Phase 1 Clinical Trial of Prion-Filtered Red Cell Concentrates (pfRCC) in Patients Requiring Allogeneic Blood Transfusion.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 994-994
Author(s):  
Tracy Murphy ◽  
Mary R Cahill ◽  
Jim Fagan ◽  
Croxon Harry ◽  
Mohammed Khan ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Blood Donors ◽  
Phase 1 ◽  
Autologous Blood ◽  
Safety Data ◽  
Full Blood Count ◽  
Red Cell ◽  
Serious Adverse Events ◽  
Degree Of Protection

Abstract Background; Transmission of vCJD by blood transfusion from pre-symptomatic blood donors has occurred in 4 reported cases to date. Screening blood donors for infectivity is unlikely to be feasible for several years. Removing infectivity from blood using selective filtration may provide a useful degree of protection from transfusion transmission of the disease. A filter that may remove infectivity from red cell concentrates has been developed and trialed in volunteers receiving autologous blood. No studies have been carried out to date of pfRCC in allogeneic transfusions in the clinical setting. Aims; To establish safety and tolerability of transfusion of prion filtered red cell concentrates. Methods; Twenty patients scheduled to receive transfusion were recruited following ethical approval and with informed consent. Prion filtered units were prepared by the Irish Blood Transfusion Service. A mean loss of 9 gm of haemoglobin per unit of RCC occurred during the filtration process. Each patient received one unit of pfRCC, and a median of 2 units overall (range 1 to 4 units) per transfusion episode. A cross-match sample, full blood count (FBC), renal and liver profile was taken from each patient prior to transfusion. Patients were observed for adverse reactions. After 24 hours, FBC, renal and liver profile were repeated. Six weeks after the transfusion a further sample was tested for red cell antibodies. Six of these patients have consented to undergo re-transfusion with pfRCC. Two re-infusions have taken place uneventfully six months after the first exposure to pfRCC and 4 more are planned. Results No serious adverse events were encountered during the study, or at 24 hour and 6 week follow up after the initial transfusion episode. Mean haemoglobin increment per unit transfused was 0.68g (SD 0.45g; range −0.5 to 1.35g ). Recruitment and follow-up is ongoing in patients exposed to repeat transfusion challenge. Summary The first clinical transfusions of pfRCC were well tolerated. Two patients were rechallenged with transfusions of pfRCC without adverse effect. Further studies with transfusions of prion filtered red cells are now warranted to extend the safety data and to determine whether efficacy is comparable to standard transfusions in adult and paediatric populations.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study

2017 ◽  
Vol 25 (2) ◽  
pp. 235-245 ◽  
Author(s):  
Mark A Agius ◽  
Gabriela Klodowska-Duda ◽  
Maciej Maciejowski ◽  
Andrzej Potemkowski ◽  
Jing Li ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Phase 1 ◽  
B Cell Depletion ◽  
Serious Adverse Events ◽  
T2 Lesions ◽  
Subcutaneous Dose ◽  
Dose Study

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

scholarly journals Navigating the Quagmire: Comparison and Interpretation of COVID-19 Vaccine Phase 1/2 Clinical Trials

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 746
Author(s):  
Luca Tudor Giurgea ◽  
Matthew James Memoli
Keyword(s):  
Adverse Events ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Safety Studies ◽  
Antibody Titers ◽  
Public Health Strategies

Vaccines against Coronavirus Disease 2019 Originated-19) have been developed with unprecedented rapidity, many utilizing novel strategies. As of November 2020, a series of publications have outlined the results of phase 1/2 studies of nine different vaccines planned to move forward to phase 3 trials. The results are encouraging, demonstrating a paucity of severe or serious adverse events and robust induction of antibody titers. Determination of the vaccine candidates with the highest protective efficacy and best adverse event profiles will be essential in refining public health strategies. However, differences in study design and reporting of data make comparisons of existing phase 1/2 studies difficult. With respect to safety, studies have variable follow-up times and may use different definitions for adverse events. Immunogenicity outcomes are even more inconsistent, with variations in timepoints and critical differences in the types of antibodies studied as well as methodological differences in assays. Furthermore, the correlates of protection in COVID-19 are not known. Harmonization of phase 3 trial designs and use of objective and meaningful clinical outcomes will be crucial in streamlining future global responses to the pandemic.

scholarly journals First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Mammen P. Mammen ◽  
Danielle Armas ◽  
Frank H. Hughes ◽  
Andrew M. Hopkins ◽  
Cindy L. Fisher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Safety Data ◽  
Healthy Adults ◽  
Antifungal Drug ◽  
Renal Elimination ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Time Curve

