Reported Treatment Emergent Adverse Events Research Articles

Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study

Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients. In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113. Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. Agrade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported. The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

Phase 1 trial of the safety, pharmacokinetics, and antiviral activity of EDP-514 in untreated viremic chronic hepatitis B patients.

Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection. Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were -2.9, -3.3, -3.5 and -0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was -2.9, -2.4, -2.0, and -0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events of mild or moderate severity with no discontinuations, serious AEs or deaths. In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.

Abstract CT024: REDIRECT: A Phase 2 study of AFM13 in patients with CD30-positive relapsed or refractory (R/R) peripheral T cell lymphoma (PTCL)

Abstract PTCLs are aggressive hematologic malignancies often with poor prognoses; for patients with R/R PTCL there is no standard-of-care therapy and novel treatments are required. AFM13 is a tetravalent, bispecific Innate Cell Engager (ICE ® ) that binds CD30 when expressed on PTCL cells, and CD16A on innate effector cells, redirecting and enhancing the innate immune response to CD30+ tumor cells. Phase 1 clinical studies of AFM13 in patients with R/R Hodgkin lymphoma and cutaneous CD30+ lymphomas showed a tolerable safety profile and clinical activity; early correlative science data in a small group of patients with HL showed increased natural killer (NK) cell activity in responsive patients. A Phase 2, open-label, multi-cohort study (NCT04101331) assessing the efficacy of AFM13 in patients with R/R PTCL was initiated in 2019. Patients had histologically confirmed CD30 expression in ≥1% of tumor cells and had received ≥1 prior systemic therapy. The primary endpoint was to assess the overall response rate (ORR) based on FDG-PET per independent review committee. Secondary endpoints included safety, complete response rate (CRR), duration of response (DoR), pharmacokinetics, immunogenicity, and quality of life. Progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. Patients received 200 mg AFM13 intravenously once weekly until disease progression, intolerable toxicity, termination at the investigator’s discretion, or withdrawal of consent. A total of 108 patients (age 21-93; 61% male) received AFM13, with a median (min, max) number of infusions of 9.0 (1, 116). Numbers of patients per PTCL subtype assessed were: PTCL not-otherwise-specified (PTCL-NOS), 41; angioimmunoblastic T cell lymphoma (AITL), 30; anaplastic large cell lymphoma (ALCL), 26; other, 11. Patients received a mean number of 2.7 prior treatment lines; 46.3% received prior brentuximab vedotin (BV), 17.6% received prior auto-transplant. The ORR was 32.4% (CRR was 10.2%); ORR in each subgroup was 22.0% (PTCL-NOS), 53.3% (AITL), 23.1% (ALCL), and 36.4% (other). Median DoR, PFS, and OS were 2.3 months, 3.5 months, and 13.8 months, respectively. Reported treatment emergent adverse events (TEAEs) were as anticipated based on previous studies. AFM13-related TEAEs occurred in 79/108 patients (73.1%), with 14 events in 9 patients (8%) considered serious. The most frequent TEAE was infusion-related reactions, observed in 34/108 patients (31.5%), including 12 Grade 3 events in 6 patients (5.7%). Neutropenia was the most frequent TEAE with Grade ≥3 occurring in 9.3% of patients. AFM13 monotherapy was well managed and showed robust clinical activity in selected R/R PTCL subtypes. These data, together with encouraging preliminary efficacy seen in AFM13 combination studies in HL, support further evaluation of AFM13 in combination with NK cells to augment the innate immune response to CD30+ tumors. Citation Format: Won Seog Kim, Jake Shortt, Pier Luigi Zinzani, Natalya Mikhaylova, Ana Marin-Niebla, Dejan Radeski, Vincent Ribrag, Eva Domingo Domenech, Ahmed Sawas, Karenza Alexis, Michael Emig, Linta Garcia, Andre Overesch, Kerstin Pietzko, Steven Horwitz. REDIRECT: A Phase 2 study of AFM13 in patients with CD30-positive relapsed or refractory (R/R) peripheral T cell lymphoma (PTCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT024.

