30 results on '"Iris Kuss"'
Search Results
2. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide
- Author
-
M. Luz, Mindaugas Jievaltas, Boris Alekseev, Aramis Investigators, Neal D. Shore, Toni Sarapohja, Sergey Polyakov, Iris Kuss, Karim Fizazi, Matthew R. Smith, Teuvo L Tammela, Marie-Aude Le Berre, Egils Vjaters, Amir Snapir, Oana Petrenciuc, and Albertas Ulys
- Subjects
Male ,Oncology ,medicine.medical_specialty ,MEDLINE ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Castration resistant ,law.invention ,Fractures, Bone ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Androgen Receptor Antagonists ,medicine ,Humans ,030212 general & internal medicine ,Neoplasm Metastasis ,Fatigue ,Aged ,Cross-Over Studies ,business.industry ,General Medicine ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Crossover study ,Clinical trial ,Prostatic Neoplasms, Castration-Resistant ,Darolutamide ,Multicenter study ,Pyrazoles ,business - Abstract
Darolutamide is a structurally distinct androgen-receptor inhibitor that is approved for the treatment of nonmetastatic, castration-resistant prostate cancer. In the planned primary analysis of a phase 3 trial, the median metastasis-free survival was significantly longer with darolutamide (40.4 months) than with placebo (18.4 months). The data for the analysis of overall survival were immature at the time of the primary analysis.In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment. At the time of this prespecified final analysis, which had been planned to be performed after approximately 240 deaths had occurred, overall survival and all other secondary end points were evaluated.The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossed over to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy. Overall survival at 3 years was 83% (95% confidence interval [CI], 80 to 86) in the darolutamide group and 77% (95% CI, 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (hazard ratio for death, 0.69; 95% CI, 0.53 to 0.88; P = 0.003). Darolutamide was also associated with a significant benefit with respect to all other secondary end points, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy. The incidence of adverse events after the start of treatment was similar in the two groups; no new safety signals were observed.Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
- Published
- 2020
3. Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial
- Author
-
Michael Jeffers, Christian Kappeler, Iris Kuss, Georg Beckmann, Daniel H. Mehnert, Johannes Fredebohm, and Michael Teufel
- Subjects
Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,Gastrointestinal Stromal Tumors ,Pyridines ,Phenylurea Compounds ,Gastroenterology ,Antineoplastic Agents ,General Medicine ,Proto-Oncogene Proteins c-kit ,Oncology ,Stomach Neoplasms ,Mutation ,Humans ,Retrospective Studies - Abstract
Background In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern. Methods Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96). Results In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment. Conclusion These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.
- Published
- 2021
4. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer
- Author
-
Toni Sarapohja, M. Luz, Iris Kuss, Aramis Investigators, Christian Kappeler, Matthew R. Smith, Amir Snapir, Boris Alekseev, Neal D. Shore, Teuvo L.J. Tammela, Mindaugas Jievaltas, Sergey Polyakov, Albertas Ulys, Karim Fizazi, Egils Vjaters, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Kirurgia, anestesiologia, tehohoito, radiologia - Surgery, anesthesiology, intensive care, radiology ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Castration resistant ,urologic and male genital diseases ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Double-Blind Method ,Syöpätaudit - Cancers ,Internal medicine ,Androgen Receptor Antagonists ,medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,Fatigue ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,business.industry ,Apalutamide ,Antagonist ,General Medicine ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Progression-Free Survival ,Intention to Treat Analysis ,Clinical trial ,Prostatic Neoplasms, Castration-Resistant ,Darolutamide ,chemistry ,Multicenter study ,Quality of Life ,Pyrazoles ,business - Abstract
Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer.We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
- Published
- 2019
5. Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial
- Author
-
Toni Sarapohja, Matthew R. Smith, Albertas Ulys, Ateesha F. Mohamed, Egils Vjaters, Sergey Polyakov, Amir Snapir, Dawn Odom, Iris Kuss, Neal D. Shore, Mindaugas Jievaltas, Murilo Luz, Marie Aude Le Berre, Karim Fizazi, Teuvo L.J. Tammela, Jennifer Bartsch, Boris Alekseev, Tampere University, Department of Surgery, and Clinical Medicine
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,3122 Cancers ,Placebo ,Asymptomatic ,Androgen deprivation therapy ,Prostate cancer ,Quality of life ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Hazard ratio ,Cancer ,Androgen Antagonists ,Middle Aged ,medicine.disease ,3126 Surgery, anesthesiology, intensive care, radiology ,Prostatic Neoplasms, Castration-Resistant ,Darolutamide ,Oncology ,Quality of Life ,Pyrazoles ,medicine.symptom ,business - Abstract
Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes. Patients and methods: This double-blind, placebo-controlled, phase III trial randomised patients with nmCRPC and prostate-specific antigen doubling time ≤10 months to darolutamide 600 mg (n = 955) twice daily or matched placebo (n = 554) while continuing ADT. The primary end-point was MFS; the secondary end-points included OS and time to pain progression. In this analysis, HRQoL was assessed by the time to deterioration using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) prostate cancer subscale (PCS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (EORTC QLQ-PR25) subscales. Results: Darolutamide significantly prolonged time to deterioration of FACT-P PCS versus placebo (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.70–0.91; P = 0.0005) at the primary analysis (cut-off date: 3rd September 2018). Time to deterioration of EORTC QLQ-PR25 outcomes showed statistically significant delays with darolutamide versus placebo for urinary (HR 0.64, 95% CI 0.54–0.76; P < 0.0001) and bowel (HR 0.78, 95% CI 0.66–0.92; P = 0.0027) symptoms. Time to worsening of hormonal treatment–related symptoms was similar between the two groups. Conclusion: In patients with nmCRPC who are generally asymptomatic, darolutamide maintained HRQoL by significantly delaying time to deterioration of prostate cancer–specific quality of life and disease-related symptoms versus placebo. publishedVersion
- Published
- 2021
6. Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer : a sub-group analysis of the phase III ARAMIS trial
- Author
-
Toni Sarapohja, Neal D. Shore, Mutsushi Kawakita, Hiroya Mizusawa, Marie Aude Le Berre, Matthew R. Smith, Kazuhiro Suzuki, Masahiro Iinuma, Tetsuo Momma, Mototsugu Oya, Kazuki Kobayashi, Teuvo L.J. Tammela, Hiroji Uemura, Amir Snapir, Hirotsugu Uemura, Satoshi Fukasawa, Hisashi Matsushima, Nobuaki Matsubara, Iris Kuss, Ken-ichi Tabata, Tadahiro Kobayashi, Karim Fizazi, Hiroaki Nishimatsu, Tampere University, Department of Surgery, and Clinical Medicine
- Subjects
Male ,medicine.medical_specialty ,Efficacy ,Placebo ,Androgen deprivation therapy ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Double-Blind Method ,Japan ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,030212 general & internal medicine ,Adverse effect ,business.industry ,Nonmetastatic castration-resistant prostate cancer ,Androgen Antagonists ,Hematology ,General Medicine ,medicine.disease ,3126 Surgery, anesthesiology, intensive care, radiology ,Androgen receptor inhibitor ,Discontinuation ,Clinical trial ,Prostatic Neoplasms, Castration-Resistant ,Darolutamide ,Oncology ,Metastasis-free survival ,030220 oncology & carcinogenesis ,Japanese ,Pyrazoles ,Original Article ,Surgery ,Safety ,business - Abstract
Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.
