scholarly journals Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies

2015 ◽  
Vol 48 ◽  
pp. 45-52 ◽  
Author(s):  
David Ko ◽  
Haichen Yang ◽  
Betsy Williams ◽  
Dongyuan Xing ◽  
Antonio Laurenza
Keyword(s):  
Adverse Events ◽  
Phase Iii ◽  
Partial Seizures ◽  
Time To Onset

Peripheral Neuropathy In Multiple Myeloma Patients Treated with Lenalidomide

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5024-5024
Author(s):  
Carmen Castaneda ◽  
Lilia Weiss ◽  
Neil A. Minton ◽  
Alex Kim ◽  
John Freeman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Median Time ◽  
Study Drug ◽  
Phase Iii ◽  
Immunomodulatory Activity ◽  
Pivotal Phase ◽  
History Of ◽  
Time To Onset

Abstract Abstract 5024 Background: Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity. As demonstrated by 2 randomized, double-blind, placebo-controlled pivotal phase III registration trials, lenalidomide plus dexamethasone (Len/Dex) was well tolerated and achieved significant clinical efficacy and survival outcomes vs placebo plus Dex (PBO/Dex) in patients (pts) with relapsed/refractory multiple myeloma (MM) (Weber 2007; Dimopoulos 2007). In MM, the rate of symptomatic peripheral neuropathy (PN) is 3–13%, although the rate of subclinical neuropathy detected by electrophysiological studies or histopathological evaluation is estimated to be much higher (40-60%; Kwan 2007). Published incidence of PN has been notable with thalidomide (Thal) ranging from 0 to 90%, depending on pt characteristics, concomitant treatments, dose/exposure duration, and techniques for identifying PN. We present the result of our analysis of PN adverse events (AEs) reported with Len. Methods: Reports of PN from the 2 registration studies (MM-009, MM-010; data cutoff June and August 2005, respectively), and postmarketing safety reports (Dec 2005 to Dec 2009) were retrieved from Celgene clinical and safety databases utilizing the Preferred Terms for PN AEs within the PN Standardized MedDRA (v13.0) Query (SMQ) to obtain all possible cases. Severity grades were according to the NCI CTCAE (V3). Results: Clinical Studies 703 pts (353 Len/Dex; 350 PBO/Dex) from the 2 registration studies were included in this analysis. The proportion of pts with ≥1 Grade (G) 1–4 PN AEs and ≥1 serious adverse event (SAE) was similar between the Len/Dex and PBO/Dex arm (45.6% vs 44.9% and 1.1% vs 1.1%, respectively). However, the proportion of pts with ≥1 G3/4 PN was slightly higher with Len/Dex vs PBO/Dex (9.3% vs 5.1%). Among the Len/Dex pts with PN AEs, prior Thal or vincristine was reported in 39.1% and 60.9% of pts, respectively and 24.8% of pts had history of PN. Among the PBO/Dex pts with PN AEs, prior Thal or vincristine was reported in 46.5% and 58.0% of pts, respectively and 29.3% of pts had a history of PN. Within this SMQ analysis, the PN AEs reported in ≥5% of the pts were peripheral neuropathy, hypoaesthesia, paraesthesia, and muscle weakness in both treatment arms. 98.3% of PN AEs were not SAEs and 83.2% were G1/2 in the Len/Dex arm. Among pts in the Len/Dex arm and with PN AEs, PN resolved in 61.5% and study drug was continued in 78.9% of pts. Study drug was reduced due to PN in 12.4% and interrupted in 5.0% of pts in the Len/Dex arm. The median time to onset of PN event was longer in the Len/Dex arm compared with the PBO/Dex arm (41 vs 31 days). Postmarketing A total of 2857 PN AEs were reported in 2329 of an estimated 73,592 MM pts. The reporting rate of PN AEs is 3.2% in the MM indication. Within this SMQ analysis, the PN AEs reported in ≥0.5% of the pts were peripheral neuropathy, hypoaesthesia, and paraesthesia. 93.8% of PN AEs were not SAEs. Most pts were males and elderly with a median age of 66 yrs (range: 29–95). Among MM pts with PN AEs and available information, 13% had prior Thal, 5% had prior bortezomib, and 11% had a history of PN. In the majority of reports, outcome was unknown and Len was continued. The median time to onset of PN event was 60 days (range: 1–1460). Conclusion: In 2 pivotal phase III registration trials, the incidence rate of peripheral neuropathy adverse events was similar between the Len/Dex and PBO/Dex arms. Most pts had prior anti-myeloma therapies associated with PN and a quarter of the pts had a history of PN. Limited information in postmarketing reports on prior therapies and medical history may have underestimated pre-existing PN and exposure to prior anti-myeloma therapies associated with PN. PN AEs occurred within a median of 60 days of starting Len. In conclusion, peripheral neuropathy adverse events in MM pts treated with Len are generally not SAEs and did not commonly require dose modification or interruption. References Dimopoulos et al. NEJM 2007;357(21):2123-2132. Kwan JY. Neurol Clin 2007;25(1):47-69. Weber et al. NEJM 2007;357(21):2133-2142. Disclosures: Castaneda: Celgene: Employment. Weiss:Celgene: Employment. Minton:Celgene: Employment. Kim:Celgene: Employment. Freeman:Celgene: Employment. Yu:Celgene: Employment. Knight:Celgene: Employment.

