study. The primary endpoint of the study was the ELISA measured change in plasma sP-selectin levels after 28 days of placebo or study drug exposure. Analysis was performed on an intention to treat principle. D-dimer levels and Thrombin anti-thrombin (TAT) complex were measured by Immunoturbidimetric assays and ELISA. Statistical analyses was performed using analysis of covariance (ANCOVA) and Wilcoxon rank-sum test. Results: The mean (± SD) age of the study population was 40 years (± 11.57), and 56% were female. The majority had HbSS disease and were receiving HU therapy. A subset (28%) reported a prior history of venous thrombosis (VTE) and four of these were on extended duration oral anticoagulation (Table 1). Baseline characteristics between the two study groups were relatively similar. For the primary endpoint, at the end of study the effect of IQ on the change in plasma sP-selectin levels after adjusting for the baseline was not significant (Figure 1) (IQ mean change= 0.10 ± 6.53 vs. placebo mean change= 0.74 ± 4.54; p= 0.66). Since treatment with HU could confound a treatment effect of IQ in a small sample, we compared the change of sP-selectin among those receiving and not receiving HU but did not find any significant difference (p= 0.67). In a sensitivity analysis we did not find an interaction between HU and IQ treatment (p= 0.48). A similar examination for the potential role of VTE history (n= 5 in IQ and n= 8 in placebo arm) as a confounder did not show a VTE effect on change in sP-selectin (p= 0.68) nor an interaction between VTE history and treatment (p= 0.65). In addition to the primary outcome, we explored the effect of IQ treatment on traditional biomarkers of thrombosis. In contrast to studies in patients with cancer, IQ exposure for 28 days did not have a noticeable effect on change from baseline in either D-dimer levels (IQ mean change= 0.15 mcg/ml ± 0.92 vs. placebo mean change= -0.10 mcg/ml ± 2.11; p= 0.82) or thrombin-antithrombin (TAT) complexes (IQ mean change= 0.09 ng/ml ± 1.60 vs. placebo mean change= -0.05 ng/ml ±1.29; p= 0.57). Conclusion: Short term Isoquercetin exposure in steady state SCD did not appreciably lower plasma sP-selectin but was well tolerated, safe and did not have bleeding side effects. Clinical studies of higher dose IQ with greater exposure duration may yield more measurable effects on antithrombotic activity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Direct Oral Anticoagulants Versus Warfarin for Venous Thromboembolism Prophylaxis in Patients With Nephrotic Syndrome: A Retrospective Cohort Study.

Evidence supporting venous thromboembolism (VTE) prophylaxis with direct oral anticoagulants (DOACs) in patients with nephrotic syndrome (NS) is limited to case reports. The purpose of this study was to compare bleeding and thromboembolic events in this population. A retrospective cohort study was conducted in adults with NS initiated on a DOAC or warfarin for VTE prophylaxis between January 2013 and July 2021 within the Ochsner Health System. Patients with study drug exposure within the preceding 7 days, acute VTE within the preceding 6 months, or ≤7 days of study drug exposure were excluded. The primary outcome was the composite rate of major bleeding and clinically relevant nonmajor bleeding. Secondary outcomes included time to major bleeding and rate of new thromboembolic events. This study was approved by the Ochsner Health System Institutional Review Board. Twenty-five DOAC and 19 warfarin patients were included. The primary outcome occurred in 8% vs 26.3% (P = 0.21) of patients treated with a DOAC or warfarin, respectively, and was driven by major bleeding (4% vs 21%, P = 0.25). Other secondary outcomes were similar between cohorts. The study was limited by a small sample size. Use of DOACs for VTE prophylaxis resulted in a nonstatistically significant, but clinically relevant lower rate of major bleeding compared to warfarin. This study provides comparative data showing safe and effective use of DOACs in patients with NS. Prospective, randomized studies are needed to confirm results.