- Published
- 2021
7. Efficacy and safety of darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen doubling time (PSADT) >6 months
- Author
-
Toni Sarapohja, Egils Vjaters, M.W.H. Bögemann, Sergey Polyakov, Iris Kuss, N.D. Shore, Boris Alekseev, M-A. Le Berre, Mindaugas Jievaltas, M. Luz, T Tammela, Amir Snapir, Karim Fizazi, and Albertas Ulys
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Urology ,Castration resistant ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Prostate cancer ,Prostate-specific antigen ,Darolutamide ,Internal medicine ,medicine ,Doubling time ,Non metastatic ,In patient ,business - Published
- 2020
8. Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial
- Author
-
Olaf Prien, Iris Kuss, Kristina Graudenz, Karim Fizazi, Bart Ploeger, Gustavo Borghesi, Teuvo L.J. Tammela, Neal D. Shore, Robert Fricke, Jonathan Moss, Hille Gieschen, Oana Petrenciuc, Frank Verholen, Christian Zurth, Mikko Koskinen, and Matthew R. Smith
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Population ,Antineoplastic Agents ,Comorbidity ,Placebo ,law.invention ,Placebos ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,medicine ,Androgen Receptor Antagonists ,Humans ,Pharmacology (medical) ,Drug Interactions ,Castration ,Original Research Article ,Neoplasm Metastasis ,Rosuvastatin Calcium ,education ,Adverse effect ,Aged ,Polypharmacy ,Aged, 80 and over ,education.field_of_study ,business.industry ,Anticholesteremic Agents ,Incidence ,Prostatic Neoplasms ,Middle Aged ,medicine.disease ,Clinical trial ,030104 developmental biology ,Darolutamide ,Oncology ,030220 oncology & carcinogenesis ,Pyrazoles ,Neoplasm Recurrence, Local ,business - Abstract
Background Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug–drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential—other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. Objective Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. Patients and Methods Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. Results Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. Conclusions These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users., Plain Language Summary Background Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects. Study Aim To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines. Study Participants Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. What Did the Researchers Measure? The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. Results As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. Conclusion In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users.
- Published
- 2019
9. 222P Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase III ARAMIS trial
- Author
-
Matthew R. Smith, Christian Zurth, Karim Fizazi, M-A. Le Berre, T Tammela, Iris Kuss, Oana Petrenciuc, and N.D. Shore
- Subjects
Oncology ,medicine.medical_specialty ,Treatment response ,business.industry ,Hematology ,Castration resistant ,medicine.disease ,Prostate cancer ,Darolutamide ,Tolerability ,Internal medicine ,medicine ,Non metastatic ,In patient ,business - Published
- 2020
10. LBA-09 DAROLUTAMIDE DELAYS PROSTATE-SPECIFIC ANTIGEN PROGRESSION AND TIME TO NEXT ANTICANCER THERAPIES IN PATIENTS WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER
- Author
-
Neal D. Shore, Matthew R. Smith, Toni Sarapohja, Boris Alekseev, Iris Kuss, Amir Snapir, Marie-Aude Le Berre, Albertas Ulys, Mindaugas Jievaltas, Sergey Polyakov, T Tammela, Murilo Luz, Egils Vjaters, and Karim Fizazi
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Urology ,Disease progression ,Castration resistant ,medicine.disease ,Asymptomatic ,Prostate-specific antigen ,Prostate cancer ,Darolutamide ,Internal medicine ,medicine ,In patient ,medicine.symptom ,business - Abstract
INTRODUCTION AND OBJECTIVES:Asymptomatic nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients (pts) would benefit from treatments (Tx) that delay disease progression with minimal Tx-r...
