Niraparib is an oral poly(adenosine diphosphate ADP-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of ...niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer.
In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival.
Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval CI, 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.
Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).
Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the ...efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.
Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).
Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.
Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm Pemmaraju, Naveen; Lane, Andrew A; Sweet, Kendra L ...
New England journal of medicine/The New England journal of medicine,
04/2019, Letnik:
380, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit ...alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.
In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response.
Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.
In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).
The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most ...frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM).
In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively.
After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants.
The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.
Metreleptin, a recombinant analog of human leptin, is an approved therapy, adjunct to diet, to treat the metabolic complications of leptin deficiency in patients with lipodystrophy - a group of rare ...diseases characterized by a paucity of adipose tissue. MEASuRE (Metreleptin Effectiveness And Safety Registry) is a post-authorization, voluntary registry that gathers long-term safety and effectiveness data on metreleptin. Here, we present the aims and evolution of MEASuRE.
MEASuRE was established to collect data from patients receiving commercially supplied metreleptin in the United States (US) and European Union (EU). MEASuRE aims to determine the incidence and severity of safety events and describe the clinical characteristics and therapeutic outcomes in the metreleptin-treated population. A key feature of MEASuRE is that it accumulates data from different sources to meet post-authorization objectives. US data are received directly from treating physicians via a contract research organization-mediated electronic data capture system. In the EU, data are received via the European Registry of Lipodystrophies managed by the European Consortium of Lipodystrophies (ECLip), a platform established by researchers and physicians to advance the knowledge of lipodystrophy. MEASuRE complies with applicable regulatory requirements governing privacy, and the storage, management, and access of data.
Leveraging processes, infrastructure, and data from the ECLip registry presented several challenges that were addressed during MEASuRE's development, including the expansion of the ECLip registry to accommodate MEASuRE-specific data elements, extensive data matching processes to ensure data consistency regardless of source, and rigorous data validation following the amalgamation of global data. Through the support of ECLip, MEASuRE is now a fully operational registry with the capacity for gathering and integrating standardized US- and EU-derived data. As of 31st October 2022, 15 US and four EU sites have participated in the MEASuRE, enrolling 85 patients globally.
Our experiences show that a post-authorization product registry can be successfully integrated into an existing patient registry. We propose that, through collaboration with existing registries and use of their established resources, patient enrolment timelines and data collection for new registries can be expedited. The learnings presented here may be applicable to other registries with similar objectives.
NCT02325674; Registered 25 December 2014 - Retrospectively registered'. https://clinicaltrials.gov/ct2/show/NCT02325674 .
An inactivated cell-culture vaccine against yellow fever Monath, Thomas P; Fowler, Elizabeth; Johnson, Casey T ...
New England journal of medicine/The New England journal of medicine,
04/2011, Letnik:
364, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Yellow fever is a lethal viral hemorrhagic fever occurring in Africa and South America. A highly effective live vaccine (17D) is widely used for travelers to and residents of areas in which yellow ...fever is endemic, but the vaccine can cause serious adverse events, including viscerotropic disease, which is associated with a high rate of death. A safer, nonreplicating vaccine is needed.
In a double-blind, placebo-controlled, dose-escalation, phase 1 study of 60 healthy subjects between 18 and 49 years of age, we investigated the safety and immunogenicity of XRX-001 purified whole-virus, β-propiolactone-inactivated yellow fever vaccine produced in Vero cell cultures and adsorbed to aluminum hydroxide (alum) adjuvant. On two visits 21 days apart, subjects received intramuscular injections of vaccine that contained 0.48 μg or 4.8 μg of antigen. Levels of neutralizing antibodies were measured at baseline and on days 21, 31, and 42.
The vaccine induced the development of neutralizing antibodies in 100% of subjects receiving 4.8 μg of antigen in each injection and in 88% of subjects receiving 0.48 μg of antigen in each injection. Antibody levels increased by day 10 after the second injection, at which time levels were significantly higher with the 4.8-μg formulation than with the 0.48-μg formulation (geometric mean titer, 146 vs. 39; P<0.001). Three adverse events occurred at a higher incidence in the two vaccine groups than in the placebo group: mild pain, tenderness, and (much less frequently) itching at the injection site. One case of urticaria was observed on day 3 after the second dose of 4.8 μg of vaccine.
A two-dose regimen of the XRX-001 vaccine, containing inactivated yellow fever antigen with an alum adjuvant, induced neutralizing antibodies in a high percentage of subjects. XRX-001 has the potential to be a safer alternative to live attenuated 17D vaccine. (Funded by Xcellerex; ClinicalTrials.gov number, NCT00995865.).
Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A ...and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US.
The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period.
Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval CI lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity.
Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk.
NCT00216242.
Despite the eradication of smallpox as a naturally occurring disease, concern persists over its potential use as a bioterrorist agent. The development of a new-generation smallpox vaccine represents ...an important contribution to a cogent biodefense strategy. We conducted a phase 2 randomized, double-blind, controlled trial at four sites in the United States to determine whether a clonal smallpox vaccine manufactured in cell culture, ACAM2000, is equivalent to the standard calf-lymph vaccine, Dryvax
®, in terms of cutaneous response rate, antibody responses and safety. Subjects received either Dryvax
® or one of four dose levels of ACAM2000 administered percutaneously using a bifurcated needle. All subjects in the highest ACAM2000 dose group and the Dryvax
® group experienced a successful vaccination. Dilution doses of ACAM2000 were associated with success rates below the 90% threshold established for efficacy. There were no differences in the proportion of subjects who developed neutralizing antibody: 94% in the highest ACAM2000 dose group (95% CI, 84–99) and 96% in the Dryvax
® group (95% CI, 86–100). No significant differences were seen between the effective ACAM2000 and Dryvax
® groups regarding the occurrence of adverse events. One subject who received ACAM2000 developed myopericarditis. In healthy, primary vaccines ACAM2000 has a similar vaccination success rate, antibody response, and safety profile to Dryvax.
Because the exclusive source of sex steroids (at least estrogens) after menopause is recognized to be dehydroepiandrosterone (DHEA), this study examines the interindividual variability of serum DHEA ...and its metabolites as well as the contribution of the ovary to global sex steroid physiology in postmenopausal women.
Serum levels of DHEA and 11 of its metabolites were measured by gas or liquid chromatography/mass spectrometry in 442 intact and 71 ovariectomized postmenopausal women aged 42 to 74 years.
With a mean ± SD concentration of 2.03 ± 1.33 ng/mL, serum DHEA in intact postmenopausal women is highly variable with 5th and 95th centiles at 0.55 and 4.34 ng/mL, respectively, for a 7.9-fold difference. A comparable variability is observed for the 11 metabolites of DHEA. The 22.3% higher serum DHEA in intact compared with ovariectomized women is accompanied by parallel differences for all the other steroids, thus indicating that all sex steroids originate from circulating DHEA in postmenopausal women with no direct secretion of active estrogens or androgens by the postmenopausal ovary.
The 7.9-fold difference between low and high serum DHEA levels provides an explanation for the lack of signs of hormone deficiency in some women, whereas most of them have symptoms or signs. The approximately 20% contribution of the ovary to the total pool of DHEA with no direct secretion of estrogens or androgens in the circulation could possibly explain the reported negative effect of oophorectomy on longevity, especially from coronary heart disease events.
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