scholarly journals Combination of Bedaquiline plus Delaminid within a treatment regimen for Pre-XDR TB; experience of a tolerable regimen and acceptable safety profile for the first time in Scotland

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Katherine Cobb ◽  
Aline Wilson ◽  
Nikolas Rae ◽  
Neil Stevenson
Keyword(s):  
Treatment Regimen ◽  
Safety Profile ◽  
Acceptable Safety Profile ◽  
First Time

scholarly journals OR26-08 Efficacy and Safety of Higher Dulaglutide Doses (3.0 MG and 4.5 MG) When Added to Metformin in Patients With Type 2 Diabetes: A Phase 3, Randomized, Double-Blind, Parallel ARM Study (Award-11)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Juan Pablo Frias ◽  
Luis Nevárez Ruiz ◽  
Ying Grace Li ◽  
Zhuoxin Yu ◽  
Zvonko Milicevic ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Adverse Events ◽  
Treatment Regimen ◽  
Safety Profile ◽  
Statistical Significance ◽  
Type I ◽  
Double Blind ◽  
Acceptable Safety Profile

Abstract Dulaglutide (DU) approved at doses of 0.75 and 1.5 mg once-weekly is an effective glucose lowering agent for treatment of type 2 diabetes (T2D). We hypothesized that higher investigational DU doses may provide further improvements in glucose control and body weight (BW) with an acceptable safety profile. The primary objective was to demonstrate superiority of once-weekly DU 3 mg and/or 4.5 mg to DU 1.5 mg for A1C change from baseline (BL) at 36 weeks (wks) in patients (pts) with inadequately controlled T2D on metformin therapy. Secondary objectives (controlled for multiplicity) included change in BW and % of pts achieving A1C <7% at 36 wks. Patients were randomized (1:1:1) to once-weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All pts initiated once-weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Two estimands were defined for efficacy analyses: an efficacy estimand (data on-treatment without rescue medication) and a treatment-regimen estimand (all data regardless of adherence or initiation of rescue). At BL, patients had a mean of: age 57.1 yrs, T2D duration 7.6 yrs, and A1C 8.6%, BW 95.7 kg, and BMI 34.2 kg/m2. Using the efficacy estimand, the DU 3 mg and 4.5 mg doses were superior to the DU 1.5 mg dose for A1C change from BL (1.5 mg, 1.53%; 3 mg, 1.71% [p=0.003]; 4.5 mg, 1.87% [p<0.001]), % of patients achieving HbA1c <7% (1.5 mg, 57%; 3.0 mg, 65% [p=0.006]; 4.5 mg, 71% [p<0.001]) and BW change from BL (1.5 mg, 3.1 kg; 3 mg, 4.0 kg [p=0.001]; 4.5 mg, 4.7 kg [p<0.001]). Using the treatment-regimen estimand, DU 4.5 mg was superior to DU 1.5 mg for A1C change, while the DU 3 mg dose did not achieve statistical significance (1.5 mg, 1.54%; 3.0 mg, 1.64% [p=0.096]; 4.5 mg, 1.77% [p<0.001]). Using the treatment-regimen estimand, more patients achieved A1C <7% with higher DU doses (1.5 mg, 50%; 3 mg, 56%; 4.5 mg, 62%) and results for BW change were similar to the efficacy estimand (1.5 mg, 3.0 kg; 3 mg, 3.8 kg; 4.5 mg, 4.6 kg), but the approach for type I error control did not permit formal statistical comparisons of these secondary objectives using this estimand. The safety profile for the higher DU doses was consistent with that known for 1.5 mg. The most commonly reported adverse events were nausea (DU 1.5 mg, 13.4%; DU 3 mg, 15.6%; DU 4.5 mg, 16.4%), vomiting (DU 1.5 mg, 5.6%; DU 3 mg, 8.3%; DU 4.5 mg, 9.3%), and diarrhea (DU 1.5 mg, 7.0%; DU 3 mg, 11.4%; DU 4.5 mg, 10.7%). Treatment discontinuation due to adverse events through 36 wks was low and similar across dose groups (DU 1.5 mg, 4.2%; DU 3 mg, 5.5%; DU 4.5 mg, 5.0%). In pts with T2D and inadequate glycemic control on metformin, escalation from DU 1.5 mg to DU 3 mg or DU 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycemic control and BW with an acceptable safety profile.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

Union of forces advances myeloma care

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 674-675 ◽  
Author(s):  
A. Keith Stewart
Keyword(s):  
Treatment Regimen ◽  
Academic Medical Centers ◽  
Pharmaceutical Companies ◽  
Team Approach ◽  
Newly Diagnosed ◽  
Medical Centers ◽  
Academic Medical ◽  
First Time

In this issue of Blood, Richardson et al report on a landmark treatment regimen for newly diagnosed myeloma patients that for the first time combines lenalidomide and bortezomib. This effort required a team approach comprising 2 competing pharmaceutical companies (joining forces to study this promising regimen) and multiple academic medical centers.1

scholarly journals Current Approaches to the Treatment of Gastrointestinal Infections: Focus on Nitazoxanide

2009 ◽  
Vol 1 ◽  
pp. CMT.S2297 ◽  
Author(s):  
Jennifer L. Halsey
Keyword(s):  
Side Effects ◽  
Drug Interactions ◽  
Broad Spectrum ◽  
Safety Profile ◽  
Taenia Saginata ◽  
Gastrointestinal Infections ◽  
Oral Tablet ◽  
Acceptable Safety Profile ◽  
H Pylori ◽  
Immunocompetent Patients

Nitazoxanide is a broad-spectrum agent active against several protozoa, helminths, and bacteria, including C. difficile and H. pylori. It is available as an oral tablet and suspension, both with adequate bioavailability. Nitazoxanide is associated with minimal side effects, has an acceptable safety profile, and has been classified as a pregnancy category B agent. It is 99% protein bound, which could result in drug interactions. It is the preferred agent for the treatment of Cryptospordiosis and Giardiasis in immunocompetent patients and has shown promise for the treatment of rotavirus, mild to moderate initial C. difficile infection, refractory C. difficile infection, Amoebiasis, Blastocystosis, and Taenia saginata.

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1860-1860 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey Zonder ◽  
Adam Cohen ◽  
Robert Z. Orlowski ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

scholarly journals A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Blood ◽  
2014 ◽  
Vol 123 (9) ◽  
pp. 1302-1308 ◽  
Author(s):  
John C. Byrd ◽  
John M. Pagel ◽  
Farrukh T. Awan ◽  
Andres Forero ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Safety Profile ◽  
Phase 1 ◽  
Single Agent ◽  
Therapeutic Protein ◽  
Lymphocytic Leukemia ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Key Points

Key Points Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL. Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.

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