- Published
- 2019
11. 223P Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for non-metastatic castration-resistant prostate cancer (nmCRPC)
- Author
-
N.D. Shore, M. Luz, Toni Sarapohja, Sergey Polyakov, Albertas Ulys, M-A. Le Berre, Amir Snapir, Iris Kuss, Matthew R. Smith, Boris Alekseev, T Tammela, Mindaugas Jievaltas, Oana Petrenciuc, Karim Fizazi, and Egils Vjaters
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Hematology ,Castration resistant ,medicine.disease ,Androgen deprivation therapy ,Prostate cancer ,Darolutamide ,Internal medicine ,medicine ,Overall survival ,Non metastatic ,business - Published
- 2020
12. 633P Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase III ARAMIS trial
- Author
-
Matthew R. Smith, M-A. Le Berre, Teuvo L.J. Tammela, N.D. Shore, Christian Zurth, Oana Petrenciuc, Karim Fizazi, and Iris Kuss
- Subjects
Oncology ,Treatment response ,medicine.medical_specialty ,business.industry ,Hematology ,Castration resistant ,medicine.disease ,Prostate cancer ,Darolutamide ,Tolerability ,Internal medicine ,medicine ,Non metastatic ,In patient ,business - Published
- 2020
13. Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial
- Author
-
Toni Sarapohja, Amir Snapir, Sergey Polyakov, Egils Vjaters, Mindaugas Jievaltas, J.S.-T. Pang, M. Luz, T Tammela, Matthew R. Smith, M.-A. Le Berre, Karim Fizazi, Iris Kuss, Albertas Ulys, N.D. Shore, and Boris Alekseev
- Subjects
medicine.medical_specialty ,Urinary symptoms ,business.industry ,Disease progression ,Stock options ,PSA PROGRESSION ,Hematology ,Castration resistant ,Cytotoxic chemotherapy ,Darolutamide ,Oncology ,Family medicine ,medicine ,Non metastatic ,business - Abstract
Background Asymptomatic nmCRPC patients (pts) would benefit from treatments (Tx) that delay disease progression and maintain quality of life (QoL), with minimal Tx-related adverse events (AEs). In ARAMIS, darolutamide (DARO) prolonged metastasis-free survival vs placebo (PBO) (40 vs 18 months; HR 0.41; 95% CI 0.34–0.50; P Methods Pts were randomized to DARO 600 mg twice daily (n = 955) or PBO (n = 554), while androgen deprivation therapy continued in both arms. Secondary/exploratory endpoints included safety, time to cytotoxic chemotherapy, time to antineoplastic therapy, time to PSA progression, and QoL. Results DARO substantially delayed times to PSA progression (33 vs 7 months; HR 0.13; 95% CI 0.11–0.16; P 10% of pts. Discontinuation rates due to AEs were 8.9% with DARO and 8.7% with PBO. AEs noted with other androgen receptor inhibitors (including fracture, falls, seizures, hypertension and cognitive disorder) showed minimal or no difference in incidence between groups. DARO maintained QoL, and delayed the onset of pain and disease-related urinary symptoms compared with PBO. Conclusions DARO delays disease progression and subsequent Tx for metastatic castration-resistant prostate cancer vs PBO, maintaining QoL without increasing incidence of key AEs. Clinical trial identification NCT02200614. Editorial acknowledgement Medical writing support for the development of this abstract was provided by Lucy Smithers, PhD, and editorial support, including formatting, proofreading, and submission was provided by Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the study Orion Corporation, Orion Pharma and Bayer AG. Funding Orion Corporation and Bayer AG. Disclosure J.S-T. Pang: Non-remunerated activity/ies, Writing support: Bayer. N. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Myovant Sciences; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nymox. M.R. Smith: Honoraria (self): Amgen; Honoraria (self): Astellas; Honoraria (self): Bayer; Honoraria (self): Clovis; Honoraria (self): Gilead; Honoraria (self): Janssen; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer. T.L. Tammela: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (self): Lidds AB; Advisory / Consultancy, Research grant / Funding (self): Astellas. E. Vjaters: Research grant / Funding (self): Ipsen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Orion. M. Jievaltas: Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Janssen. M. Luz: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Research grant / Funding (self): Janssen; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Ferring; Speaker Bureau / Expert testimony: Sanofi. B. Alekseev: Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Astellas; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Ferring; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: MSD; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi. I. Kuss: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M-A. Le Berre: Full / Part-time employment: Bayer Healthcare. A. Snapir: Full / Part-time employment: Orion Pharma. T. Sarapohja: Full / Part-time employment: Orion Corporation. K. Fizazi: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self): Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Curevac; Advisory / Consultancy: ESSA; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.