A real-world analysis on the efficacy and tolerability of liposomal irinotecan plus 5-fluorouracil and folinic acid in metastatic pancreatic ductal adenocarcinoma in Belgium.

Currently, nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil/folinic acid (5-FU/LV) is the only approved second-line treatment for patients suffering from metastatic pancreatic ductal adenocarcinoma (mPDAC). However, also other chemotherapeutic regimens are used in this setting and due to the lack of clear real-world data on the efficacy of the different regimens, there is no consensus on the optimal treatment sequence for mPDAC patients. To provide information on the safe and efficacious use of nal-IRI + 5-FU/LV in clinical practice in Belgium, which is needed for healthcare professionals to estimate the risk-benefit ratio of the intervention. Medical data of adult patients with mPDAC who were treated with nal-IRI + 5-FU/LV in one of the participating Belgian hospitals were retrospectively collected. Kaplan-Meier analysis was performed to obtain survival curves to estimate the median overall survival (OS) and progression-free survival (PFS). All other results were presented descriptively. A total of 56 patients [median age at diagnosis: 69 years (range 43 years), 57.1% male] were included. Patients received a median of 5 (range 49 cycles) nal-IRI + 5-FU/LV cycles, extended over 10 weeks (range 130.8 weeks). The median start dose for nal-IRI was 70 mg/m² (range 49.24 mg/m²) and chemotherapy dose reduction and delay occurred in, respectively, 42.8% and 37.5% of the patients. The median OS was 6.8 months (95% CI: 5.6-8.4 months) with a 6-month survival rate of 57.4% and a 1-year survival rate of 27.8% in the overall study population. The median OS for patients treated with nal-IRI as second-line therapy or as later-line treatment was, respectively, 6.8 months (95% CI: 5.9-7.0 months) and 5.6 months (95% CI: 4.2-no upper limit). In the overall study population, a median PFS of 3.1 months (95% CI: 2.4-4.6 months) and a disease control rate of 48.3%, comprising 30.4% stable disease, 16.1% partial and 1.8% complete response, was observed. The median PFS for patients treated with nal-IRI as second-line therapy was 3.9 months (95% CI: 2.8-4.8 months) while this was 2.4 months (95% CI: 1.9-9.1 months) for those that received nal-IRI in a later-line treatment. In terms of safety, gastrointestinal problems occurred most (64.3% of the patients) and from all reported treatment emergent adverse events, 39.2% were grade 3 or 4. Nal-IRI + 5-FU/LV is a valuable, effective, and safe sequential treatment option following gemcitabine-based therapy in patients with mPDAC. Retrospective study on the efficacy and tolerability of liposomal irinotecan (NALIRI); ClinicalTrials.gov Identifier: NCT0509506 (https://clinicaltrials.gov/ct2/show/NCT05095064?term=naliri&draw=2&rank=2).

Abstract 9318: The Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Ebronucimab in Healthy Volunteers: Result From a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated to be effective therapeutic agents for lowing low-density lipoprotein cholesterol (LDL-C). Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. The objective of this study is to investigate the safety and tolerability of ebronucimab in healthy subjects. Methods: A total of 32 healthy adult subjects were planned to be enrolled and treated in a dose escalation manner. In each cohort, 8 subjects were randomized in a 3:1 ratio to receive a single dose of ebronucimab (75, 150, 300 or 500 mg) or matching placebo via subcutaneous injection (Figure 1). Blood was drawn at pre-selected timepoints to evaluate the pharmacokinetic parameters, free PCSK9 concentration and anti-drug antibody (ADA). Safety assessment was carried out up to day 85 ± 3 or early termination visit. Results: Safety Among the 32 subjects recruited, 87.5% (21/24) subjects administrated ebronucimab and 75% (6/8) subjects treated with placebo reported treatment emergent adverse events (TEAEs). The majority of adverse events were mild and moderate in severity. No relationship was identified between the dose of ebronucimab and the incidence of TEAEs. No TEAEs leading to study discontinuation and death were reported. Pharmacokinetics (PK)/Pharmacodynamics (PD) Following a single subcutaneous injection of 75 mg to 500 mg ebronucimab in healthy subjects, the median of T max ranged from 2.0 to 6.0 days and t 1/2 was within 4.11 to 5.01 days across cohorts. C max, AUC 0-t , and AUC 0-∞ increased approximately in a dose-proportional manner, see Table 1 and Figure 2. Serum free PCSK9 was almost completely inhibited after ebronucimab injection. The lowest level of free PCSK9 was observed around 2 days post administration and maintained at a low level 14-22 days post injection, see Figure 3. Immunogenicity A total of 3 subjects were tested ADA positive at least once during the study (75 mg, 1 subject; 500 mg, 2 subjects). The incidence of ADAs in subjects treated with ebronucimab was 12.5 % (3/24). Conclusions: Ebronucimab was well tolerated in healthy subjects and no special safety signal was identified during the study.