ABSTRACT VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

Results of the ADRRAD Trial of pelvic IMRT plus radium-223 in men with mHSPC metastatic to bone.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 136-136
Author(s):  
Joe O'Sullivan ◽  
Philip Geoffrey Turner ◽  
Suneil Jain ◽  
Arthur Grey ◽  
Sandra Biggart ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase 1 ◽  
Palliative Radiotherapy ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Pelvic Radiotherapy ◽  
Serious Adverse Events ◽  
Radium 223

136 Background: Radiotherapy to the Prostate in mHSPC improves overall survival (OS) and Progression free survival (PFS) for patients with low-volume-disease[1]. Radium-223 in metastatic castration resistant prostate cancer (mCRPC) improves OS [2]. We conducted a prospective phase 1/2 clinical trial in mHSPC, testing the combination of with LHRHa, concurrent pelvic radiotherapy and radium-223. Methods: Thirty patients were recruited with mHSPC; they had a minimum of 3 bone metastases (majority had > 20 bone mets), nil visceral metastases, PS0-1. Patients were encouraged to receive up front docetaxel. They were treated with ongoing LHRHa, pelvic radiotherapy aiming for 74Gy in 37 fractions to prostate PTV with 60Gy concomitantly delivered to pelvic nodal PTV. Concurrently, patients received radium-223, 55kBq/kg for 6 cycles q28 days; fraction 1 radiotherapy was synchronous with cycle 1 day 1 radium-223. Results: Median age was 63 years and 28 (93%) received at least 4 cycles of docetaxel. One patient received prostate only radiotherapy due to bowel constraints. Three patients had cycle 6 radium-223 omitted. At a median follow-up of 28 months, there have been 415 Adverse events, (3% Grade >3), and 6 serious adverse events (SAEs) ( 2 episodes of UTI, 1 each of cystitis non-infective, cardiac chest pain, pyrexia and AKI). Commonest AEs by number were: leucopenia, neutropenia, and diarrhoea. Ten SSE’s have occurred including 8 courses of palliative radiotherapy for bone pain, 1 course of radiotherapy for impending MSCC and 1 pathological fracture. At median follow up 28.0 months, median biochemical PFS is 17.9 months, median OS not yet reached. Conclusions: This trial shows clear tolerability and promising early efficacy data requiring further exploration in a randomised phase 3 trial. Clinical trial information: 2014-000273-39.

Pipeline for uncoilable or failed aneurysms: 3-year follow-up results

2017 ◽  
Vol 127 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Tibor Becske ◽  
Matthew B. Potts ◽  
Maksim Shapiro ◽  
David F. Kallmes ◽  
Waleed Brinjikji ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Internal Carotid ◽  
Late Onset ◽  
Safety Data ◽  
Flow Diversion ◽  
Serious Adverse Events ◽  
Clinical Trial Registration

OBJECTIVEThe long-term effectiveness of endovascular treatment of large and giant wide-neck aneurysms using traditional endovascular techniques has been disappointing, with high recanalization and re-treatment rates. Flow diversion with the Pipeline Embolization Device (PED) has been recently used as a stand-alone therapy for complex aneurysms, showing significant improvement in effectiveness while demonstrating a similar safety profile to stent-supported coil treatment. However, relatively little is known about its long-term safety and effectiveness. Here the authors report on the 3-year safety and effectiveness of flow diversion with the PED in a prospective cohort of patients with large and giant internal carotid artery aneurysms enrolled in the Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial.METHODSThe PUFS trial is a prospective study of 107 patients with 109 aneurysms treated with the PED. Primary effectiveness and safety end points were demonstrated based on independently monitored 180-day clinical and angiographic data. Patients were enrolled in a long-term follow-up protocol including 1-, 3-, and 5-year clinical and imaging follow-up. In this paper, the authors report the midstudy (3-year) effectiveness and safety data.RESULTSAt 3 years posttreatment, 74 subjects with 76 aneurysms underwent catheter angiography as required per protocol. Overall, complete angiographic aneurysm occlusion was observed in 71 of these 76 aneurysms (93.4% cure rate). Five aneurysms were re-treated, using either coils or additional PEDs, for failure to occlude, and 3 of these 5 were cured by the 3-year follow-up. Angiographic cure with one or two treatments of Pipeline embolization alone was therefore achieved in 92.1%. No recanalization of a previously completely occluded aneurysm was noted on the 3-year angiograms. There were 3 (2.6%) delayed device- or aneurysm-related serious adverse events, none of which led to permanent neurological sequelae. No major or minor late-onset hemorrhagic or ischemic cerebrovascular events or neurological deaths were observed in the 6-month through 3-year posttreatment period. Among 103 surviving patients, 85 underwent functional outcome assessment in which modified Rankin Scale scores of 0–1 were demonstrated in 80 subjects.CONCLUSIONSPipeline embolization is safe and effective in the treatment of complex large and giant aneurysms of the intracranial internal carotid artery. Unlike more traditional endovascular treatments, flow diversion results in progressive vascular remodeling that leads to complete aneurysm obliteration over longer-term follow-up without delayed aneurysm recanalization and/or growth.Clinical trial registration no.: NCT00777088 (clinicaltrials.gov)