- Published
- 2019
14. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial
- Author
-
Iris Kuss, Toshirou Nishida, Akira Sawaki, George D. Demetri, Yasuhide Yamada, Toshihiko Doi, Tatsuo Kanda, and Yoshito Komatsu
- Subjects
Adult ,medicine.medical_specialty ,Indoles ,Adolescent ,Gastrointestinal Stromal Tumors ,Pyridines ,Antineoplastic Agents ,Subgroup analysis ,Placebo ,Gastroenterology ,Article ,Young Adult ,chemistry.chemical_compound ,Asian People ,Double-Blind Method ,Internal medicine ,Regorafenib ,Sunitinib ,Maculopapular rash ,medicine ,Humans ,Pyrroles ,Adverse effect ,Aged ,Gastrointestinal Neoplasms ,Aged, 80 and over ,business.industry ,Phenylurea Compounds ,Hazard ratio ,Hematology ,General Medicine ,Middle Aged ,Survival Analysis ,Surgery ,Imatinib mesylate ,Oncology ,chemistry ,Imatinib Mesylate ,medicine.symptom ,business ,medicine.drug - Abstract
The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19–0.39; p
- Published
- 2015
15. ARASENS: A phase 3 trial of darolutamide in males with metastatic hormone-sensitive prostate cancer (mHSPC)
- Author
-
K. Yamada, Maha Hussain, E.D. Crawford, Bertrand Tombal, Karim Fizazi, Christian Kappeler, Cora N. Sternberg, Fred Saad, Matthew R. Smith, and Iris Kuss
- Subjects
Oncology ,medicine.medical_specialty ,Hormone sensitive prostate cancer ,Prostate cancer ,Darolutamide ,business.industry ,Internal medicine ,medicine ,Hematology ,business ,medicine.disease - Published
- 2017
16. Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck
- Author
-
Iris Kuss, William E. Gooding, Albert D. Donnenberg, and Theresa L. Whiteside
- Subjects
Male ,Cancer Research ,Apoptosis ,CD8-Positive T-Lymphocytes ,Cohort Studies ,T-Lymphocyte Subsets ,immune system diseases ,Annexin ,Interferon gamma ,Annexin A5 ,Aged, 80 and over ,naïve T cells ,Ionomycin ,Age Factors ,hemic and immune systems ,Middle Aged ,Flow Cytometry ,Isotype ,Oncology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Tetradecanoylphorbol Acetate ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Biology ,Interferon-gamma ,Immune system ,memory T cells ,Internal medicine ,medicine ,Humans ,cancer ,ζ chain ,Aged ,Ionophores ,Molecular and Cellular Pathology ,T lymphocyte ,Molecular biology ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,Endocrinology ,Case-Control Studies ,Carcinogens ,Leukocyte Common Antigens ,Immunologic Memory ,CD8 - Abstract
A subset of circulating T cells (CD8(+)CD45RO(-)CD27(-)) with a naïve phenotype, but mediating effector function, is considered to play an important role in host antitumour defence. To investigate the attributes of these effector T cells in patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous blood was obtained from 39 individuals with cancer and 45 normal controls (NC). Peripheral blood mononuclear cells were isolated, stained with labelled monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-zeta as well as isotype controls and examined by multicolour flow cytometry. Annexin V binding to CD8(+) T cells and PMA/ionomycin-induced IFN-gamma expression were also evaluated in patients and NC. The proportions of CD45RA(+)CD45RO(-) (naïve) and CD45RA(-)CD45RO(+) (memory) cells were found to be comparable within the CD8(+) T-cell subset. However, relative to NC, the frequency of effector CD8(+)CD45RO(-)CD27(-) cells was strikingly increased in all SCC patients regardless of the disease status (P=0.0003). The proportion of these cells was found to increase with age in both patients and NC. In NC, stimulated IFN-gamma expression was largely restricted to CD8(+)CD45RO(-)CD27(+) cells, while in patients CD8(+)CD45RO(-)CD27(-) expressed IFN-gamma after ex vivo stimulation. Expression of the TCR-associated zeta chain was decreased or absent in freshly isolated CD8(+)CD45RO(-)CD27(-) T cells in patients (P0.0001). Annexin V was found to bind to a higher proportion of circulating CD8(+) T cells in patients than NC (P0.006), and significantly more Annexin V(+) T cells were present in the effector (P0.0059) than the naïve subset within the CD8(+)CD45RO(-) compartment. The data indicate that the expanded CD8(+)CD45RO(-)CD27(-) T cells, which contain precursors of IFN-gamma-producing T cells, are zeta-negative and sensitive to apoptosis in the circulation of patients with HNC.
- Published
- 2003
17. ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer
- Author
-
Iris Kuss, Matthew R. Smith, Kazuhiro Suzuki, and Karim Fizazi
- Subjects
Oncology ,medicine.medical_specialty ,Prostate cancer ,business.industry ,Internal medicine ,Medicine ,Hematology ,Castration resistant ,business ,medicine.disease - Published
- 2016
18. Randomized phase II study of lonaprisan as second-line therapy for progesterone receptor-positive breast cancer
- Author
-
John F.R. Robertson, Iris Kuss, Thomas Ruhstaller, Walter Jonat, T. Bachelot, and U. Reimann
- Subjects
Adult ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Nausea ,Phases of clinical research ,Breast Neoplasms ,Gastroenterology ,Breast cancer ,Internal medicine ,medicine ,Humans ,Estrenes ,Adverse effect ,Aged ,Gynecology ,Aged, 80 and over ,business.industry ,Hematology ,Mifepristone ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Treatment Outcome ,Oncology ,Tolerability ,Vomiting ,Female ,medicine.symptom ,business ,Receptors, Progesterone ,medicine.drug - Abstract
Background: The progesterone-receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed modest activity in hormone-receptor-positive breast cancer; however, onapristone in particular was associated with hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies. Patients and methods: This randomized, open-label, phase II study evaluated the efficacy and tolerability of lonaprisan as second-line endocrine therapy in postmenopausal women with stage IV, PR-positive, HER2-negative, metastatic breast cancer. Results: Patients received once-daily lonaprisan 25 mg (n= 34) or 100 mg (n= 34). The primary objective was not met (≥35% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for ≥6 months from start of treatment). There were no complete/partial responses. In the 25 mg and 100 mg groups, 6 of 29 patients (21%) and 2 of 29 patients (7%), respectively, had SD ≥6 months. Overall, 61 of 68 patients (90%) had ≥1 adverse event (AE), the most frequent (≥10% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation, vomiting, and decreased appetite; 33 patients had serious AEs. Conclusion: Lonaprisan showed limited efficacy as second-line endocrine therapy in postmenopausal women with PR-positive metastatic breast cancer.