The effect of rifampin on the pharmacokinetics of famitinib in healthy subjects

BackgroundFamitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. As famitinib is metabolized mainly by cytochrome P450 3A4 (CYP3A4), the study was conducted to investigate the effect of potent CYP3A4 inducer rifampin on the pharmacokinetics of famitinb.MethodsThis single-center, single-arm and fixed-sequence drug–drug interaction study enrolled 21healthy Chinese male subjects. Subjects received a single oral dose of famitinib 25 mg on days 1 and 16 and repeated administration of oral rifampin 600 mg once daily on days 10–23. Blood samples were collected and plasma concentrations of famitinib were measured by validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. Pharmacokinetic parameters were calculated using noncompartmental analysis and safety was assessed.ResultsIn the presence of rifampin, the famitinib geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to infinity (AUC0–∞) decreased by 48% and 69%, respectively, and the mean elimination half-life was shortened from 33.9 to 18.2 h. The geometric mean ratio (GMR) of famitinib Cmax and AUC0–∞ and their 90% CI were 0.52 (0.50, 0.54) and 0.31 (0.29, 0.33). Single dose of famitinib 25 mg was well tolerated and eight subjects (38.1%) reported treatment emergent adverse events, which were all grade 1–2 in severity.ConclusionCo-administration of rifampin considerably reduces plasma concentration of famitinb due to CYP3A4 induction. Concomitant administration of famitinib and strong CYP3A4 inducers should be avoided, whereas when simultaneous use with inducers of CYP3A4, dose adjustment of famitinb is recommended.Clinical trial registration numberNCT04494659 (July 31, 2020).

ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Protocol for the Treatment of High-Grade B Cell Lymphoma

