scholarly journals Treat-to-target strategy with secukinumab as a first-line biological disease modifying anti-rheumatic drug compared to standard-of-care treatment in patients with active axial spondyloarthritis: protocol for a randomised open-label phase III study, AScalate

BMJ Open ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. e039059
Author(s):  
Denis Poddubnyy ◽  
Ludwig Hammel ◽  
Marvin Heyne ◽  
Justyna Veit ◽  
Claudia Jentzsch ◽  
...  
Keyword(s):  
Axial Spondyloarthritis ◽  
Treatment Options ◽  
Standard Of Care ◽  
Phase Iii ◽  
Treat To Target ◽  
Institutional Review Boards ◽  
Inadequate Response ◽  
First Line ◽  
Open Label ◽  
Disease Modifying

IntroductionIn patients with axial spondyloarthritis (axSpA), biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended to those with inadequate response or contraindications to non-steroidal anti-inflammatory drugs (NSAIDs). In case of failure of the first bDMARD, a switch within the class or to other bDMARD is recommended. Despite these treatment options, there is no optimal treat-to-target (T2T) strategy. This study aims to evaluate the efficacy of a T2T strategy in patients with axSpA, with secukinumab as a first-line bDMARD, compared with standard-of-care (SOC) treatment.Methods and analysesThis is a randomised, parallel-group, open-label, multicentre ongoing study in patients with axSpA who are naïve to bDMARD and who have had an inadequate response to NSAIDs. The study will include an 8-week screening period, a 36-week treatment period and a 20-week safety follow-up period. At baseline, patients will be randomised (1:1) to T2T or SOC group. In the T2T group, patients will be treated with secukinumab 150 mg subcutaneous (s.c.) weekly until week 4 and then at week 8. For non-responders (patients without Ankylosing Spondylitis Disease Activity Score [ASDAS] clinically important improvement; change from baseline ≥1.1) at week 12, dose will be escalated to 300 mg s.c. every 4 weeks until week 24. Non-responders at week 24 will be switched to adalimumab biosimilar 40 mg s.c. every 2 weeks until week 34. In the SOC group, patients will receive treatment at the discretion of the physician. The primary endpoint is the proportion of patients achieving an Assessment in SpondyloArthritis International Society 40% (ASAS40) response at week 24.Ethics and disseminationThe study is being conducted as per the ethical principles of the Declaration of Helsinki and after approval from independent ethics committees/institutional review boards. The first results are expected to be published in early 2022.Trial registration numberThis study is registered with ClinicalTrials.gov, NCT03906136.

First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4696-TPS4696
Author(s):  
Stephane Oudard ◽  
Lisa Sengelov ◽  
Paul N. Mainwaring ◽  
Antoine Thiery- Vuillemin ◽  
Christine Theodore ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Current Standard ◽  
Open Label ◽  
Measurable Disease ◽  
Ecog Ps

TPS4696^ Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients (pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models. Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts, designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first DMC meeting recommended continuing the study without change.

AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9633-TPS9633 ◽  
Author(s):  
Benjamin Besse ◽  
Enriqueta Felip ◽  
Corinne Clifford ◽  
Melinda Louie-Gao ◽  
Jennifer Green ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Survival Duration ◽  
First Line ◽  
Open Label ◽  
Eligibility Criteria ◽  
Multiple Tumor ◽  
Platinum Based Chemotherapy

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .

scholarly journals Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial

2018 ◽  
Vol 36 (30) ◽  
pp. 3031-3039 ◽  
Author(s):  
Shukui Qin ◽  
Jin Li ◽  
Liwei Wang ◽  
Jianming Xu ◽  
Ying Cheng ◽  
...  
Keyword(s):  
Survival Time ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
End Points ◽  
Phase Iii Trial ◽  
Free Survival

Purpose Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. Patients and Methods TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt ( KRAS/ NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. Results In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. Conclusion The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.

scholarly journals A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naïve patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial

2019 ◽  
Vol 79 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Philip J Mease ◽  
Josef S Smolen ◽  
Frank Behrens ◽  
Peter Nash ◽  
Soyi Liu Leage ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Psoriatic Arthritis ◽  
Treat To Target ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Open Label ◽  
Disease Modifying ◽  
Blinded Assessor ◽  
Disease Modifying Antirheumatic Drug

ObjectivesTo compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).MethodsPatients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24.ResultsThe primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients.ConclusionsIXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 543-543 ◽  
Author(s):  
Thomas Powles ◽  
Elizabeth R. Plimack ◽  
Viktor Stus ◽  
Rustem Airatovich Gafanov ◽  
Robert E. Hawkins ◽  
...  
Keyword(s):  
Clear Cell ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Geographic Region ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

543 Background: A phase 1b study of pembro (anti–PD-1) plus axi (VEGFR-TKI) showed promising antitumor activity and manageable safety in patients (pts) with previously untreated mRCC. The global, open-label, phase 3 KEYNOTE-426 study assessed the efficacy and safety of pembro + axi vs sunitinib as first-line therapy for mRCC (NCT02853331). Methods: Eligible pts with clear-cell mRCC, no previous systemic therapy for mRCC, and KPS ≥70% were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID or sunitinib 50 mg orally QD (4-wk on/2-wk off schedule). Treatment was given until PD, intolerable toxicity, or pt/investigator decision. Randomization was stratified by IMDC risk group and geographic region. Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR was the key secondary endpoint. At the protocol-specified first interim analysis, the superiority thresholds were P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS and PFS were significant). Results: 861 pts were randomized: 432 to pembro + axi, 429 to sunitinib. After a 12.8-mo median follow-up, 59.0% of pts in the pembro + axi arm and 43.1% in the sunitinib arm remained on treatment. Pembro + axi significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P < 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P < 0.0001). Duration of response was prolonged with pembro + axi (median not reached vs 15.2 mo). The pembro + axi benefit was observed in all subgroups tested, including all IMDC risk and PD-L1 expression subgroups. Treatment-related AEs were grade 3-5 in 62.9% of pts in the pembro + axi arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%. Conclusions: Pembrolizumab + axitinib provided superior OS, PFS, and ORR compared with sunitinib and had manageable safety in pts with previously untreated, advanced or metastatic clear-cell RCC. These data suggest that pembrolizumab + axitinib should be a new standard of care for this population. Clinical trial information: NCT02853331.

scholarly journals Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

2021 ◽  
Vol 13 ◽  
pp. 175883592110311
Author(s):  
Chiun Hsu ◽  
Lorenza Rimassa ◽  
Hui-Chuan Sun ◽  
Arndt Vogel ◽  
Ahmed O. Kaseb
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Healthcare Providers ◽  
Safety Data ◽  
Standard Of Care ◽  
Antiangiogenic Agents ◽  
Efficacy And Safety ◽  
First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

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