- Published
- 2013
19. CLINICAL BENEFIT WITH REGORAFENIB ACROSS SUBGROUPS AND POST-PROGRESSION IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR (GIST) AFTER PROGRESSION ON IMATINIB (IM) AND SUNITINIB (SU): PHASE 3 GRID TRIAL UPDATE
- Author
-
Piotr Rutkowski, M. von Mehren, D. Laurent, Martin E. Blackstein, A. Le Cesne, Robert G. Maki, Heikki Joensuu, Paolo G. Casali, Y-K Kang, Toshirou Nishida, Peter Hohenberger, Patrick Schöffski, J.-Y. Blay, Iris Kuss, George D. Demetri, Giuseppe Badalamenti, Hans Gelderblom, Jie Xu, Peter Reichardt, and Michael F. Leahy
- Subjects
Oncology ,Prior treatment ,medicine.medical_specialty ,GiST ,business.industry ,Sunitinib ,Imatinib ,Hematology ,Kinase inhibition ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Regorafenib ,Clinical endpoint ,Medicine ,In patient ,business ,medicine.drug - Abstract
Background Regorafenib (REG) therapy significantly improved progression-free survival (PFS) in patients (pts) with GIST after failure of both IM and SU (J Clin Oncol 2012; 30: suppl; abstr LBA10008). Results of subgroup and post-progression analyses are presented here. Methods Pts were randomized (2:1) to receive best supportive care plus either REG 160 mg or placebo (PL) po once daily (3 wks on/1 wk off). The primary endpoint was PFS. Upon progression in either arm, unblinding could occur. Pts on PL were eligible for crossover to open-label (OL) REG and progressive pts on REG were allowed to continue REG upon local physician's choice. Results GRID screened 234 pts and randomized 199 (REG: 133, PL: 66), well balanced for baseline characteristics. The PFS primary endpoint (according to RECIST) was met both per central review (median PFS 4.8 mo for REG vs. 0.9 mo for PL), and by investigator assessment (median PFS 7.4 mo for REG vs. 1.7 mo for PL). Exploratory sensitivity analyses demonstrate similar positive impact on PFS across pre-specified subgroups by number of prior systemic therapy, geographical region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/PDGFRA mutation. Median overall survival has not been reached in either arm. Taking the double-blind and OL periods together, 188 pts received REG. Post-progression PFS per investigator assessment was 5.0 mo for pts in the PL arm who crossed over to REG (n = 56), and 4.5 mo for pts in the REG arm who continued to receive REG after unblinding (n = 41). Conclusion REG induced significant PFS benefit in GIST pts following resistance to both IM and SU across all pre-specified subgroups. Interestingly, 41 pts on REG (out of 133) whose physicians decided to continue REG after RECIST progression had an additional PFS benefit which was in the same range. This suggests that continuous kinase inhibition after progression may benefit pts by slowing tumor progression and/or that RECIST criteria for progression applied by blind central review have clinical shortcomings. Disclosure P.G. Casali: Consultant/advisory: Bayer, MSD, GSK, Infinity, Novartis, Pfizer, PharmaMar, Sanofi Honoraria: Novartis, Pfizer, PharmaMar Research funds: Amgen Dompe, Bayer, MSD, GSK, Imclone, Infinity, Lilly, Molmed, Novartis, Pfizer, PharmaMar, Sanofi. P. Reichardt: Consultant/advisory: Bayer. Y. Kang: Consultant/advisory: Bayer Research funding: Bayer. J. Blay: Honoraria: Pharmama, Novartis, Pfizer, Roche, GSK Research funding: Pharmama, Novartis, Pfizer, Roche, GSK. P. Rutkowski: Consultant/advisory: Novartis, MSD, BMS Honoraria: Novartis, Pfizer, BMS, MSD, Roche. M. Leahy: Research funding as PI for GRID study at Christie Hospital, Manchester, UK. M. von Mehren Consultant/advisory: Novartis, Pfizer, Astex; Honoraria: Novartis, Pfizer. H. Joensuu Consultant/advisory: Novartis, Boehringer-Ingelheim. A. Le Cesne Honoraria: Novartis, Pfizer, Pharmamar. P. Schoffski: Research funding: Bayer. R. Maki: Consultant/advisory: Bayer, Pfizer, Novartis; Honoraria: Bayer, Pfizer, Novartis; Research funding: Pfizer; Expert testimony: Pfizer. I. Kuss: Employment: Bayer. D. Laurent: Employment: Bayer Stock ownership: Bayer. G.D. Demetri: Consultant/advisory: Novartis, Pfizer, GSK, Roche, Deciphra (uncompensated), Infinity Research funding: Novartis, Pfizer, GSK, Infinity Expert testimony (uncompensated): Infinity, Pfizer, Novartis, Bayer. All other authors have declared no conflicts of interest.
- Published
- 2012
20. An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID)
- Author
-
Heikki Joensuu, Paolo G. Casali, Yoon-Koo Kang, Jean-Yves Blay, Peter Reichardt, George D. Demetri, Iris Kuss, Christian Kappeler, and Klaus Bernd Schaefer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Randomization ,Stromal cell ,GiST ,Sunitinib ,business.industry ,Hazard ratio ,Placebo-controlled study ,Imatinib ,Hematology ,Placebo ,Surgery ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Regorafenib ,medicine ,Overall survival ,business ,medicine.drug - Abstract
110 Background: The GRID study showed that regorafenib improves progression-free survival compared with placebo in patients with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p
- Published
- 2015
21. Abstract 929: Tumor genotyping in the phase III GRID study of regorafenib vs placebo in tyrosine kinase inhibitor (TKI)-refractory GIST: Detection of KIT mutations in circulating tumor DNA comparing digital PCR and massive parallel sequencing
- Author
-
Michael Jeffers, Michael Teufel, Mark Rutstein, Christian Kappeler, Joachim Reischl, Susanne Schwenke, Henrik Seidel, and Iris Kuss
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Massive parallel sequencing ,GiST ,Biology ,Exon ,chemistry.chemical_compound ,Oncology ,chemistry ,Regorafenib ,Genotype ,Cancer research ,medicine ,Digital polymerase chain reaction ,Liquid biopsy ,Genotyping - Abstract