Background: Intensified immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) has been shown to improve outcomes in younger adults with high-grade B-cell lymphomas (hg-BCL) when compared to standard therapy with R-CHOP (Cyclophosphamide-Adriamycin-Vincristine-Prednisone) (Recher C. Lancet 2011). Due to unavailability of vindesine at our institution, we primarily aimed at assessing the safety and efficacy of replacing vindesine with vincristine in a modified R-ACVBP protocol (mR-ACVBP). Secondary endpoints included progression-free survival (PFS), and overall survival (OS). Methods: This is a retrospective study performed at the American University of Beirut Medical Center (AUBMC), Lebanon, including all consecutive adult patients (pts) with newly diagnosed hg-BCL who received first-line mR-ACVBP from 10/2014 to 10/2019. mR-ACVBP protocol was similar to published original protocol with the exception of vindesine being replaced by vincristine 1.5 mg intravenously on days 1 and 5 of each cycle (initial protocol included vincristine 2 mg on days 1 and 5, later adjusted for toxicity). Pts were assessed for response after 4 cycles of mR-ACVBP. Responders continued with consolidation consisting of 2 cycles of high-dose methotrexate followed by 4 cycles of Rituximab-Ifosfamide-Etoposide then low-dose cytarabine x2. Pts with inadequate response on interim imaging were offered consolidative autologous stem cell transplantation (ASCT). Incomplete responders after 4 cycles (CR defined as delta SUVmax more than 70%) were shifted to salvage therapy including R-ICE (Rituximab, Ifosfamide, Cytarabine, Etoposide), or R-DHAP (Rituximab, Dexamethasone, Cytarabine, Cisplatin). Pts with age-adjusted IPI ≥ 2 could receive consolidative ASCT at the physician's discretion. Results: We identified 56 pts with hg-BCL, with a median age of 41 years [range: 21-67]. 64% of patients were males. 45 (80%) pts had advanced stage (III/IV), and 37 (66%) pts had an age-adjusted-IPI score >1. Fifty-one pts were evaluable for response after 4 cycles by PET CT scan. The overall response rate was achieved in 46 (90%) pts; complete response (CR) in 41 (80%), partial response (PR) in 5 (10%), 2 of which considered to have inadequate response as per delta SUVmax. 12 (27%) pts received consolidative ASCT, 27 (61%) continued consolidation chemotherapy, and 5 (11%) pts received subsequent salvage treatment. The most common reported treatment emergent adverse events, encountered during induction mR-ACVBP, were anemia (n=51, 91%), followed by febrile neutropenia (n=36, 64%, grade 4 in 26 (46%) pts, of whom four required intensive care monitoring), thrombocytopenia (n=22, 39%), and mucositis (n=12, 21%). Peripheral neuropathy was encountered in 7 (12%) pts (grade 1, n=2, grade 2, n=4, grade 3, n =1). Two deaths were attributed to treatment due to febrile neutropenia and septic shock during first and third cycle of mR-ACVBP in patients who had an aaIPI of 3. After a median follow up of 17 months [range, 0.5-55], a total of 4/44 (9%) pts progressed, 3 while on treatment after high-dose methotrexate, 1 after therapy completion. The median PFS and OS were not reached. The 2-year PFS and OS were 86% and 87% respectively. At last follow up, 47 pts were alive (44 (94%) pts were in continuous CR, 1 (2%) pt in PR and 2 (4%) pts progressive disease), 6 pts died, and 3 were lost to follow up. Conclusion: The use of vincristine in mR-ACVBP instead of vindesine seems to be feasible, with acceptable manageable adverse events. Despite higher risk disease, survival rates seem to be comparable to published data of the original R-ACVBP protocol. Disclosures No relevant conflicts of interest to declare.

Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib

Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib

Phase I/Ib Study of Tenalisib (RP6530), a Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma.

Tenalisib (RP6530), a dual phosphoinositide 3-kinase δ/γ inhibitor was evaluated in a phase I/Ib study for maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed/refractory peripheral and cutaneous T-Cell Lymphoma (TCL). Histologically confirmed (TCL) patients, with ≥1 prior therapy received Tenalisib orally in a 28-day cycle in doses of 200 to 800 mg twice daily (800 mg in fasting and fed state) in escalation phase (n = 19) and 800 mg twice daily (fasting) in expansion phase (n = 39). The most frequently reported treatment emergent adverse events (TEAE) and related TEAE were fatigue (45%) and transaminase elevations (33%), respectively. Most frequently reported related Grade ≥3 TEAE was transaminase elevation (21%). Two dose-limiting toxicities occurred in the 800 mg fed cohort; hence, 800 mg fasting dose was deemed MTD. Tenalisib was absorbed rapidly with a median half-life of 2.28 h. Overall response rate in 35 evaluable patients was 45.7% (3 complete response (CR); 13 partial response (PR)) and median duration of response was 4.9 months. Responding tumors showed a marked downregulation of CD30, IL-31 and IL-32α. With an acceptable safety and promising clinical activity, Tenalisib can be a potential therapeutic option for relapsed/refractory TCL. Currently, a phase I/II combination study with romidepsin is ongoing.