Time course of regorafenib-associated adverse events in the phase III CORRECT study

2013 ◽  
Vol 51 (08) ◽  
Author(s):  
C Denzlinger ◽  
A Grothey ◽  
AF Sobrero ◽  
E van Cutsem ◽  
S Siena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Time Course ◽  
Phase Iii

558 Programmed death (PD)-1 and PD-ligand-1 inhibitors in the treatment of non-small cell lung cancer: a systematic review of their efficacy and safety

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A592-A592
Author(s):  
Melissa Lingohr-Smith ◽  
Chelsea Deitelzweig ◽  
Grace Lin ◽  
Jay Lin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Patient Outcomes ◽  
Nsclc Patient ◽  
Response Rates ◽  
Phase Iii ◽  
Combination Therapies ◽  
Phase Iii Clinical Trials ◽  
Programmed Death ◽  
Grade 3

BackgroundTreatment advances have been made in non-small cell lung cancer (NSCLC) with the development and approval of programmed death (PD)-1 and PD-ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1 inhibitors may be used as monotherapies or in combination with other agents and have been shown to improve NSCLC patient outcomes in clinical trials. We conducted a systematic search to compare the efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of NSCLC.MethodsA systematic literature search of PubMed was conducted to identify phase III clinical trials in which the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC was evaluated. PD-1 inhibitors included nivolumab and pembrolizumab; PD-L1 inhibitors included atezolizumab, avelumab, and durvalumab. Patient characteristics and efficacy data were extracted.ResultsSixteen phase III clinical trials were identified (nivolumab=4; pembrolizumab=5; atezolizumab=5; avelumab=1; durvalumab=1). Across the 3 nivolumab monotherapy trials (n=638; median ages: 61–63 years), median progression-free survival (PFS) ranged 2.3–4.2 months; response rates ranged 19%-26%; grade 3/4 adverse events occurred in 7%-18% of patients. Nivolumab in combination with iplimumab (n=583; median age: 64 years) had a median PFS of 5.1 months and response rate of 33%; grade 3/4 adverse events occurred in 33% of patients. Across the 3 pembrolizumab monotherapy trials (n=1,481; median ages: 63–64 years), median PFS ranged 3.9–10.3 months; response rates ranged 18%-45%; grade ≥3 adverse events occurred in 13%-27% of patients. In the 2 pembrolizumab combination therapy trials (n=688; median ages: 65 years), median PFS ranged 6.4–8.8 months; response rates ranged 48%-58%; grade ≥3 adverse events occurred in 67%-70% of patients. In the 4 atezolizumab combination therapy trials (n=1,486; median ages: 63–64 years), median PFS ranged 6.3–8.3 months; response rates ranged 47%-63.5%; grade 3/4 adverse events occurred in 54%-73% of patients. In the 3 monotherapy trials of atezolizumab (n=613; median age: 63 years), avelumab (n=396; median age: 64 years), and durvalumab (n=476; median age: 64 years), the median months of PFS were 2.7, 2.8, and 17.2, respectively; response rates were 14%, 15%, and 30%, respectively; grade ≥3 adverse events occurred in 15%, 10%, and 30.5% of patients, respectively.ConclusionsAlthough treatment responses varied, most of the evaluated PD-1/PD-L1 inhibitors were associated with a clinical benefit for NSCLC trial patients. Generally, treatment efficacy was greater with combination therapies, but adverse events occurred more frequently. Innovations in the targeting/personalization of PD-1/PD-L1 combination therapies will likely lead to improved NSCLC patient outcomes and further research is needed in this regard.

