Cetuximab with or without sorafenib in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6047-6047 ◽  
Author(s):  
Jill Gilbert ◽  
Michael J. Schell ◽  
Xiuhua Zhao ◽  
Barbara A. Murphy ◽  
Tawee Tanvetyanon ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Infusion Reaction ◽  
Study Endpoint ◽  
Controlled Study ◽  
Primary Study ◽  
Clinical Activity ◽  
Patients Âgés ◽  
Significant Difference ◽  
The Mean

6047 Background: For patients with R/M SCCHN, cetuximab, a monoclonal antibody against EGFR, is approved as a single agent and has a survival benefit when combined with chemotherapy. We hypothesized that addition of sorafenib, a multi-kinase inhibitor of targets including VEGFR, to cetuximab may have greater clinical benefit than cetuximab alone. Methods: This trial was designed as a blinded, randomized phase II, placebo-controlled study of cetuximab at 400 mg/m2 IV on day 1 followed by 250 mg/m2 IV weekly plus placebo bid (Arm A) or cetuximab at the same dose and schedule plus sorafenib 400 mg po bid (Arm B), each in 21 day cycles. After 19 patients were enrolled, the trial was amended to remove the placebo (and blinding) due to issues with placebo tablet solubility. Target sample size was 84 patients with 83% power to detect a 2-month increase in PFS, the primary study endpoint. Interim analysis was planned at midpoint, requiring hazard ratio < 1 to proceed to the second stage of study. Serum cytokine and tumor HPV ISH and p16 analyses were performed. Results: Of 56 patients (ages 26-74, 80% male) enrolled, 53 patients received treatment and 41 were evaluable for response. Of the patients who received therapy, 26 received cetuximab only (Arm A). For Arm A, the mean number of cycles delivered was 4.3 (range 1-16) and the mean for Arm B was 3.3 (range 1-11). The most common grade 3/4 AEs were fatigue (2 A, 1 B), hypertension (3 B), infusion reaction (both arms), and diarrhea (2 B). Arm A had 2 PRs and Arm B had 4 PRs. Median OS was 7 mo and 5.9 mo respectively. Median PFS was 3.1 mo for both arms. 24 patients had pre-treatment cytokine measurements. Of the 12 measured cytokines, high TGFB1 level was significantly correlated with inferior PFS (4.6 mo vs 1.6 mo), regardless of arm (p=0.015). 38 patients had tumors available for p16 staining (31 neg and 7 pos). 3 of 7 p16 pos were also HPV ISH pos. The p16 neg patients had significantly improved PFS (3.5 mo vs 1.6 mo) regardless of arm (p=0.032) but no difference in OS (p=1.0). Conclusions: Both arms demonstrated clinical activity although no significant difference was observed. However, a subset of patients with p16 neg tumors or low serum TGFB1 may have a greater benefit with cetuximab-based therapy. Clinical trial information: NCI-2012-02847.

Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV no squamous non-small cell lung cancer (NSCLC) (STELLA study): Results for the primary endpoint in a confirmatory, double-blind, randomized, controlled study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21542-e21542
Author(s):  
Susana Millan ◽  
Dmytro Trukhin ◽  
Oleksii Kolesnik ◽  
Elena Poddubskaya ◽  
Andric Zoran ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Objective Response ◽  
Stage Iiib ◽  
Study Endpoint ◽  
Controlled Study ◽  
Primary Study ◽  
Double Blind ◽  
Study Results ◽  
Significant Difference ◽  
Secondary Endpoints

