scholarly journals Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1277
Author(s):  
Anand Rotte ◽  
Srikumar Sahasranaman ◽  
Nageshwar Budha
Keyword(s):  
Clinical Studies ◽  
Metastatic Cancer ◽  
Safety Data ◽  
Clinical Development ◽  
Activated T Cells ◽  
Evaluation Phase ◽  
Immunotherapy Of Cancer ◽  
Advanced Stages ◽  
Immune Checkpoint Blockers ◽  
Critical Aspects

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

scholarly journals 3. A Review of the Clinical Development of MenACWY-TT, a Quadrivalent Meningococcal Vaccine Conjugated to Tetanus Toxoid, in Adolescents

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S23-S24
Author(s):  
Paula Peyrani ◽  
Chris Webber ◽  
Cindy Burman ◽  
Paul Balmer ◽  
John L Perez
Keyword(s):  
Clinical Studies ◽  
Safety Data ◽  
Primary Vaccination ◽  
Clinical Development ◽  
Antibody Responses ◽  
The European Union ◽  
Study Program ◽  
Vaccination Programs ◽  
Primary Series ◽  
Adolescents And Adults

Abstract Background As a peak in meningococcal disease often occurs during adolescence, meningococcal vaccination programs are available for this age group in various regions across the globe. Quadrivalent meningococcal (MenACWY) conjugate vaccines are being incorporated in an increasing number of programs in response to changing meningococcal serogroup epidemiology. MenACWY-TT (Nimenrix®) is a MenACWY conjugate vaccine available in the European Union and 50 other countries for preventive vaccination of serogroup A, C, W, and Y disease (Figure 1). MenACWY-TT is licensed in some countries as a 2-dose primary series in individuals as young as 6 weeks of age, while a single dose may be given to previously unvaccinated individuals ≥ 6 months of age, adolescents, and adults. Here, we provide an overview of the 3 primary and 5 extension studies evaluating the clinical development of MenACWY-TT in adolescents (Table 1). Figure 1. Global Registration Status of MenACWY-TT (Nimenrix®) in Adolescents Table 1. Pivotal Clinical Studies of MenACWY-TT (Nimenrix®) Supporting Licensure in Adolescents Methods Immunogenicity and safety data from these 8 clinical studies are summarized. Results Across studies, MenACWY-TT antibody responses against all vaccine serogroups were comparable to those of other MenACWY vaccines 1 month post vaccination (Table 1). Antibody responses to MenACWY-TT persisted for up to 10 years in those vaccinated during adolescence. A MenACWY-TT booster given 10 years after primary meningococcal vaccination in early childhood or adolescence elicited robust antibody responses. MenACWY-TT had an acceptable safety profile, with reactogenicity events most commonly reported. Reactogenicity profiles with MenACWY-TT booster were similar to those seen after primary MenACWY-TT. Conclusion The MenACWY-TT clinical study program demonstrated the immunogenicity and safety of primary and booster dosing in adolescents. Immune responses persisted through 10 years after primary vaccination. Funding Pfizer. Disclosures Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)

Monoklonális ellenanyag-alapú terápia myeloma multiplexben

2021 ◽  
Vol 54 (1) ◽  
pp. 27-36
Author(s):  
Apor Hardi ◽  
András Kozma ◽  
Andrea Ceglédi ◽  
Ágnes Tomán ◽  
András Bors ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cell ◽  
Clinical Studies ◽  
Clinical Development ◽  
Bispecific Antibodies ◽  
Advanced Stages ◽  
Therapeutic Monoclonal Antibodies ◽  
Therapeutic Settings ◽  
Cell Malignancy

