An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: A three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

2011 ◽  
Vol 63 (2) ◽  
pp. 337-345 ◽  
Author(s):  
Mark C. Genovese ◽  
Arthur Kavanaugh ◽  
Michael E. Weinblatt ◽  
Charles Peterfy ◽  
Julie DiCarlo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Phase Ii ◽  
Active Rheumatoid Arthritis ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Biologic Agents ◽  
Syk Kinase

scholarly journals Efficacy and safety of levilimab in combination with methotrexate in subjects with rheumatoid arthritis: Results of phase II AURORA study

2021 ◽  
Vol 59 (2) ◽  
pp. 141-151
Author(s):  
V. I. Mazurov ◽  
E. G. Zotkin ◽  
I. Z. Gaydukova ◽  
E. P. Ilivanova ◽  
T. V. Kropotina ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Phase Ii ◽  
Safety Assessment ◽  
Active Rheumatoid Arthritis ◽  
Phase Ii Study ◽  
Interleukin 6 Receptor ◽  
Effect Difference ◽  
Antidrug Antibodies ◽  
Low Activity

Levilimab (LVL) is a monoclonal antibody against the interleukin-6 receptor (IL6R). The article presents data obtained during 56 weeks of the AURORA phase II study.Objective: to evaluate the efficacy safety and immunogenicity of LVL in methotrexate (MTX) resistant patients with active rheumatoid arthritis (RA).Materials and methods. 105 patients with active RA were randomized in a 1:1:1 ratio into two LVL or placebo groups. LVL was administered subcutaneously at a dose of 162 mg every week (QW) or every other week (Q2W). All patients received MTX. After evaluating the primary endpoint of 20% improvement in ACR criteria (ACR20) at week 12, patients in the placebo group were switched to LVL Q2W. The study duration was 56 weeks. The frequency, profile, degree and severity of adverse events were determined in each group for safety assessment. The immunogenicity of LVL was determined by the proportion of patients with identified binding and neutralizing antidrug antibodies. Results. LVL in both regimens was superior to placebo. At week 12, the incidence of ACR20 achievement was 77.1% (LVL QW), 57.1% (LVL Q2W), and 17.1% (placebo) with 95% confidence intervals [37.53; 82.54] (p<0.0001) and [19.08; 68.42] (p=0.003) for the effect difference between LVL and placebo groups. The clinical response, more pronounced in the LVL QW group, persisted until week 52 with an increase in the proportion of patients with ACR50/70, low activity and RA remission. The most common treatment-related adverse events were laboratory abnormalities (predominantly grade 1–2) such as neutropenia, elevated alanine aminotransferase, aspartate aminotransferase levels, hypercholesterolemia, and elevated triglyceride levels. Antidrug antibodies were not identified.Conclusion. In MTX-resistant patients with active RA, the efficacy of both LVL regimens at a dose of 162 mg in combination with MTX was significantly superior to MT monotherapy. LVL QW lead to highest treatment response. LVL has been shown to be well tolerated and low immunogenicity. LVL safety profile is similar to IL6R inhibitors.

scholarly journals NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii419-iii419
Author(s):  
Sheetal Phadnis ◽  
Mari Hagiwara ◽  
Anna Yaffe ◽  
Carole Mitchell ◽  
Theodore Nicolaides ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas ◽  
Volumetric Response

Abstract INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group

2007 ◽  
Vol 25 (22) ◽  
pp. 3296-3301 ◽  
Author(s):  
Christopher W. Ryan ◽  
Bryan H. Goldman ◽  
Primo N. Lara ◽  
Philip C. Mack ◽  
Tomasz M. Beer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Renal Carcinoma ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Interferon Alfa

Purpose This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma. Patients and Methods Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 × 106 U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate. Results Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens. Conclusion The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191

2015 ◽  
Vol 57 (6) ◽  
pp. 1463-1466 ◽  
Author(s):  
Annette E. Hay ◽  
Alli Murugesan ◽  
Ashley M. DiPasquale ◽  
Tom Kouroukis ◽  
Irwindeep Sandhu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Refractory Multiple Myeloma

A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma (mRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4529-4529 ◽  
Author(s):  
P. H. De Mulder ◽  
J. Roigas ◽  
S. Gillessen ◽  
S. Srinivas ◽  
P. Pisa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Colon Perforation ◽  
Efficacy Data ◽  
Significant Difference ◽  
Hand Foot Syndrome