e21542 Background: MB02 is a proposed biosimilar of the reference bevacizumab. A multinational, double-blind, randomized, parallel group clinical study (STELLA) is undergoing to confirm clinical similarity between MB02 and bevacizumab in patients with stage IIIB/IV no squamous NSCLC. Methods: Subjects were randomized 1:1 to MB02 or bevacizumab (15 mg/kg) plus chemotherapy (paclitaxel [P] 200 mg/m2 and carboplatin [C] AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (Week 52). As primary study endpoint, the efficacy by means of the objective response rate (ORR) evaluated by an independent radiological committee (IRC) was compared between arms at Week 18. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS), safety and immunogenicity (assessed at 18 and 52 weeks). Results: 627 patients were randomized: MB02 (n = 315) and bevacizumab (n = 312). Demographic and baseline characteristics were well balanced between arms. The ORR results were comparable for subjects receiving MB02 or bevacizumab plus P/C. A Risk Ratio (RR) of 1.013 (90% CI: -0.037% to 0.059) and a Risk Difference (RD) of 0.011 (90% CI: -0.037% to 0.059), were within the similarity margin predefined by FDA (0.73, 1.36) and EMA (-12%, +12%) respectively. This ORR assessed by IRC was consistent with the investigator assessment criteria. There was no significant difference between arms for secondary efficacy endpoints (PFS/OS) at week 18. Up to primary endpoint cut-off point, the safety assessment showed no significant differences between MB02 and bevacizumab arms (including the immunogenicity assessment) in terms of nature, frequency and severity of the adverse events (AE), being anaemia and hypertension the most common IMP-related AEs, with a RD between treatment groups < 5%. New signals or observable trends were no reported for MB02-treated subjects. Additional information on the secondary endpoints will be available at week 52 (end of monotherapy period). Conclusions: The statistical analysis executed for ORRs confirm the equivalence of MB02 and bevacizumab, supporting the clinical activity of MB02 treatment. MB02 was well tolerated with manageable AEs in patients with Stage IIIB/IV NSCLC. Clinical trial information: NCT03296163.

Efficacy and Tolerability of Amitriptylinoxide in the Treatment of Chronic Tension-Type Headache: A Multi-Centre Controlled Study

Cephalalgia ◽  
1994 ◽  
Vol 14 (2) ◽  
pp. 149-155 ◽  
Author(s):  
V Pfaffenrath ◽  
H-C Diener ◽  
H Isler ◽  
C Meyer ◽  
E Scholz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tension Type Headache ◽  
Study Endpoint ◽  
Controlled Study ◽  
Primary Study ◽  
Chronic Tension Type Headache ◽  
Headache Intensity ◽  
Primary Study Endpoint ◽  
Significant Difference ◽  
Type Headache

Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 ±13 (18–68)) efficacy and tolerability of 60–90 mg amitriptylinoxide (AO) were compared with 50–75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity ( p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO. Adverse events occurred in 75.8% on AO, 82.1% on AM and 76.6% on PL (PAO-PL = 1.000, PAM-PL =.5188, PAO-AM = .4017). Neither depressive symptoms, measured by the SCL-90-R, nor study drug-related adverse events had any influence on the results.

scholarly journals Mortality after cardiopulmonary resuscitation on a medical ICU

2021 ◽  
Author(s):  
Richard Rezar ◽  
Bernhard Wernly ◽  
Michael Haslinger ◽  
Clemens Seelmaier ◽  
Philipp Schwaiger ◽  
...  
Keyword(s):  
Cardiopulmonary Resuscitation ◽  
Neurological Outcome ◽  
Cox Regression ◽  
Cerebral Performance Category ◽  
Hospital Length ◽  
Hospital Length Of Stay ◽  
Study Endpoint ◽  
Primary Study ◽  
Postresuscitation Care ◽  
Significant Difference

Summary Background Performing cardiopulmonary resuscitation (CPR) and postresuscitation care in the intensive care unit (ICU) are standardized procedures; however, there is evidence suggesting sex-dependent differences in clinical management and outcome variables after cardiac arrest (CA). Methods A prospective analysis of patients who were hospitalized at a medical ICU after CPR between December 2018 and March 2020 was conducted. Exclusion criteria were age < 18 years, hospital length of stay < 24 h and traumatic CA. The primary study endpoint was mortality after 6 months and the secondary endpoint neurological outcome assessed by cerebral performance category (CPC). Differences between groups were calculated by using U‑tests and χ2-tests, for survival analysis both univariate and multivariable Cox regression were fitted. Results A total of 106 patients were included and the majority were male (71.7%). No statistically significant difference regarding 6‑month mortality between sexes could be shown (hazard risk, HR 0.68, 95% confidence interval, CI 0.35–1.34; p = 0.27). Neurological outcome was also similar between both groups (CPC 1 88% in both sexes after 6 months; p = 1.000). There were no statistically significant differences regarding general characteristics, pre-existing diseases, as well as the majority of clinical and laboratory parameters or measures performed on the ICU. Conclusion In a single center CPR database no statistically significant sex-specific differences regarding post-resuscitation care, survival and neurological outcome after 6 months were observed.