Abstract PD1-06: Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer

Abstract Background Ladiratuzumab vedotin (LV) is an investigational anti-LIV-1 antibody-drug conjugate with a protease-cleavable linker to monomethyl auristatin E (MMAE). LIV-1 is highly expressed in metastatic triple negative breast cancer (TNBC). LV mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). LV monotherapy has demonstrated encouraging activity in TNBC. Anti-PD-(L)1 agents are emerging as part of the TNBC treatment paradigm and showing promising activity. Combining LV and pembrolizumab (pembro) may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-(L)1 activity. Methods This ongoing phase 1b/2 study evaluates safety, tolerability, activity, and recommended phase 2 dose of LV + pembro (NCT03310957; 2017-002289-35) in a dose-finding (Part A) followed by expansion phase (Part B) as front-line therapy for TNBC patients (pts). Eligible pts receive LV 2.0 mg/kg or 2.5mg/kg + pembro 200mg every 3 wks. Pts must have TNBC per ASCO/CAP guidelines (absence of HER2, estrogen receptor, and progesterone receptor expression) and are not pre-selected for either LIV-1 or PD-L1 expression. Tumor assessment is performed every 6 weeks per RECIST v1.1. Results As of 23 May 2019, a total of 51 pts have received LV + pembro (7 and 44 pts at LV 2.0 and 2.5 mg/kg, respectively). Nineteen pts enrolled in dose finding (7 and 12 at LV 2.0 and 2.5 mg/kg, respectively) and 32 pts enrolled in dose expansion all at LV 2.5 mg/kg. Median age was 55 yrs (range: 30, 82), ECOG 0/1 was 47%/53%, and invasive ductal carcinoma histology was 69%. All patients were first-line for LA/M TNBC, and 24% of pts had de novo mTNBC at initial diagnosis. Two pts experienced dose-limiting toxicities (DLT) out of 12 pts enrolled at LV 2.5 mg/kg in Part A: Grade 3 colitis and Grade 3 diarrhea. No DLT was observed at LV 2.0mg/kg. Of the 51 pts evaluable for safety (defined as all pts who received any amount of LV or pembro), 44 (86%) reported treatment emergent adverse events (TEAEs). Most common TEAEs across the 2 LV dose levels were nausea (53%); fatigue (45%); diarrhea (43%); alopecia (33%); constipation and hypokalemia (29% each); vomiting (27%); decreased appetite (25%); abdominal pain (24%); decreased weight (22%); and neutropenia and peripheral sensory neuropathy (20% each). Across the 2 dose levels, the most common Grade 3+ AEs were neutropenia (16%); diarrhea, fatigue, hypokalemia, and maculo-papular rash (8% each); and abdominal pain, increased ALT, and urinary tract infection (6% each). The most common SAEs were abdominal pain and constipation (6% each). In this ongoing trial, 26 pts were followed for at least 3 months with an opportunity for 2 post-baseline disease assessments. Among these 26 pts, the confirmed objective response rate was 54% (95% CI, 33.4, 73.4). Two additional pts have a single scan showing PR and are pending confirmatory assessment. Updated data will be provided at the meeting. Conclusion LV + pembro appears tolerable with a manageable safety profile to date. Preliminary efficacy data show encouraging clinical activity as first-line therapy in pts with unresectable LA/M TNBC. Citation Format: Hyo (Heather) Han, Sami Diab, Carlos Alemany, Reva Basho, Ursa Brown-Glaberman, Jane Meisel, Timothy Pluard, Javier Cortes, Patrick Dillon, Johannes Ettl, Sherko Kuemmel, Luis Manso Sanchez, Mafalda Oliveira, Joyce O'Shaughnessy, Steven Papish, Rajni Sinha, Danielle Sterrenberg, Erica Stringer-Reasor, Michaela Tsai, Rafael Villanueva Vazquez, Rachel Wuerstlein, Yinghui Wang, Zejing Wang, Valentina Boni. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-06.

87Effects of the chymase inhibitor fulacimstat on adverse cardiac remodelling after acute myocardial infarction - Results of the CHIARA MIA 2 trial