Background: The GRID study demonstrated that regorafenib provides a significant improvement in progression-free survival (HR 0.27; p Methods: 91 plasma samples from patients enrolled in the Ph 3 study (GRID) for which BEAMing data (Jeffers et al 2013 JCO 31:10503) were subjected to Safe-SeqS covering cKit Exon 8 to Exon 18. Results: In 6 of 32 samples reported to be cKIT wildtype by BEAMing, mutations were identified by SafeSeqS. The detection of primary KIT exon 9 mutations showed a high degree of concordance among the two mutation-detection methods evaluated. Secondary / resistance hotspot mutations were also readily detected by both methods, although a greater number of such mutations were detected by Safe-SeqS than by BEAMing. The localization of the additional mutations detected by Safe-SeqS in known mutational hotspots supports their legitimacy. Safe-SeqS also detected KIT mutations for which BEAMing assays had not been developed, whereas in 17 samples a mutation for which a BEAMing assay was available was not detectable by Safe SeqS. In 58% (10/17) of samples, the mutant allele frequency found by BEAMing was close to the detection limit of this platform ( Conclusion: Our data support the use of Safe-SeqS as a sensitive and specific “liquid biopsy” method for non-invasive tumor genotyping of patients with GIST, enabling the identification of known and novel tumor-associated mutations using circulating DNA. These results confirm and extend the genotypic heterogeneity that had previously been identified in GRID circulating DNA samples by BEAMing. The comprehensive tumor mutational profiles generated by Safe-SeqS will be used to evaluate potential correlations between tumor genotype and clinical outcome. Citation Format: Michael Jeffers, Henrik Seidel, Susanne Schwenke, Joachim Reischl, Mark Rutstein, Christian Kappeler, Iris Kuss, Michael Teufel. Tumor genotyping in the phase III GRID study of regorafenib vs placebo in tyrosine kinase inhibitor (TKI)-refractory GIST: Detection of KIT mutations in circulating tumor DNA comparing digital PCR and massive parallel sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 929. doi:10.1158/1538-7445.AM2015-929
- Published
- 2015
22. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck
- Author
-
Bridget Hathaway, Iris Kuss, Theresa L. Whiteside, William E. Gooding, and Robert L. Ferris
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Time Factors ,CD3 Complex ,Lymphocyte ,CD8 Antigens ,T-Lymphocytes ,Apoptosis ,CD8-Positive T-Lymphocytes ,Gastroenterology ,T-Lymphocyte Subsets ,Internal medicine ,Lymphocyte homeostasis ,medicine ,Carcinoma ,Humans ,Lymphocytes ,Neoplasm Metastasis ,Aged ,Aged, 80 and over ,Radiotherapy ,business.industry ,Age Factors ,Cancer ,T lymphocyte ,Venous blood ,Middle Aged ,medicine.disease ,Flow Cytometry ,medicine.anatomical_structure ,Oncology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,CD4 Antigens ,Carcinoma, Squamous Cell ,Regression Analysis ,Female ,business ,CD8 - Abstract
Purpose: Apoptosis of circulating CD8+ T cells seen in patients with squamous cell carcinoma of the head and neck [SCCHN (Hoffmann T, et al. Clin Cancer Res 2002;8:2553–62)] suggested a possibility of lymphocyte imbalance. Therefore, absolute numbers and percentages of lymphocyte subsets were examined in the peripheral blood of SCCHN patients and controls. Experimental Design: Venous blood was obtained from 146 patients with SCCHN and 54 normal volunteers. Absolute numbers of CD3+, CD4+, and CD8+ T lymphocytes were determined using fluorobeads in a flow cytometry-based technique. Percentages of T lymphocyte subsets were also evaluated by flow cytometry. The patients were grouped at the time of blood draw [active versus no evidence of disease (NED), type of therapy administered, and the length of follow-up]. Results: Patients with SCCHN had significantly lower absolute numbers of CD3+ CD4+, and CD8+ T cells than normal controls. However, no differences in the percentages of T-cell subsets between patients and normal controls were observed. Patients with active disease had significantly lower CD3+ and CD4+ T-cell counts than those with NED. Patients who had NED after surgery and radiotherapy had the lowest T-cell counts among the NED cohort. Patients who had NED for >2 years did not recover their T-cell counts, and the T-cell imbalance was evident many years after curative surgery. The tumor-node-metastasis (TNM) stage or site of the disease was not related to the absolute T-cell count. Patients with recurrent disease at the time of blood draw tended to have the lowest CD4+ T-cell counts. Conclusions: Patients with SCCHN have altered lymphocyte homeostasis, which persists for months or years after curative therapies.
- Published
- 2004
23. Adjuvant Regorafenib in Stage IV Colorectal Cancer (CRC) After Curative Treatment of Liver Metastases: A Phase III Randomized, Placebo-Controlled Study (COAST)
- Author
-
Eric, Van Cutsem, primary, Takayuki, Yoshino, additional, Rui-Hua, Xu, additional, John, Zalcberg, additional, Daniel, Sargent, additional, Michael, Choti, additional, Mark, Rutstein, additional, Lisa, Cupit, additional, Iris, Kuss, additional, and Axel, Grothey, additional
- Published
- 2014
- Full Text
- View/download PDF
24. Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer
- Author
-
Iris Kuss, U Friebe-Hoffmann, Theresa L. Whiteside, T Bauernhofer, Andrew Baum, Grzegorz Dworacki, and B K Vonderhaar
- Subjects
Interleukin 2 ,Cancer Research ,medicine.medical_specialty ,prolactin ,prolactin receptor ,Receptors, Prolactin ,Lymphocyte ,medicine.medical_treatment ,T-Lymphocytes ,Breast Neoplasms ,Biology ,Jurkat cells ,Annexin V ,Interleukin 21 ,Jurkat Cells ,Antigens, CD ,Reference Values ,Internal medicine ,medicine ,Humans ,Experimental Therapeutics ,IL-2 receptor ,fas Receptor ,Aged ,Neoplasm Staging ,apoptosis ,Receptors, Interleukin-2 ,Middle Aged ,Fas ,Fas receptor ,Fetal Blood ,medicine.anatomical_structure ,Cytokine ,Endocrinology ,Oncology ,Apoptosis ,Female ,medicine.drug - Abstract
Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P0.0001 and0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.