scholarly journals THU0521 EVALUATION OF LIVER FIBROSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS UNDER METHOTREXATE TREATMENT. UTILITY OF FIBROSCAN AND BIOMARKERS IN ROUTINE CLINICAL PRACTICE.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 499.2-500
Author(s):  
A. De Diego Sola ◽  
M. Vaamonde Lorenzo ◽  
A. Castiella Eguzkiza ◽  
M. J. Sánchez Iturri ◽  
N. Alcorta Lorenzo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Metabolic Syndrome ◽  
Liver Fibrosis ◽  
Controlled Study ◽  
Type I ◽  
Concomitant Treatment ◽  
Duration Of Treatment ◽  
Significant Difference ◽  
Apri Score ◽  
The Mean

Background:Despite therapeutic advances in recent years, methotrexate (MTX) remains the gold standard for the treatment of rheumatoid arthritis (RA). Among the side effects that have been blamed on it are liver fibrosis (LF) and cirrhosis, although late studies have failed to show such a relation1,2. The only validated test in the diagnosis of LF is biopsy. Given the relevance of MTX in the treatment of RA, it is important to evaluate non-invasive diagnostic options for LF such as transitional elastography (FibroScan, FS).Objectives:To evaluate the percentage of LF in RA patients treated with MTX. Secondly, to assess the correlation between altered liver function, RA activity, and LF. To determine whether dose and/or duration of treatment with MTX may affect the development of LF in such patients.Methods:We did a prospective study between February 2019 and January 2020. Patients affected of RA treated with MTX were included. Patients with basal liver disease (hepatitis B, hepatitis C and steatohepatitis), alcohol consumption, type I diabetes mellitus, chronic renal failure, heart failure, obesity and concomitant treatment with leflunomide or antiretrovirals were excluded. Demographic, clinical, analytical and therapeutic variables were collected. Liver fibrosis was assessed by FS in kilopascals (kpa) and using the APRI score. RA activity was assessed by DAS28 score. Continuous variables are described with mean and standard deviation (SD), and qualitative variables are shown with absolute value and percentage. Spearman’s and Mann-Whitney’s U tests were used for the bivariate analysis.Results:Fifty patients were included (Table 1 and 2). Of these, 38 were women (76%) with mean age of 61.8 years (SD 11.7) and mean RA evolution time of 13.7 years (SD 8.2). The mean DAS28 at the visit was 2.39 (SD 1.1). The FS showed an average of 4.8 kpa (SD 2). The mean duration of treatment with MTX was 85.8 months (SD 93.3) and that of AD-MTX was 5414.6mg (SD 5011). Patients were divided into those with DA-MTX greater than 4000mg (21, 42%) and less than 4000mg (29, 58%) and no significant differences were found in terms of LF in FS (p 0.637) or APRI scale (p 0.806). No significant differences were found in terms of treatment duration either. Six patients (12%) had elevated aspartate aminotransferase (AST) and 9 (18%) had elevated alanine aminotransferase (ALT). No significant difference was found in FS values in relation to ALT, but it was with elevated AST (p 0.021). Similarly, differences were found in APRI based on AST (p 0.045). Metabolic syndrome was collected in 4 patients (8%) without significant differences with FS or APRI values. There were no significant differences in LF depending on gamma-glutamyl transpeptidase (GGT) values.Conclusion:FS and APRI score are useful for the determination of LF in RA patients treated with MTX. There is no evidence of a relationship between AD-MTX and LF by FS or APRI. AST values may be related to the presence of fibrosis as determined by FS or APRI. and the presence of the metabolic syndrome are not.References:[1]G.L. Erre, et al. Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography. European Journal of Internal Medicine 69 (2019) 57–63. Internet.[2]R. Conway et al. Risk of liver injury among methotrexate users: a meta-analysis of randomised controlled trials. Semin Arthritis Rheum 2015 Oct;45(2):156–62. Internet.Disclosure of Interests:None declared

scholarly journals Osteoarthritis Severely Decreases the Elasticity and Hardness of Knee Joint Cartilage: A Nanoindentation Study

2019 ◽  
Vol 8 (11) ◽  
pp. 1865 ◽  
Author(s):  
Mieloch ◽  
Richter ◽  
Trzeciak ◽  
Giersig ◽  
Rybka
Keyword(s):  
Elastic Modulus ◽  
Articular Cartilage ◽  
Weight Bearing ◽  
Patients Âgés ◽  
Low Weight ◽  
Starting Point ◽  
Significant Difference ◽  
The Mean ◽  
Grade 3 ◽  
Insight Into