P136 Efficacy and safety of olokizumab in a phase III trial in patients with moderately to severely active RA inadequately controlled by TNF-α inhibitor therapy

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Eugen Feist ◽  
Saeed Fatenejad ◽  
Sergey Grishin ◽  
Elena Korneva ◽  
Michael Luggen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
Inhibitor Therapy ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Research Support ◽  
Acr20 Response ◽  
Phase Iii Trial ◽  
Tnf Α ◽  
To Receive

Abstract Background/Aims  Olokizumab (OKZ) is a new humanised monoclonal antibody targeting IL-6. Here we present the results of the phase III study of OKZ in anti-TNF-IR patients. Methods  Patients with moderately to severely active RA who had previously failed TNF inhibitors (ClinicalTrials.gov Identifier NCT02760433/CREDO3) were randomized in a 2:2:1 ratio to receive subcutaneous (SC) injections of OKZ 64 mg every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or placebo (PBO), plus MTX. At week 16, all subjects in the PBO group were randomized in a 1:1 ratio to receive either of OKZ regimes. The primary endpoint was ACR20 response at week 12. Results  368 subjects were randomised according to the protocol and 320 patients (87%) completed the 24-week treatment period. Baseline characteristics were comparable across arms. Both regimens of OKZ were significantly better in primary endpoint: ACR20 were 60.9% (p = 0.0029 in comparison vs. PBO) in OKZ q2w, 59.6% in OKZ q2w (p = 0.0040 in comparison vs. PBO) and 40.6% in PBO. The key efficacy outcomes were maintained throughout the 24-week period of the study. Overall incidences of treatment-emergent adverse events (TEAE) were 65.5% in OKZ q2w, 65.0% in OKZ q4w and 50.7% in PBO. Subsequent randomization of PBO arm at week 16 did not change TEAEs incidence rate per treatment group significantly: 64.3% in any OKZ q2w and 59.7% in any OKZ q4w. The majority of TEAEs in all groups were not serious and were of mild or moderate severity. Incidence of treatment-emergent serious adverse events (TESAE) were: 12 (7.0%) subjects in any OKZ q2w; 6 subjects (3.2%) in any OKZ q4w group, all in the first 16 weeks. The most frequently reported TESAEs across all treatment groups were infections and infestations: 2 (1.2%) in OKZ q2w group, 2 (1.1%) in OKZ q4w group. No opportunistic infections including active tuberculosis, major adverse cardiovascular events, gastrointestinal perforations or deaths were reported. Conclusion  In this global Phase III trial in patients with moderately to severely active RA inadequately controlled by TNF-α inhibitor therapy, treatment with OKZ plus MTX in both regimes (OKZ 64 mg q2w and OKZ 64 mg q4w) was associated with significant improvements in the signs and symptoms of RA compared to PBO plus MTX over a 24-week period. Treatment with OKZ q2w and q4w in this difficult to treat population was well tolerated and consistent with the established safety profile of anti-IL-6 agents. Disclosure  E. Feist: Consultancies; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi. Honoraria; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Member of speakers’ bureau; R-Pharm, Abbvie, AB2Bio, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Grants/research support; Lilly, Novartis, Pfizer, Roche/Chugai. S. Fatenejad: Consultancies; RPharm International. Shareholder/stock ownership; Pfizer. S. Grishin: Corporate appointments; Employed by R-Pharm. E. Korneva: Corporate appointments; Employed by R-Pharm. M. Luggen: Consultancies; Amgen, Sun Pharmaceuticals, R-Pharm International. Grants/research support; I havAbbvie, R-Pharm, Sun Pharmaceuticals, Pfizer, Novartis, Lilly, and GSK. E. Nasonov: Honoraria; Lilly, Abbnie, Prizer, Biocad, R-Pharm. Member of speakers’ bureau; Lilly, Abbnie, Prizer, Biocad, R-Pharm. M. Samsonov: Corporate appointments; Employed by R-Pharm.