Two Phase 1b Studies Evaluating the Safety and Tolerability of BET Inhibitors, ABBV-744 and Mivebresib, as Monotherapies and in Combination with Ruxolitinib or Navitoclax in Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by uncontrolled inflammation and fibrotic deposition in the extracellular bone marrow space, resulting in cytopenias, constitutional symptoms, and splenomegaly. A minority of patients are eligible for allogeneic hematopoietic stem cell transplant (allo-HSCT), which can be curative but is associated with substantial risks. Janus-associated kinase inhibitors (JAKi), including ruxolitinib (Rux), are approved for treatment of MF but do not reliably alter the disease course or generate durable responses. The limited treatment options for MF after Rux failure highlight a clear unmet need. In murine models of MPN, bromodomain and extra-terminal family protein inhibitors (BETi) reduced inflammatory cytokine levels and, combined with JAKi, reduced MF disease burden (Kleppe et al, 2018). BETi also modulated key nodes in the intrinsic apoptosis pathway and synergized with the B-cell lymphoma-2 (BCL-2) family inhibitor navitoclax (Nav) in solid tumor models (data on file). Pan-BETi have shown activity in patients with MF, including reduction in spleen volume and improvements in symptom burden, anemia, and bone marrow fibrosis as monotherapy and in combination with Rux (Mascarenhas et al, 2019). Selective BETi may reduce off-target toxicity relative to pan-BETi. The studies described here aim to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of ≥2 dosing regimens of 2 novel BETi: mivebresib, an oral pan-BETi that demonstrated antitumor activity in preclinical models of malignancy, and ABBV-744, a novel, potent small molecule that selectively inhibits bromodomain II of the BET family. Both BETi will be investigated as monotherapy and in combination with Nav or Rux in patients with MF. Methods: The 2 Phase 1b, multicenter, open-label studies will recruit patients with MF to receive ABBV-744 (NCT04454658) or mivebresib (NCT04480086), respectively, as monotherapy or in combination with Nav or Rux. Patients ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly (intermediate-1 with palpable splenomegaly ≥5 cm below costal margin eligible for Segment A) and Eastern Cooperative Oncology Group Performance Status &amp;lt;2 who are not candidates for allo-HSCT will be enrolled into 4 segments (Figure). Segment A: JAKi-experienced and BETi-naïve patients will receive 1 of 2 dosing regimens of ABBV-744 or 1 of 2 dosing regimens of mivebresib. Segment B: BETi-naïve patients currently receiving Rux will receive ABBV-744 or mivebresib plus Rux; Segment C: JAKi-experienced, and BETi-naïve, and/or BCL-XL/BCL-2 inhibitor-naïve patients will receive ABBV-744 or mivebresib plus Nav; Segment D: JAKi-naïve and BETi-naïve patients will receive ABBV-744 or mivebresib plus Rux. A dose regimen will be stopped if ≥3 of the first 9 dose-limiting toxicity (DLT)-evaluable patients given that dose in Segment A experience a DLT, or if the DLT rate is ≥33% at any point thereafter. Segments B and C will begin only once a dose regimen is deemed safe in Segment A. Segment D will commence after safety is established in Segment B. Treatment may continue until ≥1 discontinuation criterion has been met. The primary endpoint in both studies is adverse events (AEs) defined by the Common Terminology Criteria for AEs v5, including DLTs at a dose considered tolerable in patients with MF. Key secondary endpoints include the proportion of patients with spleen volume reduction of ≥35% at Weeks 12 and 24, PK parameters, proportion of patients with ≥50% reduction in Total Symptom Score at Week 24, and objective response rate (complete remission + partial remission). Key exploratory endpoints include change from baseline in allelic frequency, improvement in bone marrow fibrosis grade, and cytokine modulation. The planned sample size is approximately 130 patients per study. Analyses will include all patients who received ≥1 dose of study drug. Safety will be assessed by study drug exposure, AEs (including DLTs), serious AEs, deaths, and changes from baseline in laboratory determinations and vital sign parameters. AEs will include treatment-emergent events with an onset after first dose and ≤30 days after the last dose of study drug. Efficacy analyses will include summary statistics for categoric and continuous variables. Confidence intervals will be derived from the Clopper Pearson method. First dosing is planned for Q4 2020. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Saab:AbbVie: Current Employment, Other: may own stock or stock options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Modi:AbbVie: Current Employment, Other: may own stock or stock options. Abraham:AbbVie: Current Employment, Other: may own stock or stock options. Ward:AbbVie: Current Employment, Other: may own stock or stock options. Verstovsek:Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; ItalPharma: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding.