The nanoindentation method was applied to determine the elastic modulus and hardness of knee articular cartilage. Cartilage samples from both high weight bearing (HWB) and low weight bearing (LWB) femoral condyles were collected from patients diagnosed with osteoarthritis (OA). The mean elastic modulus of HWB cartilage was 4.46 ± 4.44 MPa in comparison to that of the LWB region (9.81 ± 8.88 MPa, p < 0.001). Similarly, the hardness was significantly lower in HWB tissue (0.317 ± 0.397 MPa) than in LWB cartilage (0.455 ± 0.434 MPa, p < 0.001). When adjusted to patients’ ages, the mean elastic modulus and hardness were both significantly lower in the age group over 70 years (p < 0.001). A statistically significant difference in mechanical parameters was also found in grade 3 and 4 OA. This study provides an insight into the nanomechanical properties of the knee articular cartilage and provides a starting point for personalized cartilage grafts that are compatible with the mechanical properties of the native tissue.

scholarly journals P1481STRAIN REPOLARISATION ON ECG, NOT LEFT VENTRICULAR MASS, ASSOCIATES WITH CARDIOVASCULAR OUTCOMES IN A PROSPECTIVE COHORT OF HAEMODIALYSIS PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sofia Skampardoni ◽  
Diana Y Y Chiu ◽  
Philip A Kalra ◽  
Darren Green
Keyword(s):  
Regression Analysis ◽  
Cox Regression ◽  
Final Analysis ◽  
Left Ventricular ◽  
Study Endpoint ◽  
Primary Study ◽  
Cardiac Events ◽  
Cox Regression Analysis ◽  
Maintenance Haemodialysis ◽  
The Mean

Abstract Background and Aims Cardiovascular disease is common in chronic and end stage kidney disease. Left ventricular hypertrophy (LVH) has been identified as contributor to cardiovascular risk in this population. The aim of the study was to assess whether the combined use of electrocardiography and echocardiography in assessing LVH in a haemodialysis population can provide improved risk stratification. Method Prospective study of 192 prevalent maintenance haemodialysis ( HD) patients 12 lead ECGs were performed on a mid week non –dialysis day. Electrocardiographic strain was defined as a down slopping convex ST segment with inverted T waves in leads V5 and / or V6. Transthoracic echocardiographic was performed immediately after ECG .LV mass was indexed to body surface area (LVMIBSA). LVH was determined if LVMI &gt;116g/m2 for male patients, and &gt;100g/m2 for female patients. The primary study endpoint was major cardiac events (MACE). A secondary endpoint was all cause mortality. Results 192 patients included in the final analysis, 137 (71.4%) male.. The mean ejection fraction (EF) was 60.6± 11.1 % and the mean LVMI (BSA) was 115.0± 36.8 g/m2. During a mean follow up period of 2.4 ± 1.0 years, 50 patients reached a MACE end point and 62 patients died. On univariate Cox regression analysis, the factors associated with MACE were the presence of ECG strain (HR 2.961, CI: 1.254 – 6.990, p= 0.013)) URR (HR 0.968, CI: 0.942 – 0.994, p=0.015) and history of CAD (HR: 2.397 CI: 1.363 -4.2515, p= 0.002). In multivariate Cox regression analysis adjusting for baseline cardiovascular phenotype and dialysis parameters ECG strain remained significantly associated with MACE. Conclusion The presence of electrocardiographic strain increases the risk for MACE independently of LVH in haemodialysis patients. ECG strain has potential to be a simple bedside prognostic biomarker and even therapeutic target in haemodialysis patients.

scholarly journals Comparative Study of 0.2% Glyceryl Trinitrate Ointment for Pain Reduction after Hemorrhoidectomy Surgery

2019 ◽  
Vol 05 (04) ◽  
pp. e192-e196 ◽  
Author(s):  
Sepideh Vahabi ◽  
Siavash Beiranvand ◽  
Arash Karimi ◽  
Mahmoudreza Moradkhani
Keyword(s):  
Glyceryl Trinitrate ◽  
Controlled Study ◽  
Analog Scale ◽  
Double Blind ◽  
Mean Values ◽  
Analgesic Effects ◽  
Total Pain ◽  
Significant Difference ◽  
The Mean ◽  
Glyceryl Trinitrate Ointment