Abstract Introduction Adverse cardiac remodelling represents the most important risk factor for the development of heart failure (HF) after myocardial infarction (MI). Chymase is a protease that generates locally pro-fibrotic factors such as angiotensin II, TGFβ, and matrixmetallproteases that contribute to tissue remodelling. Purpose This phase IIa study examined the effects of the chymase inhibitor fulacimstat on functional parameters of adverse cardiac remodelling after acute MI. Methods A double-blind, multinational, randomized, placebo-controlled study was performed in patients after first STEMI who were treated with primary percutaneous coronary intervention within 24h of symptom onset. To enrich for patients at risk of adverse remodelling, main inclusion criteria were a left-ventricular ejection fraction (LVEF)≤45% and an infarct size>10% on day 5 to 9 post MI as measured by cardiac MRI. On day 6 to 12 post MI, patients were randomized to treatment with either 25 mg fulacimstat (n=54) or placebo (n=53) twice daily on top of standard of care. The changes in LVEF, LVEDVI, and LVESVI from baseline to 6 months of treatment were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated, 64.8% of patients treated with fulacimstat and 75.5% of patients treated with placebo reported treatment emergent adverse events. Fulacimstat achieved exposures that were approximately 10-fold higher than those predicted to be required for minimal therapeutic activity. After six months of treatment, there were no effects of fulacimstat compared to placebo on the changes in LVEF, LVEDVI, and LVESVI (see Table). Analysis of primary efficacy parameters Parameter Placebo Fulacimstat p-value LVEF (%) baseline 37.2±6.1 39.1±5.5 0.15 6 months 41.2±8.4 42.6±8.4 0.45 delta 4.0±5.0 3.5±5.4 0.69 LVEDVI (mL/m2) baseline 80.0±17.1 77.4±18.2 0.51 6 months 85.1±19.1 84.7±23.4 0.94 delta 5.1±18.9 7.3±13.3 0.54 LVESVI (mL/m2) baseline 50.5±13.0 47.3±12.3 0.26 6 months 51.1±16.9 49.6±18.1 0.71 delta 0.6±14.8 2.3±11.2 0.56 Data are given as mean ± standard deviation. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study. Acknowledgement/Funding The study was funded by its sponsor BAYER AG

Results of a Randomized Phase III Trial of Mirabegron in Patients with Overactive Bladder

Many patients with overactive bladder discontinue pharmacotherapy due to suboptimal efficacy or side effects. Mirabegron, a β3-adrenoceptor agonist, may offer an effective and well tolerated alternative treatment for overactive bladder. A randomized, double-blind, placebo controlled trial was conducted in the United States and Canada. After a 2-week placebo run-in period, adults with overactive bladder symptoms for 3 or more months were randomized 1:1:1 to receive placebo, 50 or 100 mg mirabegron once daily for 12 weeks. Efficacy data were collected via patient completed diaries and quality of life assessments. Co-primary efficacy end points were changes from baseline to final visit in mean number of incontinence episodes per 24 hours and micturitions per 24 hours. Key secondary micturition and incontinence end points were also evaluated. Safety assessments included treatment emergent adverse events, laboratory assessments, vital signs, electrocardiograms and post-void residual volume. Compared to placebo, 50 and 100 mg mirabegron groups demonstrated statistically significantly greater mean decreases (95% CI) from baseline for incontinence episodes (-1.13 [-1.35, -0.91], -1.47 [-1.69, -1.25] and -1.63 [-1.86, -1.40]) and micturitions (-1.05 [-1.31, -0.79], -1.66 [-1.92, -1.40] and -1.75 [-2.01, -1.48]) per 24 hours (p <0.05). Significant improvements in all key secondary end points were observed for both mirabegron doses vs placebo. The incidence of frequently reported treatment emergent adverse events (hypertension, urinary tract infection, headache, nasopharyngitis) was similar in the mirabegron and placebo groups. Dry mouth was reported for 1.5%, 0.5% and 2.1% of patients in the placebo, 50 and 100 mg mirabegron groups, respectively. Once daily mirabegron in a 50 or 100 mg dose is an effective treatment for overactive bladder symptoms with a low occurrence of side effects.

Azithromycin in Acute Bacterial Upper Respiratory Tract Infections: An Indian Non-Interventional Study