Összefoglaló. A monoklonális ellenanyagokat termelő plazmasejtburjánzás, a myeloma multiplex kezelésére a monoklonális ellenanyag-terápia viszonylag későn lépett a klinikumba. 2020 végén már három törzskönyvezett antitest, az elotuzumab, a daratumumab és az isatuximab áll rendelkezésre különböző gyógyszer-kombinációk részeként a myeloma betegség eltérő terápiás helyzeteinek megoldására. Emellett számos új antitest, nemcsak „csupasz” antitestek, hanem antitestdrug konjugátumok és bispecifikus antitestek állnak viszonylag előrehaladott klinikai fejlesztési stádiumban, közvetlenül a bevezetés előtt. Összefoglalónkban a rendelkezésünkre álló nagyszámú tanulmány eredményeit ismertetjük, fogódzót kínálva a terület eredményeit kritikus szemmel megismerni kívánó olvasóknak. Summary. Although multiple myeloma is a plasma cell malignancy known to produce monoclonal antibodies, therapeutic monoclonal antibodies entered late into this clinical field. At the end of 2020, we already have three approved monoclonal antibodies: elotuzumab, daratumamab, and isatuximab – available in different drug combinations at different therapeutic settings of multiple myeloma. Additionally, there are a number of new antibodies, not just „bare” antibodies but antibody-dug conjugates and bispecific antibodies stand at advanced stages of clinical development, frequently just before approval. In this review, results of the large number of clinical studies are critically detailed in order to provide assistance for our interested readers.

scholarly journals Targeting B cells to modify MS, NMOSD, and MOGAD

2020 ◽  
Vol 8 (1) ◽  
pp. e919
Author(s):  
Jonas Graf ◽  
Jan Mares ◽  
Michael Barnett ◽  
Orhan Aktas ◽  
Philipp Albrecht ◽  
...  
Keyword(s):  
B Cell ◽  
Case Series ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Clinical Development ◽  
B Cell Depletion ◽  
Phase 2 ◽  
Proven Efficacy ◽  
Advanced Stages ◽  
Related Proteins

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell–related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell–depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G–associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell–depleting agents will be discussed.

An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Burcu Isler ◽  
Patrick Harris ◽  
Adam G Stewart ◽  
David L Paterson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Studies ◽  
Bacterial Infections ◽  
Animal Studies ◽  
Wide Spectrum ◽  
Clinical Development ◽  
Phase Iii ◽  
Lactam Antibiotic ◽  
Tract Infections

Abstract Cefepime, a wide-spectrum β-lactam antibiotic, has been in use for the treatment of serious bacterial infections for almost 25 years. Since its clinical development, there has been a dramatic shift in its dosing, with 2 g every 8 hours being preferred for serious infections to optimize pharmacokinetic/pharmacodynamic considerations. The advent of ESBLs has become a threat to its ongoing use, although future coadministration with β-lactamase inhibitors (BLIs) under development is an area of intense study. There are currently four new cefepime/BLI combinations in clinical development. Cefepime/zidebactam is generally active against MBL-producing Enterobacterales and Pseudomonas aeruginosa, in vitro and in animal studies, and cefepime/taniborbactam has activity against KPC and OXA-48 producers. Cefepime/enmetazobactam and cefepime/tazobactam are potential carbapenem-sparing agents with activity against ESBLs. Cefepime/enmetazobactam has completed Phase III and cefepime/taniborbactam is in Phase III clinical studies, where they are being tested against carbapenems or piperacillin/tazobactam for the treatment of complicated urinary tract infections. While these combinations are promising, their role in the treatment of MDR Gram-negative infections can only be determined with further clinical studies.

scholarly journals Master protocols in immuno-oncology: do novel drugs deserve novel designs?

2020 ◽  
Vol 8 (1) ◽  
pp. e000475
Author(s):  
Luca Mazzarella ◽  
Stefania Morganti ◽  
Antonio Marra ◽  
Dario Trapani ◽  
Giulia Tini ◽  
...  
Keyword(s):  
Trial Design ◽  
Clinical Development ◽  
Decision Makers ◽  
Interesting Aspect ◽  
Rapid Rise ◽  
Multiple Stakeholders ◽  
Cultural Changes ◽  
Novel Drugs ◽  
Regulatory Bodies ◽  
Critical Aspects