- Published
- 2003
25. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer
- Author
-
Iris Kuss, Theresa L. Whiteside, Andrew Baum, Brent N. Henderson, and Thomas Bauernhofer
- Subjects
Adult ,Male ,Immunology ,chemical and pharmacologic phenomena ,Apoptosis ,Biology ,Peripheral blood mononuclear cell ,Natural killer cell ,Interleukin 21 ,Annexin ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Immunology and Allergy ,Humans ,IL-2 receptor ,Annexin A5 ,Aged ,Cancer ,Receptors, Interleukin-2 ,Middle Aged ,medicine.disease ,Molecular biology ,CD56 Antigen ,Lymphocyte Subsets ,Killer Cells, Natural ,medicine.anatomical_structure ,Female ,Protein Binding - Abstract
Natural killer (NK) cells (CD56(+)/CD3(-)) in the circulation of cancer patients were reported to have low NK activity and undergo spontaneous apoptosis. A possible relationship between apoptosis and impaired NK activity was studied by Annexin V-binding and NK-cell assays performed with peripheral blood mononuclear cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3, CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was tested against K562 targets in 4-h (51)Cr-release assays. The ratio of CD56(dim)/CD56(bright) NK cells was significantly different in patients vs. controls (10 vs. 16; p
- Published
- 2003
26. Subgroup Analysis of Asian Patients in the Phase III Trial (GRID) of Regorafenib in Pretreated Metastatic GIST
- Author
-
Jianming Xu, R. Takimoto, C. Kappeler, Y-K. Kang, S-A. Im, George D. Demetri, Iris Kuss, Toshirou Nishida, Yoshito Komatsu, Juan Li, and R. Quek
- Subjects
Oncology ,medicine.medical_specialty ,chemistry.chemical_compound ,chemistry ,business.industry ,Regorafenib ,Internal medicine ,medicine ,Hematology ,business ,Metastatic gist ,Surgery - Published
- 2013
27. Abstract LB-295: Detection of oncogenic kinase mutations in circulating plasma DNA and correlation with clinical benefit in the phase III GRID study of regorafenib vs placebo in TKI-refractory metastatic GIST
- Author
-
Michael F. Leahy, Heikki Joensuu, Sebastian Bauer, Margaret von Mehren, Yoon-Koo Kang, Michael Jeffers, George D. Demetri, Axel Le Cesne, Iris Kuss, Peter Hohenberger, Robert G. Maki, D. Laurent, Binh Bui Nguyen, Piotr Rutkowski, Jean-Yves Blay, Christian Kappeler, Jianming Xu, Martin E. Blackstein, Peter Reichardt, John Chung, Toshirou Nishida, Patrick Schöffski, Chetan D. Lathia, Giuseppe Badalamenti, Hans Gelderblom, and Paolo G. Casali
- Subjects
Sanger sequencing ,Cancer Research ,Pathology ,medicine.medical_specialty ,GiST ,business.industry ,Sunitinib ,Cancer ,Imatinib ,PDGFRA ,medicine.disease ,symbols.namesake ,chemistry.chemical_compound ,Oncology ,chemistry ,Regorafenib ,Genotype ,medicine ,symbols ,Cancer research ,business ,medicine.drug - Abstract
Background: GRID is a phase III study for patients with advanced gastrointestinal stromal tumors (GIST) following failure of imatinib (I) and sunitinib (S) who were randomized to receive either the multikinase inhibitor regorafenib (R) or placebo (P). R demonstrated a highly significant improvement in progression-free survival compared with P (HR 0.27, p Methods: DNA was isolated from archival tumor tissue and analyzed for KIT mutations via Sanger sequencing. The expectation was that primary KIT mutations would be detectable in archival tissue but that secondary KIT mutations may be undetectable in tissues obtained before treatment with I or S. To overcome this potential limitation, plasma samples drawn at GRID study entry, post I and S failure, were used as a source of circulating DNA for evaluation of GIST oncogenic mutations (KIT, PDGFRA, BRAF) via BEAMing technology. Results: KIT mutations were detected in 83 of 138 (60%) plasma samples and 64 of 99 (65%) tumor tissue samples analyzed. Primary KIT exon 11 and 9 mutations were identified in approximately 42% and 18% of the tissue samples, respectively. The frequency of the canonical exon 9 mutations was similar for plasma and tissue samples, showing consistency between mutation-detection technologies. With limitations of tumor-based assays, a lower incidence of secondary KIT resistance mutations was detected in patient-matched archival tumor tissue compared with plasma samples: resistance mutations were detected in 12% of tissue samples vs 48% of plasma samples. Most (76%) secondary KIT mutations detected in plasma DNA were located in the KIT activation loop encoding structural alterations known to mediate resistance to I and S. Nearly half of the plasma samples in which secondary KIT mutations were identified harbored multiple secondary mutations, consistent with the results of previous studies on fresh tumor biopsies taken following resistance to both I and S. R was clinically active compared with P in all KIT mutational subgroups evaluated (HR 0.27 in patients with KIT exon 9 mutations; HR 0.25 in patients with secondary KIT mutations identified via plasma DNA). Conclusions: In GIST patients from the GRID trial, driver oncogenic mutations and secondary oncogenic mutations leading to I and S resistance are readily detectable via BEAMing of circulating DNA from plasma. BEAMing may provide a real-time assessment of tumor genotype in GIST and other cancers using blood-derived circulating DNA, that may be more comprehensive than tumor sampling. GIST patients with a wide spectrum of primary and secondary mutations in oncogenic kinases benefit from treatment with R. Citation Format: George D. Demetri, Michael Jeffers, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Leahy, Margaret von Mehren, Heikki Joensuu, Giuseppe Badalamenti, Martin Blackstein, Axel Le Cesne, Patrick Schöffski, Robert G Maki, Sebastian Bauer, Binh Bui Nguyen, Jianming Xu, Toshirou Nishida, John Chung, Chetan D. Lathia, Christian Kappeler, Iris Kuss, Dirk Laurent, Paolo G Casali. Detection of oncogenic kinase mutations in circulating plasma DNA and correlation with clinical benefit in the phase III GRID study of regorafenib vs placebo in TKI-refractory metastatic GIST. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-295. doi:10.1158/1538-7445.AM2013-LB-295