A phase I study of Aurora kinase A inhibitor LY3295668 erbumine as a single agent and in combination in patients with relapsed/refractory neuroblastoma.

TPS10561 Background: Aurora kinase A (AurA) has been implicated in high-risk neuroblastoma, including roles stabilizing and increasing expression of MYCN protein. AurA impacts the function of MYCN in mediating transcription in a cell cycle dependent manner, suggesting that neuroblastoma and other MYC/MYCN-driven tumors may be sensitive to AurA inhibition. LY3295668 is a selective AurA inhibitor. The lack of AurB inhibitory activity is hypothesized to minimize on-target hematologic toxicity associated with AurB inhibition. The molecule’s selectivity is intended to allow for continuous dosing at exposures associated with &gt; 90% target inhibition at trough. In an analysis of LY3295668 antiproliferative effects in 560 cancer cell lines, neuroblastoma was among the most sensitive histologies tested. This screen also separately evaluated genomic predictors of response to LY3295668, with MYC/ MYCN amplification identified as among the strongest predictors of sensitivity to this agent. LY3295668 is currently being evaluated in early phase adult trials. The current trial (J10-MC-JZHD) was uniquely designed to hasten time to first-in-child oncology development for a rare unmet need of relapsed/refractory neuroblastoma patients. Methods: Study J1O-MC-JZHD (NCT04106219) is a multicenter, dual collaboration (NANT and ITCC), randomized, open-label, Phase 1 study of oral LY3295668 in children with relapsed/refractory neuroblastoma. A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan. The starting monotherapy dose will be equivalent to 80% of the adult maximum tolerated dose. Key eligibility criteria include recurrent/refractory neuroblastoma not amenable to curative treatment, age 2-21 years, mandatory archival tissue submission, ability to swallow capsules, and adequate hematologic and organ function. LY3295668 is administered in capsule form orally BID continuously. Primary objectives include assessments of safety and tolerability of study drug to identify RP2D as monotherapy and combination, and assess antitumor activity. Secondary objectives include assessment of the pharmacokinetic profile as monotherapy and in combination, and assessment of the relationship between study drug exposure and efficacy. Following determination of the RP2Ds, an expansion phase will randomize patients to monotherapy or to the combination arm. Enrollment began 16 Dec 2019 and is ongoing. Clinical trial information: NCT04106219.

41: Fetal metabolic biomarkers after late preterm betamethasone and their association with neonatal hypoglycemia

Late preterm betamethasone significantly reduced neonatal respiratory morbidity, but also increased neonatal hypoglycemia through an uncertain mechanism. Our objective was to define the fetal metabolic effects of antenatal late preterm betamethasone. Secondary analysis of a randomized trial of antenatal betamethasone versus placebo in women with threatened late preterm birth (2010-2015). Mother-neonate dyads with stored umbilical cord blood plasma were included. Major congenital anomalies were excluded. Magnetic bead-based multiplex assays were used to measure metabolic biomarkers C-peptide, insulin, leptin and insulin-like growth factor binding protein 1 (IGFBP-1) in umbilical cord blood plasma. Baseline characteristics and biomarker levels were compared between betamethasone and placebo groups. Multivariable generalized linear regression estimated the association between betamethasone and biomarker levels, adjusting for BMI, GDM, hours from study drug exposure to delivery, and hospital as a random effect. Subsequently, the associations between the fetal biomarkers and neonatal hypoglycemia (glucose< 40mg/dL) were investigated. Of 2831 women in the primary trial, 203 met inclusion criteria for this analysis: 106 (52%) exposed to betamethasone and 97 (48%) exposed to placebo. A total of 173 (85%) women delivered preterm and 23 (11%) had GDM. Overall, 61 (30%) neonates had hypoglycemia. Betamethasone was associated with higher adjusted mean C-peptide, insulin, and leptin levels (Figure). There was no difference in IGFBP-1. Fetal C-peptide and insulin levels >90th percentile were associated with 3- to 6-fold higher odds of neonatal hypoglycemia (Table). Betamethasone given in late preterm is associated with altered fetal metabolic pathways, and these alterations are associated with neonatal hypoglycemia. Further studies are needed to confirm whether fetal hyperinsulinemia is the cause of neonatal hypoglycemia after late preterm betamethasone exposure, and if this outcome can be prevented.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

