scholarly journals Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

2021 ◽  
Author(s):  
Nuria Carrillo ◽  
May C. Malicdan ◽  
Petcharat Leoyklang ◽  
Joseph A. Shrader ◽  
Galen Joe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Clinical Efficacy ◽  
Muscle Disease ◽  
Secondary Outcome ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Gne Myopathy ◽  
Open Label Phase

Abstract Purpose To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. Methods We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. Results Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. Conclusion ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

scholarly journals Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study

BMJ Open ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. e027665
Author(s):  
Faysal Dane ◽  
Kirhan Ozgurdal ◽  
Şuayib Yalçın ◽  
Mustafa Benekli ◽  
Nuri Faruk Aykan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Group Performance ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Open Label ◽  
Safety And Efficacy ◽  
Treatment Refractory ◽  
Grade 3

ObjectivesRegorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC.DesignOpen-label, single-arm, phase IIIb study conducted between July 2013 and April 2015.Setting11 tertiary centres in Turkey.ParticipantsEligible patients were adults with mCRC who had disease progression within 3 months after receiving their last dose of approved standard therapies and who had an Eastern Cooperative Oncology Group performance status ≤1. Patients were excluded if they had previously received regorafenib. Of 139 patients screened, 100 were treated and completed the study, and all 100 were analysed. Fifty-eight per cent were male.InterventionsPatients received oral regorafenib, 160 mg once daily, for the first 3 weeks of each 4-week cycle until disease progression, death or unacceptable toxicity.Primary and secondary outcome measuresThe primary endpoint was safety, assessed by incidence of treatment-emergent adverse events (TEAEs). Progression-free survival (PFS) per investigator was the primary efficacy endpoint. There were no secondary endpoints.ResultsThe median treatment duration was 2.5 months (range 0.1 to 20.6). Ninety-six per cent of patients had at least one TEAE and 77% had a grade ≥3 TEAE. The most common grade ≥3 regorafenib-related TEAEs were hypophosphataemia (11%), fatigue (8%), hyperbilirubinaemia (6%), hand–foot skin reaction (5%), hypertension (5%), anorexia (5%) and increased alanine aminotransferase (5%). TEAEs led to dose reduction in 30% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 17% of patients. Median PFS was 3.1 months (95% CI 2.9 to 3.8).ConclusionThe regorafenib safety profile and PFS in REGARD were consistent with the results of previous trials of regorafenib in mCRC. Regorafenib is an option for patients in Turkey with treatment-refractory mCRC.Trial registration numberNCT01853319, ClinicalTrials.gov.

Abstract #1219 Open-Label Phase 2 Study to Assess Safety and Efficacy Of Relacorilant (Cort125134), A Selective Cortisol Modulator, in the Treatment of Endogenous Hypercortisolism

2018 ◽  
Vol 24 ◽  
pp. 314-315
Author(s):  
Andreas Moraitis ◽  
Nidhi Agrawal ◽  
Irina Bancos ◽  
Francesco Celi ◽  
Murray Gordon ◽  
...  
Keyword(s):  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Phase 2 Study ◽  
Open Label Phase

Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 411-411 ◽  
Author(s):  
Yohann Loriot ◽  
Andrea Necchi ◽  
Se Hoon Park ◽  
Jesús García-Donas ◽  
Robert A Huddart ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Growth Factor Receptor ◽  
Phase 2 ◽  
Open Label ◽  
Significant Treatment ◽  
Improved Outcomes ◽  
Phase 2 Study ◽  
Open Label Phase

411 Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]

Interim safety analysis of the DANTE trial: Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma—A randomized, open-label phase II trial of the German Gastric Group at the AIO and SAKK.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4549-4549
Author(s):  
Nils Homann ◽  
Sylvie Lorenzen ◽  
Michael Schenk ◽  
Peter C. Thuss-Patience ◽  
Eray Goekkurt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Stage ◽  
Locally Advanced ◽  
Safety Analysis ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Phase

4549 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sep 2018; by Feb 2020, a total of 175 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 5% of the 40 patients (overall 7.4% of 175 pts enrolled) showed microsatellite instability. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: Perioperative atezolizumab plus FLOT is feasible and safe. The study continues recruitment. Clinical trial information: NCT03421288 .

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