scholarly journals Cabozantinib in Progressive Medullary Thyroid Cancer

2013 ◽  
Vol 31 (29) ◽  
pp. 3639-3646 ◽  
Author(s):  
Rossella Elisei ◽  
Martin J. Schlumberger ◽  
Stefan P. Müller ◽  
Patrick Schöffski ◽  
Marcia S. Brose ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Adverse Events ◽  
Medullary Thyroid Cancer ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Mutation Status ◽  
Medullary Thyroid ◽  
Ret Mutation

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer

2016 ◽  
Vol 34 (31) ◽  
pp. 3740-3748 ◽  
Author(s):  
Martin Reck ◽  
Alexander Luft ◽  
Aleksandra Szczesna ◽  
Libor Havel ◽  
Sang-We Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
Stage Disease ◽  
Extensive Stage ◽  
Study Therapy

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

scholarly journals Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK

2017 ◽  
Vol 28 ◽  
pp. v469 ◽  
Author(s):  
J. von Pawel ◽  
K. Syrigos ◽  
J. Mazieres ◽  
D. Cortinovis ◽  
R. Dziadziuszko ◽  
...  
Keyword(s):  
Adverse Events ◽  
Advanced Nsclc ◽  
Phase Iii ◽  
Phase Iii Study

scholarly journals Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110458
Author(s):  
Mark A. Socinski ◽  
Cornelius F. Waller ◽  
Tazeen Idris ◽  
Igor Bondarenko ◽  
Alexander Luft ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Phase Iii ◽  
European Medicines Agency ◽  
Small Cell Lung ◽  
Serious Adverse Events ◽  
Double Blind

Purpose: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. Patients and methods: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). Results: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). Conclusions: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. Trial Registry Information EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32 Plain language summary Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O ( n = 337) demonstrated comparable efficacy to bevacizumab ( n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months ( p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

scholarly journals Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism

2018 ◽  
Vol 7 (5) ◽  
pp. R196-R211 ◽  
Author(s):  
Jaafar Jaafar ◽  
Eugenio Fernandez ◽  
Heba Alwan ◽  
Jacques Philippe
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
English Language ◽  
Case Series ◽  
Immune Checkpoints ◽  
Pubmed Database ◽  
Programmed Cell Death 1 ◽  
Time To Onset

Background Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs). Purpose We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm. Methods We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue. Findings In patients treated with PD-1 Ab, hypothyroidism occurred in 2–10.1% and hyperthyroidism occurred in 0.9–7.8%. When thyroiditis was reported separately, it occurred in 0.34–2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23–45 days and 2–3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0–10% and hyperthyroidism in 0.5–2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months. Conclusion Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

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