Abstract Context Hemorrhoid is one of the most common diseases in both, men and women, affecting half of the world's population over the age of 50. Aims The aim of this study was to evaluate the analgesic effects of local ointment of glyceryl trinitrate ointment (GTN) after hemorrhoidectomy. Methods and Materials In this randomized double-blind, placebo-controlled study, the patients were grouped as the treatment, that is GTN, and placebo (P) group. After surgery, 0.2% gelatin GTN ointment (250 mg), and P ointment (n = 20 for each group) were applied topically on 1 cm on the anus using a standard ruler, three times a week in respective groups. visual analog scale was used to assess the intensity of the pain and complications of the drugs were observed at 6, 12, 18, and 24 hours. Statistical Analysis Used Data and questionnaires were analyzed statistically using SPSS17 software and results were recorded in the tabular form. Results Six hours after the application of the ointment, no significant difference was found among the groups, however, after 12, 18, and 24 hours significant reduction in pain was seen in GTN group, which was least after 18 hours. The mean values of the total pain score in the first 24 hours after surgery in the GTN group were 3.15 and 5.45 in the P group which were statistically significant. Nonetheless, headache was significantly increased in the GTN group. Conclusion Simple and safe topical GTN ointment can reduce the pain after hemorrhoidectomy, leading to the reduced need of other analgesics.

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

Combination of Sorafenib, Idarubicin, and Cytarabine Has a High Response Rate in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Younger Than 65 Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Response Rate ◽  
Clinical Activity ◽  
Mutation Burden

Abstract Background: Sorafenib is an orally active multi-kinase inhibitor with potent activity against the Raf/ERK/MEK pathway, VEGFR, PDGFR-β, and c-KIT. In vitro, it has growth-inhibitory effects in several AML cell lines with or without constitutive activation of ERK signaling. Sorafenib selectively induces cell growth arrest and apoptosis in FLT3-mutant human AML cell lines at nM concentrations. In a phase I study of single agent sorafenib in patients (pts) with AML escalating doses were well tolerated with no myelosuppression and with significant clinical activity predominantly (but not exclusively) in FLT3 mutated pts. Methods: This study was conducted to determine the tolerability and efficacy of combination of sorafenib with cytarabine 1.5 g/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and idarubicin 12 mg/m2 iv daily × 3. In the phase I portion of study, pts with relapsed AML were treated with escalating doses of sorafenib po (400 mg qod, 400 mg daily and 400 mg bid) for 7 days during induction, and 400 mg bid was established as a safe dose for phase II evaluation. Pts achieving CR receive up to 5 courses of consolidation with idarubicin 8 mg/m2 iv daily × 2 and cytarabine 0.75 g/m2 iv daily × 3 in addition to continuous sorafenib 400 mg po bid for up to 28 days per cycle. Maintenance with sorafenib 400 mg bid would continue for up to a year after consolidation. Results: Ten pts (median age 34 years, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated on the phase I portion. Seven had FLT3-ITD mutation (5 with high mutation burden, 2 with low), and 3 were negative. Four achieved CR, and 6 failed. In the phase II portion, 30 pts (including 8 with FLT3-ITD and 2 with FLT3-TKD) have been treated. Median age is 53 years (range 18 – 65) Cytogenetics were diploid in 13, +8 in 3, −5/−7 in 3, t(9;11) in 1, miscellaneous in 6, and unavailable in 4. The median presentation WBC was 4.6 × 109/L (range 1.5 –122.7 × 109/L). FLT3 mutation burden was low in blasts from 4 pts, and high in 6). Five pts were FLT3-ITD+/NPM1-. Among 25 evaluable pts, 22 (88%) have achieved CR (n=19), or CRi (n=3); 1 achieved PR, 1 died at induction from pneumonia, 1 was resistant; 5 pts are too early. The regimen is well tolerated and grade 3 adverse events thought to be possibly related to the study combination have included elevation of transaminases (3), hyperbilirubinemia (4), small bowel obstruction (1), diarrhea (2), rash (2), pericarditis (1), elevated creatinine (1), and atrial fibrillation (1). Median follow-up is 8 weeks (range, 1 – 28) with the probability of survival at 6 months of 87%; 2 pts have relapsed with CR durations of 2 and 3 months. Samples from 8 pts were studied prior to and 24–48 hours post sorafenib administration, and prior to chemotherapy. In six pts (75%), sorafenib alone induced apoptosis in peripheral blood blasts and in CD33/CD34 positive leukemia progenitor cells as determined by flow cytometry. Expression of phospho-ERK (pERK) was detectable by flow cytometry in 5 out of 7 samples tested at baseline; 24-hour exposure to sorafenib resulted in >50% downregulation of pERK in 3 of the 5 samples. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all samples with 5-fold more potent suppression against mutant versus wildtype FLT3. Conclusions: Combination of sorafenib with idarubicin and cytarabine is safe and has a high CR rate in frontline therapy of younger pts with AML. Correlative studies confirm potent activity of sorafenib against ERK and FLT3 signaling.