- Published
- 2013
28. A Phase 2 Trial of Ixabepilone in Asian Patients with Advanced Gastric Cancer Previously Treated with Fluoropyrimidine-Based Chemotherapy
- Author
-
T. Nishina, Giuseppe Badalamenti, Hans Gelderblom, J. Y. Kim, H. M. Ryoo, J. Furuse, P. G. Casali, Patrick Schöffski, Sun Young Rha, S. A. Lee, Wasaburou Koizumi, Tarek Sahmoud, M. G. Leahy, M. K. Kim, Y-K. Kang, Iris Kuss, D. Laurent, A. Ohtsu, Y. S. Chae, K. U. Park, J. M. Xu, Axel Le Cesne, P. Rutkowski, J. G. Kim, Y. R. Do, Hiroya Takiuchi, H. Yasui, Robert G. Maki, Yoshito Komatsu, T. Nishida, Y.-J. Bang, Wonyoung Kang, H. S. Song, T. Doi, S. H. Bae, N. Ohno, J. Y. Blay, K.-W. Lee, Kiheon Lee, K. Yamaguchi, J. Y. Cho, Toshihiro Kudo, X. Zhu, D-Y. Oh, K. Chin, Martin E. Blackstein, Heikki Joensuu, K. Muro, E. Warita, George D. Demetri, S. Kato, Peter Hohenberger, M. von Mehren, and P. Reichardt
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,Standard treatment ,medicine.medical_treatment ,Ixabepilone ,Cancer ,Hematology ,Neutropenia ,medicine.disease ,Gastroenterology ,chemistry.chemical_compound ,Oncology ,chemistry ,Statistical significance ,Internal medicine ,Clinical endpoint ,Medicine ,business ,Febrile neutropenia - Abstract
Background The highest rates of gastric cancer occur in Eastern Asia. Fluoropyrimidine-based therapy is used initially in unresectable and metastatic disease, following progression, 60–70% of patients in Asian countries subsequently receive second-line chemotherapy. However, there is no standard treatment in this setting. Ixabepilone, an epothilone B analog, is a non-taxane microtubule-stabilizing agent with clinical anti-tumor activity across multiple tumor types. We evaluated the efficacy and safety of single-agent ixabepilone as a second-line chemotherapy in Asian patients. Methods Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed previous fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m2 by 3-hour intravenous infusion every 3 weeks. The primary end point was objective response rate (ORR). In this study, an ORR ≤8% was not of clinical interest, and an ORR ≥20% was of strong clinical interest. The test had 80% power to reject the null hypothesis at a significance level of 5% if the true ORR is 20%. Results This phase II was conducted at 9 sites in the Asian-Pacific region including Japan, Korea, Taiwan, Hong Kong and Singapore from November 2009 to June 2011. Fifty-two patients were treated (65.4% male; median age: 56.5 years). Ixabepilone was administered for a median of 3.5 courses (range: 1–10). Of the 45 patients who received at least two courses. The ORR was 15.4% (95% CI: 6.9–28.1), with 8 patients achieving partial responses for a median duration of 3.1 months (95% CI: 2.6–4.1 months). Twenty-six patients (50.0%) had stable disease, and therefore the disease control rate was 65.4% (95% CI: 50.9–78.0). Median progression-free survival was 2.8 months (95% CI: 2.1–3.5 months). The most common grade 3 non-hematological toxic effects were fatigue (9.6%), decreased appetite (7.7%), and peripheral sensory neuropathy (5.8%). Grade 3/4 neutropenia occurred in 46.2% of patients, with febrile neutropenia in 7.7%. There was no treatment-related death. Conclusion Ixabepilone showed a modest efficacy in Asian patients with advanced gastric cancer following prior fluoropyrimidine-based therapy, and has a predictable and manageable safety profile consistent with that seen in other tumor types.
- Published
- 2012
29. Randomized Phase 3 Trial of Regorafenib in Patients (Patients) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at Least Imatinib (IM) and Sunitinib (SU) : Grid Trial
- Author
-
Robert G. Maki, Patrick Schöffski, M. von Mehren, Peter Reichardt, Jianming Xu, Y-K. Kang, Toshirou Nishida, M. G. Leahy, Heikki Joensuu, J.-Y. Blay, Giuseppe Badalamenti, Hans Gelderblom, Paolo G. Casali, Iris Kuss, Peter Hohenberger, Piotr Rutkowski, Martin E. Blackstein, George D. Demetri, D. Laurent, and Axel Le Cesne
- Subjects
Oncology ,medicine.medical_specialty ,GiST ,business.industry ,Sunitinib ,Imatinib ,Hematology ,Placebo ,medicine.disease ,Surgery ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Regorafenib ,medicine ,Clinical endpoint ,Stromal tumor ,business ,Progressive disease ,medicine.drug - Abstract
LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and...
- Published
- 2012
30. P-0266 - Adjuvant Regorafenib in Stage IV Colorectal Cancer (CRC) After Curative Treatment of Liver Metastases: A Phase III Randomized, Placebo-Controlled Study (COAST)
- Author
-
Eric, Van Cutsem, Takayuki, Yoshino, Rui-Hua, Xu, John, Zalcberg, Daniel, Sargent, Michael, Choti, Mark, Rutstein, Lisa, Cupit, Iris, Kuss, and Axel, Grothey
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.