69 NanoPac-2017-01 Mid-Study Report: Safety, Tolerability, and Preliminary Efficacy of Intracystic Submicron Particle Paclitaxel (SPP) for the Treatment of Mucinous Cysts

INTRODUCTION: Pancreatic Mucinous cystic lesions (MCL) have significant potential for malignant transformation; delivery of SPP as a direct intratumoral injection confirmed SPP present at the delivery site for at least 100 days in a prior study; intracystic therapy with SPP may prevent progression to cancer without corresponding systemic toxicities. METHODS: Aim: To determine safety and preliminary efficacy of SPP for treatment of MCLs using endoscopic ultrasound Fine Needle Injection (EUS-FNI). Materials and Methods: Subjects with confirmed MCL, based on elevated intracystic CEA and cytology, receive intracystic SPP via EUS FNI at volumes equal to the aspirated cyst fluid volume in sequential cohorts at 6, 10, and 15 mg/mL in a standard “3+3” dose-escalation protocol. The highest dose with acceptable safety and tolerability profile, as determined by a DSMB, will proceed into the second phase of the study; 9 additional subjects will receive two injections of SPP (same dose) 12 weeks apart. Subjects are followed for 6 months for clinical endpoints including: safety and tolerability evaluations, physical examination findings and vital signs; pharmacokinetic analysis of systemic paclitaxel drug levels; and cyst volume response as reported by imaging at 3 and 6 months. RESULTS: Nine subjects have been enrolled to date; 5 have completed the study (1 injection). EUS, imaging, CEA and amylase concentration were consistent with branched duct IPMN cyst (BD-IPMN) or MCNs (Table 1). To date, no dose limiting toxicities, serious adverse events related to treatment, or clinically significant blood work (chemistry; hematology; coagulation) or urinalysis have been reported. Adverse events potentially related to SPP include mild, transient abdominal pain/discomfort in 4 subjects and nausea in 2 subjects. Systemic paclitaxel concentration did not exceed 1 ng/mL, and was undetectable at 2 weeks supporting retention of SPP at delivery site. Cyst volumes in 3 of 5 completed subjects reduced by month 6, 2 remained stable (Table 2). CONCLUSION: Intracystic SPP appears safe and tolerable when administered at 6, 10, and 15 mg/mL in a volume equal to that of aspirated cyst fluid. Minimal systemic study drug exposure is experienced. No patients developed pancreatitis. Intracystic SPP appears to prevent continued growth of the cysts and may reduce total cyst volume. Subject enrollment to the second phase (2 injections 12 weeks apart) is underway at 15 mg/mL.

Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTIONDoes administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss?SUMMARY ANSWERrhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.WHAT IS KNOWN ALREADYThe only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATIONA randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK.PARTICIPANTS/MATERIALS, SETTING, METHODSOne hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat.MAIN RESULTS AND THE ROLE OF CHANCEA total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29–34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26–33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7–1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1–13.4; P = 0.93).LIMITATIONS, REASONS FOR CAUTIONThis trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy.STUDY FUNDING/COMPETING INTEREST(S)This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.TRIAL REGISTRATION NUMBEREUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063TRIAL REGISTRATION DATE31 Mar 2014DATE OF FIRST PATIENT’S ENROLMENT23 Jun 2014

1730. Outcomes of Patients With Detectable Cytomegalovirus (CMV) DNA at Randomization in the Double-blind, Placebo-Controlled Phase 3 Trial of Letermovir (LET) Prophylaxis for CMV-Seropositive Allogeneic Hematopoietic-Cell Transplantation (HCT) Recipients