To assess the effectiveness, safety and tolerability of azithromycin in acute bacterial upper respiratory tract infections (URTIs). In this open-label, prospective, multi-center, non-interventional study in bacterial URTI, the decision to prescribe azithromycin was independent of enrolment. Follow up was 1week after treatment and if possible, at Week 2. Investigators' assessment of clinical outcome (Success/Failure) at the end of study was the primary endpoint for efficacy analysis. Clinical outcome of 'Success' was defined as the global response of Cure or Improvement. A pharmacoeconomic analysis of management of URTIs was also attempted. Of the 410 patients recruited, all were evaluated for safety and 278 for efficacy. The median treatment duration was 3days. Following treatment with azithromycin, overall success rate was 98.92% (95% CI 96.88-99.78%; Clopper-Pearson method). The success rate was similar across the sub-groups of acute otitis media-100%, bacterial sinusitis-95.83%, and pharyngotonsillitis-99.38%. The success rate was 100% among children and adolescents (age ≤18years) and 98.6% among adults (age >18years). Most of the common signs and symptoms of URTI reported during baseline, significantly improved at the end of the study. Sixteen (3.90%) patients reported treatment emergent adverse events, the most common being diarrhea-5 (1.2%) and flatulence-2 (0.5%). The average cost of treating bacterial URTI was INR 716 per patient. Azithromycin is effective and well tolerated in Indian patients with bacterial URTIs.

W1127 Intensification of Infliximab (IFX) Therapy in Crohn's Disease: Efficacy and Safety

W1127 Intensification of Infliximab (IFX) Therapy in Crohn's Disease: Efficacy and Safety

Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

P157 - Intensification of infliximab (IFX) therapy in Crohn's disease: efficacy and safety

P157 - Intensification of infliximab (IFX) therapy in Crohn's disease: efficacy and safety

The Efficacy and Safety of Tigecycline for the Treatment of Complicated Intra-Adominal Infections - The European Experience

The polymicrobial nature of complicated intra-abdominal infections makes these infections particularly challenging to treat. The initial selection of antimicrobial therapy is therefore extremely important. Inappropriate empiric antimicrobial therapy has been shown to delay clinical resolution, increase length of hospital stay, and increase the risk of mortality. In addition, the increasing frequency with which resistant isolates (e.g., extended spectrum beta-lactamases [ESBLs]) are recovered from patients mandates that empiric antimicrobial therapy covers these difficult-to-treat organisms.Here, we assessed the efficacy of a new antimicrobial agent, tigecycline. This is a combined analysis of data from the European sites that participated in two Phase III, double-blind trials to evaluate the efficacy and safety of tigecycline, versus that of imipenem/cilastatin, in adults with complicated intra-abdominal infections. Patients received either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 hours) or imipenem/cilastatin (500/500 mg intravenously every 6 hours) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-44 days after therapy) in the co-primary microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations. For the ME group, clinical cure rates at the test-of-cure visit were 92.4% (219/237) for tigecycline versus 88.8% (198/223) for imipenem/cilastatin (95% CI = −2.2, 9.4). Clinical cure rates for the m-mITT populations were 87.3% (247/283) for tigecycline versus 83.5% (228/273) for imipenem/cilastatin (95% CI = −2.5, 10.0) at the test-of-cure visit. Pretherapy in vitro activity against baseline isolates for tigecycline and imipenem/cilastatin were also determined. The mean MIC90 for tigecycline against the most commonly isolated aerobes and anaerobes was >2.0 μg/mL. No pretherapy isolates displayed resistance to tigecycline based on the breakpoints used. Bacterial susceptibilities to tigecycline appeared to be consistent with clinical responses. Most commonly reported treatment emergent adverse events for tigecycline and imipenem/cilastatin were nausea (14.7% and 11.8%, respectively, p = 0.267) and vomiting (10.7% and 7.3%, respectively p = 0.146). This combined analysis demonstrates that tigecycline is safe and effective for the treatment of complicated intra-abdominal infections, and reflects the findings of the global population.

Efficacy and Safety of ReFacto AF for Surgical Hemostasis in Previously Treated Patients with Severe Hemophilia A.

ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of ReFacto AF for management of surgical hemostasis has been evaluated in an ongoing open label study of at least 25 efficacy evaluable previously treated patients, age ≥12 years, with severe hemophilia A [FVIII:C ≤ 2%] undergoing elective major surgery. ReFacto AF was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator's discretion, and up to a maximum of 6 weeks following surgery. An interim analysis has been performed on the initial 22 patients. Fourteen (14) patients treated by BI received a total of 647 infusions (range 17 to 72 infusions per patient) for a cumulative total dose of 1,279,150 IU over 457 exposure days (ED), while 8 patients assigned to treatment by CI, including 1 patient who received only 1 dose for PK assessment, received a total dose of 348,618 IU over 140 total ED (range 1 to 64 ED per patient). Of the 21 patients who underwent major surgery, 18 were evaluable for efficacy and had the following procedures: 11 total knee replacements, 3 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings of efficacy at the end of surgery and the initial postoperative period were all excellent or good [72% excellent (13/18) and 28% good (5/18) at the end of surgery; and 94% excellent (15/16) and 6% good (1/16) at the end of the initial postoperative period]. Blood loss was assessed for the intra- and post- operative periods. Sixteen (16) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Ten (10) efficacy-evaluable patients had postoperative blood loss; in 9 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery. Eleven (11) of 18 efficacy-evaluable patients were predicted to require transfusions during the intraoperative period; only 2 were transfused. No intraoperative transfusions were administered to the other 7 efficacy-evaluable patients. During the postoperative period 2 efficacy-evaluable patients received transfusions. One (1) of these had excessive hemorrhage following trauma to the epigastric artery during surgery, the other received 2 units of PRBCs in the postoperative period following normal blood loss. The most frequently reported treatment emergent adverse events (AEs) were fever, anemia and pain, not unexpected in the perioperative setting. Only one AE was related to ReFacto AF: a clinically silent low titer inhibitor was detected in one patient during a routine protocol-specified surveillance test before his surgery, after several injections of a plasma derived FVIII product that were preceded by only 1 dose of ReFacto AF. This patient had a left knee synovectomy, both of his hemostatic efficacy assessments were excellent, and he had less intraoperative blood loss than predicted. These interim data demonstrate that ReFacto AF is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.

Effect of food on the pharmacokinetics of lonafarnib (SCH 66336) following single and multiple doses

The objective was to determine whether food affects the pharmacokinetics and safety of lonafanib, an orally bioavailable farnesyl transferase inhibitor that is under clinical evaluation for the treatment of various hematologic malignancies and solid tumors. Two Phase 1 studies were conducted in separate patient populations. A single-dose study was performed in 12 healthy subjects who received lonafarnib 100 mg under fasted and fed conditions. Additionally, a multiple-dose study was performed in 19 patients with advanced cancer who received lonafarnib 200 mg Q 12 H for 28 days under fasted and fed conditions. Nine of the 19 patients completed both treatment cycles and were used for pharmacokinetic assessment. A 2-week washout period separated treatments in each study. Single-dose pharmacokinetics were assessed at various time points up to 48 hours postdose and multiple-dose pharmacokinetics were assessed at Day 15 for 24 hours postdose. The pharmacokinetics of lonafarnib were affected by food during single-dose but not multiple-dose administration. Relative oral bioavailabilities (fed vs. fasted) based on log-transformed maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) were 48% and 77%, respectively, following single-dose administration, and 87% and 96%, respectively, following multiple-dose administration. Intrasubject variability in the pharmacokinetic parameters was less pronounced after multiple dosing (17%) than that after single dosing (33%) of lonafarnib. Intersubject variability was unaffected by food in either study. In the single-dose study, 7 of the 12 subjects (58%) reported treatment emergent adverse events, the most common being headache. No clinically significant differences in adverse events were seen between fasting and fed states after a single dose administration. Thus, single dose 100 mg lonafarnib was safe and generally well tolerated. In the multiple-dose study, all 19 subjects reported at least one treatment-emergent adverse event. General disorders including fatigue and anorexia, and gastrointestinal disorders including diarrhea, vomiting and nausea, were the most commonly reported adverse events after multiple doses. While gastrointestinal adverse events were reported with equal frequency under both fasting (82%, 14/17) and fed states (83%, 15/18), the incidence of severe gastrointestinal adverse events was higher in fasted (47%, 8/17) vs. fed subjects (22%, 4/18) after multiple-dose administration. The administration of food does not affect the pharmacokinetics of lonafanib following multiple-dose administration. We recommend that multiple-dose lonafarnib should be administered with food to enhance tolerability.