4529 Background: Renal cell carcinomas are known for their vascularity and production of high levels of VEGF. Sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor of multiple receptors including VEGFR, PDGFR, KIT, RET, and FLT3, has previously demonstrated significant efficacy in 168 patients (pts) with mRCC, with a 42% objective response rate (ORR) at 50 mg/day in 6-week (wk) cycles of 4 wks on treatment followed by 2 wks off. This study sought to determine the efficacy and safety of single-agent sunitinib in mRCC when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints includedprogression-free survival, adverse events (AEs) and quality of life measures. Results: A total of 88/100 planned pts have been randomized to date: AM (43) and PM (45), and enrollment will be completed by end January 2006. 44 pts have been on continuous sunitinib treatment at 37.5 mg/day for >16 wks (3), >12 wks (9), >8 wks (12), and >4 wks (20). 2 pts (2.3%) discontinued (colon perforation and renal insufficiency) and 9 (10.2%) dose reduced to 25 mg/day due to grade 2/3 AEs: mucositis (2), hand-foot syndrome (2), thrombocytopenia (2), asthenia (1), nausea/diarrhea (1), and neutropenia (1). Preliminary efficacy data show some tumor shrinkage in the majority of patients evaluated at 4 wks, with 3 initial partial responses. There has been no significant difference between pts who received AM or PM doses. The most commonly reported AEs were mucositis, fatigue, hair/skin discoloration, and hand-foot syndrome. Conclusions: Sunitinib administered at a continuous dose of 37.5 mg/day was generally well tolerated; only a few patients required treatment breaks and/or dose reduction. Preliminary efficacy data are encouraging. Mature data will be presented. [Table: see text]

A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5576-5576
Author(s):  
S. Welch ◽  
H. J. Mackay ◽  
H. Hirte ◽  
G. F. Fleming ◽  
R. Morgan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Second Stage ◽  
Best Response ◽  
Grade 3 ◽  
Ecog Ps

5576 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free > 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in >10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving <2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC. [Table: see text]

Phase II study of efficacy of bevacizumab and erlotinib in inoperable previously untreated hepatocellular carcinoma (HCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15557-e15557
Author(s):  
R. Govindarajan ◽  
E. Siegel ◽  
I. Makhoul ◽  
S. Williamson
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Synergistic Activity ◽  
Time To Progression ◽  
Class A ◽  
Pugh Class

e15557 Background: New treatment options are needed for patients with inoperable and metastatic HCC. Sorafenib, a RAF kinase inhibitor, prolongs the time to progression and overall survival compared to best supportive care (5.5 and 10.7 months respectively). Angiogenesis plays important role in the development and progression of HCC. Erlotinib, an EGFR tyrosine kinase inhibitor that down-regulates expression of Vascular Endothelial Growth Factor (VEGF), and bevacizumab, a monoclonal anti-VEGF antibody, have synergistic activity in arresting angiogenesis. The objective of the study was designed to evaluate the efficacy of the combination of bevacizumab and erlotinib. The pre-determined endpoint for a positive result is a 27 week PFS of > 20%. Methods: A phase II study was conducted for newly diagnosed unresectable or metastatic HCC, Child-Pugh class A or B cirrhosis with bilirubin <2.0 mg/dL, transaminases < 5 x ULN, Platelet count >75,000 K/UL and ECOG PS 0–2 who had no prior systemic therapy and were not candidates for liver transplantation. Erlotinib was administered continuously at a daily dose of 150 mg, and bevacizumab was administered at a dose of 15 mg/kg intravenously every three weeks. Subjects were evaluated for disease progression by RECIST criteria. Results: At the time of analysis, 21 subjects were enrolled (16 Child- Pugh class A, 5 class B). 16 were evaluable. The median age was 60 Yrs.(range 33–81). Four subjects (27%) were progression-free at 27 weeks of enrollment (95% CI 8%- 55%). Median (quartiles) time to progression was 10.3 (9.0–57.1) weeks. The median (quartiles) overall survival (OS) was 59.7 (range 24.6- 92.6) weeks. Grade-3 events observed were (no.): fatigue (4), dehydration (2), hematemesis (1), diarrhea (1), nausea (1), and dyspnea (1). Grade-4 events (no.) observed were: myocardial infarction (1), atrial fibrillation (1), and ventricular tachycardia (1); pulmonary edema (1). Conclusions: The results met the predetermined study end point of progression free survival at 27 weeks of > 20%. The combination of bevacizumab and erlotinib should be further evauated as treatment option for patients with HCC. [Table: see text]

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