BackgroundLET prophylaxis through HCT Week 14 was highly effective in preventing clinically significant CMV infection (CS-CMVi), had a good safety profile, and was associated with lower all-cause mortality by HCT Week 24 compared with placebo (PBO). Patients with detectable CMV DNA at randomization were excluded from the trial’s efficacy analyses (NCT02137772). Here we report the outcomes of these patients.MethodsWe compared patients randomized 2:1 and treated with LET or PBO who had detectable CMV DNA at randomization (n = 70) to those with undetectable CMV DNA (n = 495; primary efficacy population, PEP). CS-CMVi was defined as CMV viremia requiring antiviral preemptive therapy (PET) or CMV disease; patients with missing data were imputed as events. PET was prescribed blinded to study drug. We analyzed CS-CMVi incidence, CMV viral load (VL) kinetics, and mortality using post study vital status. Detectable, nonquantifiable CMV VL (<151 c/mL) was imputed as 150 c/mL.ResultsOf 70 patients with detectable CMV DNA at randomization (48 LET, 22 PBO), CMV VL was 150 c/mL in 63 patients (range, 150–716). All patients had undetectable CMV VL ≤5 days before randomization. Baseline characteristics were similar to the PEP, except for more patients with myeloablative conditioning (62.9% vs. 48.3%) and longer median days post-HCT to start of study drug (15 days vs. 8 days). Median study drug exposure was 70 days (range, 1–113) in LET group and 14 days (range, 7–99) in PBO group. By HCT Week 14, CS-CMVi occurred in 15 (31.3%) LET-treated patients and 17 (77.3%) PBO patients; CS-CMVi with imputed events were 22 (45.8%) in LET group and 20 (90.9%) in PBO group (difference –44.8%; 95% CI, –64.7% to –24.8%; P < 0.0001). Median CMV VL at time of PET was 413 c/mL (range, 150–31,847) and was similar between groups. Eight patients had quantifiable CMV VL (range, 171–1,728 c/mL) 1 week after starting study drug: 6 did not receive PET (5 LET [10.4%], 1 PBO [4.5%]). CMV VL was undetectable subsequently; other 2 withdrew from study. One (2.1%) LET-treated patient developed breakthrough CMV viremia with a UL56 C325W mutation. HCT Week 48 all-cause mortality was 26.5% in LET and 40.9% in PBO (figure).ConclusionLET prevented CS-CMVi compared with PBO among patients with detectable CMV DNA at randomization. Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. Cidara: Investigator, Research support. Ansun: Investigator, Research support. Gilead: Investigator, Research support. WHISCON: Investigator, Research support. P. Ljungman, Merck: Investigator, Research support. AiCuris: Consultant, Consulting fee. Astellas: Investigator, Research support. Oxford Immunotec: Consultant and Investigator, Consulting fee and Research support. R. F. Chemaly, Merck: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant, Consulting fee. Novartis: Investigator, Research support. Oxford Immunotec: Consultant, Consulting fee. H. Wan, Merck: Employee and Shareholder, Salary. V. L. Teal, Merck: Employee and Shareholder, Salary. J. Butterton, Merck: Employee and Shareholder, Salary. W. W. Yeh, Merck: Employee and Shareholder, Salary. R. Y. Leavitt, Merck: Employee and Shareholder, Salary. C. Badshah, Merck: Employee and Shareholder, Salary.

Off-label use of tacrolimus in children with Henoch-Schönlein purpura nephritis: a pilot study

BackgroundTacrolimus is used off-label in the treatment of Henoch-Schönlein purpura nephritis (HSPN) in children, with limited evidence-based data. Based on clinical empirical experience and mechanism of action, tacrolimus might be...