The rapid rise to fame of immuno-oncology (IO) drugs has generated unprecedented interest in the industry, patients and doctors, and has had a major impact in the treatment of most cancers. An interesting aspect in the clinical development of many IO agents is the increasing reliance on nonconventional trial design, including the so-called ‘master protocols’ that incorporate various adaptive features and often heavily rely on biomarkers to select patient populations most likely to benefit. These novel designs promise to maximize the clinical benefit that can be reaped from clinical research, but are not without costs. Their acceptance as solid evidence basis for use outside of the research context requires profound cultural changes by multiple stakeholders, including regulatory bodies, decision-makers, statisticians, researchers, doctors and, most importantly, patients. Here we review characteristics of recent and ongoing trials testing IO drugs with unconventional design, and we highlight trends and critical aspects.

scholarly journals Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

2020 ◽  
Author(s):  
Parul Patel ◽  
Zhengyu Xue ◽  
Karen S King ◽  
Laura Parham ◽  
Susan Ford ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Total Bilirubin ◽  
Safety Data ◽  
Integrase Inhibitor ◽  
Clinical Development ◽  
Hiv Integrase ◽  
Two Phase ◽  
Functional Variants ◽  
Maximum Change ◽  
Long Acting

Abstract Background Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. Objectives To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). Methods Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). Results Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. Conclusions This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

Pharmacokinetic interaction and safety of enzastaurin and pemetrexed in patients with advanced or metastatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2047-2047 ◽  
Author(s):  
A. Hanauske ◽  
K. Weigang Koehler ◽  
E. Yilmaz ◽  
T. Graefe ◽  
B. Kuenen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cell ◽  
Metastatic Cancer ◽  
Geometric Mean ◽  
Single Agent ◽  
Safety Data ◽  
Pharmacokinetic Interaction ◽  
Term Treatment ◽  
Loading Dose ◽  
Tumor Cell Death

2047 Background: Enzastaurin, an orally administered potent PKC inhibitor, is an anti-angiogenic agent that also suppresses PI3K/AKT to inhibit tumor cell proliferation and induce tumor cell death. Preclinical data suggest that the combination of enzastaurin and pemetrexed (Alimta) produced additive or synergistic antitumor activity in tumor specimens. This phase 1b study evaluated the safety, pharmacokinetic (PK) interaction, and antitumor activity of enzastaurin when combined with pemetrexed. Methods: Patients (pts) with advanced or metastatic cancer and an ECOG status of 0–2 received an intravenous dose of 500 mg/m2 pemetrexed on day 1 and an oral dose of 500 mg enzastaurin once daily, (after day 4 in cycle 1) in repeat 21-day cycles for up to 6 cycles. In cycle 1, a loading dose of 1200 mg enzastaurin (400 mg/3×/day) was given on day 4. Pts were also given oral folic acid daily and vitamin B12 every 9 weeks for the duration of pemetrexed therapy, and 5–7 days before cycle 1. Results: Blood samples for PK analysis of enzastaurin (n = 21) were collected on day 21 of cycle 1 and day 1 of cycle 2, and for analysis of pemetrexed (n = 22) on day 1 of cycle 1 and cycle 2. Steady-state concentration [geometric mean (%CV)] of total analytes (enzastaurin and its metabolites) was 1270 nM (126%) when administered alone and 1130 nM (100%) when administered with pemetrexed. Thus, no significant differences in exposures were observed when combined with pemetrexed. Clearance of pemetrexed was the same when dosed either with enzastaurin (2.48 L/h/m2) or as a single agent (2.62 L/h/m2). Safety data from the first 2 cycles are consistent with the known toxicity profile of pemetrexed. No grade 3 or 4 toxicity was reported following the loading dose of 1200 mg enzastaurin. Conclusions: Preliminary data suggest that there is no significant PK interaction between enzastaurin and pemetrexed, and that the combination is well tolerated. The current study is ongoing and subsequent analyses will document tumor responses and safety for longer-term treatment of enzastaurin combined with pemetrexed. This first PK study of enzastaurin and pemetrexed will help determine if enzastaurin has an additive clinical benefit to pemetrexed treatment and support future studies in NSCLC and mesothelioma. [Table: see text]