scholarly journals ACROSTUDY: the first 5 years

2009 ◽  
Vol 161 (suppl_1) ◽  
pp. S19-S24 ◽  
Author(s):  
Peter J Trainer
Keyword(s):  
Tumour Size ◽  
Safety Data ◽  
Liver Function Tests ◽  
Dose Titration ◽  
Serious Adverse Events ◽  
Once Daily ◽  
Injection Site Reactions ◽  
The Mean ◽  
Magnetic Resonance Imaging Mri

ACROSTUDY is an observational registry intended to collect safety and efficacy data on pegvisomant therapy. A total of 792 patients have been enrolled, of whom 83% had commenced pegvisomant prior to recruitment. The mean follow-up is 1.66 years with the mean duration of pegvisomant therapy 3.31 years representing 2625 patient years of treatment. About 90% of patients were on once daily pegvisomant, and 67% were on monotherapy. Disappointingly, IGF1 was normalised in <70% of patients; furthermore, in 80% of patients with an elevated IGF1, the daily dose of pegvisomant was 20 mg or less. A total of 56 serious adverse events (AEs) were reported, of which 13 were related to pegvisomant. A total of 276 AEs were reported, of which 56 were considered related to pegvisomant. The AEs most frequently attributed to pegvisomant were disturbed liver function tests and injection site reactions. Magnetic resonance imaging (MRI) was available in 684 patients. A total of 411 patients had at least one MRI on pegvisomant compared with a baseline. In 31 patients, a decrease in tumour size has been reported, of whom 20 had previously received radiotherapy. An increase in tumour size has been reported and confirmed in 22 patients. In 11 patients, there was contradictory data on tumour size, while, in six patients, central review of the films failed to confirm increase in tumour size. In conclusion, the safety data are generally reassuring, while the IGF1 normalisation rate is disappointing, which probably reflects a failure of dose titration. Further effort is needed to understand the reasons for the failure of dose titration.

scholarly journals Dynamics of antimalarial antibodies in non-immune patients during and after a first and unique P. falciparum malaria episode

2020 ◽  
Author(s):  
Zeno Bisoffi ◽  
Marco Bertoldi ◽  
Ronaldo Silva ◽  
Giulia Bertoli ◽  
Tamara Ursini ◽  
...  
Keyword(s):  
Blood Donors ◽  
Travel Medicine ◽  
Antibody Test ◽  
Malaria Episode ◽  
Full Blood Count ◽  
Case Report Form ◽  
Retrospective Diagnosis ◽  
Laboratory Test Results ◽  
High Level

Abstract BackgroundMalaria is a major travel medicine issue. Retrospective confirmation of a malaria episode diagnosed in an endemic area can have relevant implications in trasfusional medicine in Europe, where blood donors are excluded from donation on the basis of positive malaria serology. However, there is scarce evidence on the dynamics of antimalarial antibodies after a first malaria episode in non immune individuals. First aim of this study was to describe the dynamics of antimalarial antibodies in a first malaria episode in non immune travellers. Secondary objectives were to assess the sensitivity of serology for a retrospective diagnosis in non immune travellers diagnosed while abroad and to discuss the implications in transfusional medicine.MethodsRetrospective analysis of the results of an indirect fluorescence antibody test (IFAT) for malaria available for patients with a first malaria episode by Plasmodium falciparum and admitted at the IRCCS Sacro Cuore Don Calabria hospital in a 14-year period. The antibody titres were collected at baseline and during further follow up visits. Epidemiological, demographic and laboratory test results (including full blood count and malaria parasite density) were anonymously recorded in a study specific electronic Case Report Form created with OpenClinica software. Statistical analysis was performed with SAS software version 9.4. ResultsThirty-six patients were included. Among them, all but two were Europeans (one African and one American). Median length of fever before diagnosis was two days (IQR 1-3). Thirty-five patients had seroconversion between day 1 and day 4 from admission, and the titre showed a sharply rising titre, often to a very high level in a few days. Only a single patient remained negative in the first 5 days from admission, after which he was no more tested. Six patients were followed up for at least two months, and they all showed a decline in IFAT titre, tending to seroreversion (confirmed in one patient with the longest follow up, almost four years). ConclusionsSerology demonstrated reliable for retrospective diagnosis in non immune travellers. The decline in the antimalarial titre might be included in the screening algorithms of blood donors, but further studies are needed.