Abstract B176: Results of a phase I study of PLX8394, a next-generation BRAF inhibitor, in refractory solid tumors

Abstract Background: First-generation BRAF inhibitors (BRAFi) such as vemurafenib and dabrafenib demonstrated high response rates and prolonged survival in some BRAFV600-mutated cancers; however, most patients ultimately develop resistance. Furthermore, treatment-emergent skin and other epithelial malignancies present safety concerns. PLX8394 is a next-generation, orally available, small-molecule BRAFi. Unlike first-generation BRAFi, PLX8394 [a] does not induce paradoxical activation of the RAF/MEK/ERK pathway in cells with stimulated RAS signaling, and [b] blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 mutations. Thus, we hypothesize that PLX8394 may yield improved safety and broader, more durable efficacy than first-generation BRAFi. Methods: Trial protocol PLX120-03 (NCT02428712) incorporates an open-label, multicenter, phase I study using a 3+3 design to determine the recommended phase II dose (RP2D) in patients with refractory or relapsed solid tumors with or without BRAF mutation. Other endpoints are safety, including dermatologic and ophthalmic adverse events (AEs), pharmacokinetics (PK), and response per RECIST1.1. Dose escalation includes cohorts with either PLX8394 monotherapy or PLX8394 coadministered with an oral CYP3A4 inhibitor, cobicistat 150mg, to enhance systemic PK. Enrollment at the RP2D continues in the subsequent phase II study. Results: Of 26 patients who received at least 1 dose of PLX8394, 15 patients (10 with BRAF mutation) were enrolled to cohorts with PLX8394 monotherapy: 450mg BID (n=8), 900mg BID (n=3), 450mg TID (n=4). PK studies demonstrated lower than expected drug exposures; the protocol was amended and 11 additional patients (8 with BRAF mutation) were enrolled in cohorts with PLX8394 coadministered with cobicistat: 450mg BID (n=5) and 900mg BID (n=6). As of 31 May 2017 cutoff, 15 subjects terminated the study: 14 for disease progression, 1 subject withdrawal. Duration of study drug exposure was a median of 56 (22 - 727) days. Reversible Grade (G) 3 transaminitis in a patient treated with PLX8394 900mg BID + cobicistat was the only dose-limiting toxicity (DLT); rechallenge with PLX8394 alone was tolerated without recurrence of transaminitis. PLX8394 900mg BID + cobicistat was declared as RP2D. Treatment-related G&amp;gt;3 AEs other than DLT included G3 diarrhea (n=1), G3 anorexia (n=1), both in PLX8394 monotherapy cohorts and both manageable with supportive care. There were no cutaneous or ocular AEs. Cobicistat coadministration resulted in a 2-3 fold increase in PLX8394 systemic exposure, with RP2D achieving the projected efficacious exposure range based on preclinical models. There were no objective responses in PLX8394 monotherapy cohorts; however, to date 2 (28%) of 7 evaluable BRAF mutant patients treated with PLX8394 + cobicistat achieved partial responses (BRAFV600E-mutated colorectal cancer, 42% and BRAFV600E-mutated glioma, 65%; both BRAFi naive), which were confirmed by 8-wk serial scans. Tumors without BRAF mutation showed no response. Conclusion: PLX8394 with cobicistat was very well tolerated and showed promising activity in refractory solid tumors with BRAF mutation. A phase II study in BRAF-mutated cancers is ongoing. Citation Format: Filip Janku, Ulka Vaishampayan, Vivek Khemka, Minny Bhatty, Chao Zhang, Henry H. Hsu, Paul S. Lin, Sandra Tong, Sunil Sharma. Results of a phase I study of PLX8394, a next-generation BRAF inhibitor, in refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B176.

Abstract S2-05: Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study

Abstract Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA+ per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P&amp;lt;0.05) were observed with V+C/P vs Plc+C/P. Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2-mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Table 1Efficacy (ITT population – BRCA mutation)Plc+C/P, n=98V+C/P, n=95HR (95% CI); P valuePFS(mo, 95% CI)12.3 (9.3–14.5)14.1 (11.5–16.2)0.789 (0.536–1.162); 0.231OS (mo, 95% CI)25.0 (18.1–34.8)28.5 (22.4–NR)0.725 (0.468–1.121); 0.148ORR, % (95% CI)61.3 (49.7–71.9)77.8 (66.4–86.7)P=0.027 Citation Format: Han HS, Diéras V, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [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 S2-05.