Flavopiridol Treatment of Patients Aged 70 or Older with Refractory or Relapsed Chronic Lymphocytic Leukemia Is Feasible and Not Associated with Adverse Outcome When Compared to Younger Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1378-1378
Author(s):  
Deborah M Stephens ◽  
Amy S. Ruppert ◽  
Kristie A. Blum ◽  
Jeffrey A. Jones ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Age Groups ◽  
Lymphocytic Leukemia ◽  
Cyclin Dependent Kinase ◽  
Complex Karyotype ◽  
Younger Patients ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Significant Difference

Abstract Abstract 1378 Although the most rapidly growing portion of the United States population is the elderly (Yancik R and Ries L, Semin Oncol 2004), they are consistently underrepresented in cancer clinical trials (Hutchins L et al, N Engl J Med 1999). The incidence of chronic lymphocytic leukemia (CLL) is markedly increased in older people, with a median age at diagnosis of 72 years (Ries L et al, SEER Clinical Statistics Review 2008). In contrast, an age range of between 58 and 66 years has been noted in patients (pts) enrolled in key trials to evaluate the first-line treatment for CLL (Eichhorst B et al, Leuk Lymphoma 2009). Both fludarabine and chemoimmunotherapy with rituximab have not demonstrated much promise in the older subset of patients. Developing new therapeutics that have clinical benefit and also demonstrate feasibility of administration to this patient population is of great interest. Flavopiridol, is a pan-cyclin-dependent kinase inhibitor, that has demonstrated significant clinical activity in relapsed and refractory CLL pts including those with del(17p13.1)(Christian B et al, Clin Lymphoma Myeloma 2009). We sought to determine the feasibility and impact of treating patients over the age of 70 with flavopiridol by reviewing outcomes of two clinical trials using single-agent flavopiridol in patients with relapsed or refractory CLL at our institution (Byrd J et al, Blood 2007; Lin T et al, J Clin Oncol 2009). Pts were divided into categories based on age [≥70 years old (n = 21) and <70 years old (n = 95)]. Of the 21 pts aged 70 or older, all but one (95%) presented with Rai Stage III/IV compared with 76% of the younger pts (<70 years old; P = 0.07). Older age was also associated with complex karyotype (63% vs. 37%; P = 0.04). No significant difference was observed in response rates, with 43% of older pts achieving response vs. 47% of younger pts (P = 0.81). The estimated median progression free survival (PFS) for both age groups was 0.8 years (P = 0.9). In multivariable analyses, there remained no significant differences in response rates or PFS when controlling for treatment schedule, Rai stage and presence of complex karyotype (P = 0.76 and P = 0.89, respectively). Although overall survival tended to be worse in the older pts compared with the younger pts (estimated medians of 2.1 and 2.4 years, respectively), following adjustment for other variables in a multivariable analysis, this difference was no longer significant (P = 0.54, hazard ratio = 1.20 [95% CI: 0.7 – 2.1]). With respect to toxicities, no significant difference in occurrence of tumor lysis syndrome (TLS) or cytokine release syndrome (CRS) was observed between the two age groups, TLS occurred in 48% of older pts and 45% of younger pts (P = 1.00), while CRS occurred in 33% of older pts and 36% of younger pts (P = 1.00). As for infection, only 29% of older pts experienced this toxicity compared to 62% of younger pts (P = 0.007). In multivariable pharmacokinetic (PK) analyses of a patient subset (n=56), there were no significant associations observed between PK parameters and age when controlling for age, bilirubin level, alanine transaminase level, platelet count, white blood cell count, BUN, and 14 distinct single nucleotide polymorphisms. These data demonstrate that flavopiridol administration to older CLL patients is both feasible, acceptably tolerated, and has similar efficacy as compared to younger patients. Future development of treatment approaches with both single-agent and combination strategies of flavopiridol should be considered for older CLL patients. Disclosures: Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol is under investigation in CLL. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document