Preliminary safety of bevacizumab with first-line Folfox, Capox, Folfiri and capecitabine for mCRC—First B.E.A.Trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3534-3534 ◽  
Author(s):  
S. R. Berry ◽  
D. Cunningham ◽  
M. Michael ◽  
M. Dibartolomeo ◽  
F. Rivera ◽  
...  
Keyword(s):  
Safety Data ◽  
Phase Iii ◽  
First Line ◽  
Community Based ◽  
Serious Adverse Events ◽  
Life Threatening ◽  
Large Phase ◽  
Arterial Thromboembolic Events ◽  
Grade 3

3534 Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), bevacizumab (BEV) increased overall survival by 30% when added to first-line IFL chemotherapy (CT). Safety data from controlled BEV trials have been described, and indicate that certain serious adverse events (SAE), primarily gastrointestinal (GI) perforations and arterial thromboembolic events (TE) occurred more often in pts who received CT with BEV than those who received CT alone. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of CT regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible pts starting with first-line CT (physician’s choice) are treated until progression with BEV (5mg/kg q2w [5FU based CT] or 7.5mg/kg q3w [capecitabine based CT]). SAEs include deaths, new and prolonged hospitalizations, life-threatening as well as medically significant events and are reported within 24 hours. There BEV-relatedness is assessed by investigators. Results: By Dec 20, 2005, 1915 pts had been enrolled in 40 countries. 1603/1915 pts (male 58%; median age 59 years [29% were > 65 years]; PS 0–1 99%) had baseline data available for analyses. Median follow-up was 6.7 months (mean 7.3); 1509 pts had been followed-up for >60 days. The most common first-line CT regimens used with BEV were FOLFOX (28%), CAPOX (17%), FOLFIRI (25%) and capecitabine (8%). Among the 1603 pts that had started treatment with BEV, 638 SAEs were reported in 394 pts (25%). 60-day mortality was 2.4%. The most common SAE were diarrhoea 2.7% and pyrexia 2.2% and were usually not attributed as related to BEV. Related SAEs were reported in 132 (8%) pts. venous TE 1.7%, pulmonary embolism 1.1%, bleeding 1.0%, GI perforation 0.9%, arterial TE 0.8%, hypertension 0.5% wound healing complications 0.3% were usually classified as related SAEs. Conclusions: In this ongoing, large community-based study, the safety profile of BEV in first line mCRC pts receiving a variety of CT regimens, namely FOLFOX, CAPOX, FOLFIRI and capecitabine, appears consistent with that observed in large phase III randomised studies. Updated safety data, including grade 3/4 CTC toxicities, will be presented. [Table: see text]

Phase 2 study of zanubrutinib (BGB-3111) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7568-TPS7568
Author(s):  
Stephen Opat ◽  
Robert Marcus ◽  
Craig Anthony Portell ◽  
William Reed ◽  
Melannie Co ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Critical Role ◽  
Safety Data ◽  
Drug Discontinuation ◽  
Phase 2 ◽  
Open Label ◽  
Serious Adverse Events ◽  
Major Hemorrhage

TPS7568 Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, mediating B-cell proliferation, migration, adhesion and survival. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MZL. In preclinical studies, zanubrutinib was shown to be a potent, irreversible, highly specific BTK inhibitor with excellent oral bio-availability and favorable pharmacokinetic/pharmacodynamic properties. Clinical data to date have shown that complete and sustained 24-hour BTK occupancy is associated with durable responses and suggested that zanubrutinib is generally well tolerated with low rates of serious adverse events. Preliminary results from the MZL cohort enrolled in the open-label, multicenter, phase 1 study demonstrated responses in 7 of 9 patients for an overall response rate (ORR) of 78%. Cumulative safety data also showed that zanubrutinib monotherapy was associated with infrequent incidence of atrial fibrillation and major hemorrhage and infrequent drug discontinuation due to treatment-related adverse events. This study is designed to evaluate the safety and efficacy of zanubrutinib in patients with R/R MZL. Methods: This ongoing global phase 2, single-arm, open-label study is examining zanubrutinib monotherapy in patients with R/R MZL who have received one or more prior lines of systemic therapy. Patients are treated with oral zanubrutinib at 160 mg twice-daily until progressive disease, unacceptable toxicity, or withdrawal of consent. Eligible patients must have histologically confirmed MZL, have received prior anti-CD20 antibody therapy, and have measurable disease. Disease response is assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is ORR determined by independent review committee (IRC). Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), and overall survival and safety. Recruitment is ongoing.

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