Abstract P4-22-02: Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer

Abstract Background: V is a potent, poly(ADP-ribose) polymerase (PARP) inhibitor that obstructs DNA damage repair. BRCA1/2 tumors are defective in homologous recombination, which leads to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V enhances the antitumor activity of alkylating agents such as TMZ in preclinical models. In addition, V+TMZ showed promising activity in a single-arm phase 2 study in pts with BRCA1/2 mutations. This phase 2 trial (NCT01506609) investigated the efficacy and tolerability of V+TMZ (or V+C/P) compared to Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results from the primary analysis for the V+TMZ arm vs Plc+C/P are presented, and the V+C/P vs Plc+C/P results will be presented separately. Methods: Male and female pts aged ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7 + TMZ 150–200 mg/m2 QD D1–5, 28-D cycle; 2) V 120 mg BID D1–7 + C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; 3) placebo BID D1–7 + C/P. Key eligibility criteria included known deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy (yes vs no), and ECOG PS (0–1 vs 2). The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review. Overall survival (OS), objective response rate (ORR), and safety/tolerability were also evaluated. Results: A total of 290 pts (284 BRCA+ per central lab) were randomized (V+TMZ, n=94 [91 BRCA+]). Baseline demographics and disease characteristics were comparable among treatment arms; 41.3% of pts had triple-negative breast cancer (TNBC) and 31.7% had received &amp;gt;2 prior regimens. Median study drug exposure was 6 cycles for the V+TMZ arm and 10 cycles for the Plc+C/P arm. Median PFS, median OS (interim), and ORR for V+TMZ were inferior to Plc+C/P (PFS 7.4 vs 12.3 mo, OS 19.1 vs 25.0 mo, and ORR 28.6% vs 61.3%). In pts with TNBC, median PFS was 5.5 (3.1–8.5) mo; 8.4 (6.8–10.6) mo for pts with non-TNBC. Treatment-emergent adverse events (AEs) of interest occurring differentially with V+TMZ are shown in Table 1. Grade ≥3 AEs in ≥30% of pts in the V+TMZ arm were thrombocytopenia (48%) and neutropenia (37%). Conclusions: V+TMZ provided durable responses, with less neutropenia, alopecia, and neuropathy than Plc+C/P; however, PFS, OS, and ORR were inferior in the TMZ arm compared to C/P. Table 1Treatment-Emergent AEs, n (%)V+TMZ, n=93Plc+C/P, n=96Neutropenia46 (50)71 (74)Alopecia10 (11)55 (57)Peripheral neuropathy11 (12)56 (58)Thrombocytopenia73 (79)67 (70)Nausea70 (75)56 (58) Citation Format: Diéras V, Han HS, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Puhalla S, Isakoff SJ. Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer [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 P4-22-02.

Bone Age and Mineral Density Assessments Using Plain Roentgenograms in Tenofovir-exposed Infants in Malawi and Brazil Enrolled in HIV Prevention Trials Network 057.

Tenofovir disoproxil fumarate (TDF) use during pregnancy has been increasing, and studies linking bone toxicity with exposure to TDF have raised concern for its use in infants. Hand/wrist and spine radiographs were obtained at 3 days and 12 weeks of age in infants born to HIV-infected pregnant women enrolled in the HIV Prevention Trials Network 057 pharmacokinetic study of TDF conducted in Malawi and Brazil assigned to 3 TDF dosing cohorts. In cohort 1, mothers received 600 mg of TDF during labor. In cohort 2, infants received 4 mg/kg dose on days 0, 3 and 5. In cohort 3, a 900 mg maternal dose was given during labor, followed by a 6 mg/kg infant dose on days 0, 3 and 5 of life. Across all 3 cohorts, 89 infants had radiographs performed at either time point, and 85 had radiographs performed at both time points. Metaphyseal lucency was present in 1 case in Brazil and 2 in Malawi. Fifteen percent of infants from Brazil and 9% of infants from Malawi presented bone age discrepancies. No other abnormalities were identified in Brazil, whereas in Malawi, there were 7 more cases of wrist osteopenia, 2 of spine osteopenia and 3 other abnormalities. Bone abnormalities were not uncommon in the overall cohort of HIV-exposed infants. Because of very limited study drug exposure at the time of birth, it is unlikely that TDF was associated with these findings. Untreated maternal HIV disease and/or maternal nutritional status could potentially be related to fetal bone development. This association should be explored in future cohort studies.