Ph1/2 study of Rova-T in combination with nivolumab (Nivo) ± ipilimumab (Ipi) for patients (pts) with 2L+ extensive-stage (ED) SCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8516-8516 ◽  
Author(s):  
Jyoti Malhotra ◽  
Petros Nikolinakos ◽  
Ticiana Leal ◽  
Jonathan Lehman ◽  
Daniel Morgensztern ◽  
...  
Keyword(s):  
Normal Tissue ◽  
Safety Data ◽  
Substantial Effect ◽  
Primary Objective ◽  
Immunogenic Cell Death ◽  
Antibody Drug Conjugate ◽  
Evaluation Phase ◽  
Extensive Stage ◽  
Line Of Therapy ◽  
Clinical Trial Information

8516 Background: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, a Notch ligand expressed in SCLC but not normal tissue. Nivo ± Ipi has activity in 2L+ SCLC. Preliminary data suggest Rova-T may result in immunogenic cell death, complementing effects of Nivo ± Ipi. Methods: Eligibility: DLL3 expression (DLT phase only), progression after ≥1 line of therapy including a platinum-based regimen; ECOG 0-1; no prior immunotherapy. All pts received 0.3 mg/kg Rova-T IV on Day 1 of two 6-wk cycles. Cohort 1 (C1) also received two 3-wk cycles of 360 mg Nivo beginning on wk 4. Cohort 2 (C2) received four 3-wk cycles of 1 mg/kg Nivo and 1 mg/kg Ipi beginning on wk 4. Both cohorts then received 480 mg Nivo q4wks until PD. Primary objective: safety. Secondary: antitumor activity by RECISTv1.1, OS. Exploratory: PK. Results: As of Sep 7, 2018, 30 pts were dosed in C1 and 12 in C2. 55% were DLL3 high (≥75% DLL3 expression). 28 (67%) completed 2 planned cycles of Rova-T. 4 pts (1 in C1, 3 in C2) experienced DLTs including rash (3), pneumonitis (1) and colitis (1). C1 completed recruitment, and C2 enrollment was stopped after DLT evaluation phase. Preliminary PK showed Nivo±Ipi had no substantial effect on Rova-T exposure. Clinical trial information: NCT03026166. Conclusions: Despite activity in 2L+ ED-SCLC, Rova-T with Nivo/Ipi is not appropriate due to DLTs. Rova-T/Nivo demonstrated some durable responses; however, the safety data suggest that optimization of dose and schedule is warranted. NCT03026166.[Table: see text]

scholarly journals THE CLINICAL DEVELOPMENT OF BIO-SIMILAR PRODUCTS OF INSULIN AND ITS ANALOGUES: MODERN STAGE OF PROGRESSING

2017 ◽  
Vol 23 (5) ◽  
pp. 269-274
Author(s):  
Anastasiya V. Philippova ◽  
V. Chzhao ◽  
A. S Kolbin
Keyword(s):  
Clinical Studies ◽  
Medical Science ◽  
Clinical Development ◽  
Present Moment ◽  
Recombinant Human Insulin ◽  
Insulin Glargin ◽  
The World ◽  
The Russian Federation ◽  
In The Beginning ◽  
Information Database

The article presents a review of data concerning clinical development of bio-similar products of recombinant human insulin and its analogues according beginning of 2017. The review is implemented concerning regulative requirements. The analysis is implemented concerning registries of registered medications and registries of clinical studies at the territory of the Russian Federation, European Union and USA. The review of articles in the information database MEDLINE (PubMed) is implemented too. It is established that in whole in the world regulative approaches are developed related to implementation of clinical studies of bio-similar products of insulin. However, this direction represents a new field of knowledge. The requirements to clinical studies of this type pass a stage of formation and adaptation. In the beginning of 2017 at the mentioned territories only two bio-similar insulin glargin were registered. At the same time, certain clinical studies at the present moment wait for completion. This situation testifies that the considered problem is one of the most actual and perspective fields of medical science.

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