Abstract P3-05-14: A neoadjuvant window trial of endocrine response in women with invasive lobular carcinoma

Abstract Background: Patients with invasive lobular carcinoma (ILC) would be expected to have favorable outcomes compared to patients with invasive ductal carcinoma (IDC) given that ILC is more often hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, of lower grade, and displays decreased proliferation markers. Based on our preclinical studies showing differential hormone response in HR+ ILC vs. IDC and on recent studies suggesting differences in endocrine treatment response between patients with ILC vs. IDC, we designed a biomarker-driven, neoadjuvant window trial for newly diagnosed women with HR+, HER2-negative ILC. We hypothesize that Ki67 will be reduced by 85% in the fulvestrant arm compared with 60% and 75% reduction in the tamoxifen and anastrozole arms, respectively, and that Ki67 reduction will correlate with alterations in expression of ER and ER-regulated genes. Differential Ki67 effect will serve as a surrogate for outcome of patients with ILC on endocrine therapy. Trial Design: This multicenter study (NCT02206984) will enroll 150 women with HR+ and HER2-negative ILC. A mandatory research breast tumor biopsy will be performed at baseline. Fifty patients will be randomized to each of three open-label treatment arms for 21 days: fulvestrant (two 250 mg IM injections on both day 1 and day 14), anastrozole (1mg orally daily), or tamoxifen (20 mg orally daily). Biomarkers of response will be assessed on baseline and post-treatment tumor tissue. Patients will proceed to definitive surgery on day 21 after study drug exposure, or they will undergo a second research breast core biopsy if further neoadjuvant treatment is planned. Eligibility Criteria: Eligible patients include postmenopausal women with newly diagnosed, HR+, HER2-negative ILC (excluding pleomorphic subtype) measuring ≥ 1cm, with adequate organ function, ECOG PS ≥ 2, and agreeable to baseline research breast tumor biopsy. Specific Aims: The primary endpoint is percent change from baseline to post-treatment Ki67 values in ILC tissue after 21 days of endocrine treatment. Comparisons across study arms will be made using a general linear model adjusting for institutional effect, with 80% power estimated for pairwise comparisons of log2(% staining) between treatment arms, allowing for 10% attrition. Secondary endpoints include post-therapy Ki67, and change in ER and PR protein expression by IHC. Finally, planned correlative studies include evaluation of gene expression, epigenetic markers, and DNA sequence variants in ILC tissues in an effort to identify biomarkers of endocrine response and putative drivers of endocrine resistance in ILC. Target Accrual: This study will be open to enrollment by August 2015 at the University of Pittsburgh. Additional sites will be opened through the Translational Breast Cancer Research Consortium (TBCRC). We anticipate an accrual rate of 8 patients per month. (Funding from Susan G. Komen® and AstraZeneca). Citation Format: Jankowitz RC, McAuliffe PF, Sikora MJ, Butler L, Ahrendt G, Johnson R, Diego E, Bonaventura M, Puhalla S, Lembersky B, Clark B, Brufsky A, Kurland BF, Davidson NE, Dabbs DJ, Oesterreich S. A neoadjuvant window trial of endocrine response in women with invasive lobular carcinoma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-14.

FRI0281 The Rate of Positive Conversion in the Quantiferon-TB Gold Test over 2 Years among Patients Treated with CT-P13 or Innovator Infliximab in the Extension Studies of Planetas and Planetra

BackgroundLong-term treatment of anti-TNF agents in patients with immune mediated disease can increase the risk of active tuberculosis infection (ATBI) by reactivation of latent tuberculosis infection (LTBI) or de novo...