Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)
CHRONOS-3
A Phase III, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Copanlisib in Combination With Rituximab in Patients With Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL) - CHRONOS-3
2 other identifiers
interventional
458
36 countries
184
Brief Summary
The purpose of this study was to evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Aug 2015
Longer than P75 for phase_3
184 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 12, 2015
CompletedFirst Posted
Study publicly available on registry
February 20, 2015
CompletedStudy Start
First participant enrolled
August 3, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 31, 2020
CompletedResults Posted
Study results publicly available
January 4, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
November 15, 2024
CompletedOctober 14, 2025
September 1, 2025
5.1 years
February 12, 2015
August 27, 2021
September 25, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Progression Free Survival (PFS) Based on Independent Central Review.
Progression-free survival (PFS) was defined as the time from randomization to progressive disease (PD) or death due to any cause, whichever was earlier according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section).
From first participant randomization (20-Aug-2015) up to data cut-off at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years and final analysis at 15-Nov-2024 up to 9 years
Secondary Outcomes (11)
Objective Response Rate (ORR)
From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Complete Response Rate (CRR)
From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Duration of Response (DOR)
From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Disease Control Rate (DCR)
From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Time to Progression (TTP)
From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
- +6 more secondary outcomes
Study Arms (2)
Copanlisib + Rituximab
EXPERIMENTALCombination of the Copanlisib and rituximab
Placebo + Rituximab
PLACEBO COMPARATORCombination of Copanlisib placebo and rituximab
Interventions
Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.
Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.
Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.
Eligibility Criteria
You may qualify if:
- Histologically confirmed diagnosis of Indolent non-Hodgkin's lymphoma (iNHL) in CD20 positive patients, with histological subtype limited to:
- Follicular lymphoma(FL) grade1-2-3a
- Small lymphocytic lymphoma(SLL) with absolute lymphocyte count \<5x10\*9/L at study entry
- Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
- Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
- Patients must have relapsed (recurrence after complete response or presented progression after partial response) after the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K is acceptable (except to copanlisib) provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
- Non-WM must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL (Marginal-zone lymphoma) this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease.
- Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) and positive immunofixation test .
- Male or female patients ≥ 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Life expectancy of at least 3 months
- Availability of fresh tumor tissue and/or archival tumor tissue for central pathology(obtained within 5 years of the consent date) at Screening
- Adequate baseline laboratory values collected no more than 7 days before starting study treatment
- Left ventricular ejection fraction ≥ 45%
- Patients must either:
- +6 more criteria
You may not qualify if:
- Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia
- Progression free interval or treatment free interval of less than 12 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing treatment(including maintenance with these drugs). For patients considered unwilling/unfit to receive chemotherapy : progression free interval or treatment free interval of less than 6 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment (including maintenance with these drugs), as assessed by the investigator
- History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
- Known lymphomatous involvement of the central nervous system
- Patients with HbA1c \> 8.5% at Screening
- Known history of human immunodeficiency virus (HIV) infection
- Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti- HCV antibody will be eligible if they are negative for HCV-RNA
- Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors.
- Prior treatment with copanlisib
- Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will not be eligible.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Bayerlead
Study Sites (187)
Unknown Facility
West Covina, California, 91790, United States
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Ashland, Kentucky, 41101, United States
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Louisville, Kentucky, 40207, United States
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Bethesda, Maryland, 20817, United States
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Las Vegas, Nevada, 89169, United States
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Montvale, New Jersey, 07645, United States
MSK Basking Ridge
New Jersey, New Jersey, United States
MSK Bergen
New Jersey, New Jersey, United States
MSK Monmoth
New Jersey, New Jersey, United States
MSK Westchester
Harrison, New York, United States
MSK Commack
Long Island City, New York, United States
MSK Rockville Centre
Long Island City, New York, United States
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New York, New York, 10065, United States
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Canton, Ohio, 44718, United States
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Salt Lake City, Utah, 84106, United States
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Spokane, Washington, 99208, United States
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Buenos Aires, Ciudad Auton. de Buenos Aires, TBC, Argentina
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Rosario, Santa Fe Province, S2000DEJ, Argentina
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San Miguel de Tucumán, Tucumán Province, T4000, Argentina
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Córdoba, X5000AOQ, Argentina
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Ballarat, Victoria, 3350, Australia
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Nedlands, 6009, Australia
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Graz, Styria, 8036, Austria
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Vienna, 1090, Austria
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Vienna, 1130, Austria
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Ottignies, 1340, Belgium
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Passo Fundo, Rio Grande do Sul, 99020-240, Brazil
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Porto Alegre, Rio Grande do Sul, 90850-170, Brazil
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Barretos/SP, São Paulo, 14784-400, Brazil
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Jaú, São Paulo, 17210-120, Brazil
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São Paulo, São Paulo, 01234-030, Brazil
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São Paulo, São Paulo, 08270-070, Brazil
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São Paulo, 05403-000, Brazil
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São Paulo, 05651-901, Brazil
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Plovdiv, 4000, Bulgaria
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Sofia, 1756, Bulgaria
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Varna, 9010, Bulgaria
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Temuco, Región de la Araucanía, 4800827, Chile
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Fuzhou, Fujian, 350000, China
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Guangzhou, Guangdong, 510000, China
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Guangzhou, Guangdong, TBC, China
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Wuhan, Hubei, 430079, China
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Nanjing, Jiangsu, 210000, China
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Suzhou, Jiangsu, 215000, China
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Nanchang, Jiangxi, 330029, China
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Changchun, Jilin, 130061, China
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Shengyang, Liaoning, 110042, China
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Chengdu, Sichuan, 610041, China
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Ürümqi, Xinjiang, 830011, China
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Hangzhou, Zhejiang, 310000, China
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Hangzhou, Zhejiang, 310022, China
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Beijing, 100000, China
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Beijing, 100050, China
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Beijing, 100083, China
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Beijing, 100730, China
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Chongqing, 400030, China
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Chongqing, 400042, China
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Shanghai, 200000, China
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Shanghai, 200025, China
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Shanghai, 200032, China
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Tianjin, 300000, China
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Tianjin, 300121, China
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Medellín, Antioquia, 050034, Colombia
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Bogota, Cundinamarca, 111511, Colombia
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Montería, Departamento de Córdoba, 230002, Colombia
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Cali, Valle del Cauca Department, 760032, Colombia
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Bayonne, 64100, France
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Brest, 29470, France
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Metz, 57085, France
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Nice, 6189, France
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Pessac, 33600, France
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Poitiers, 86021, France
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Saint-Herblain, 44800, France
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München, Bavaria, 81377, Germany
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Recklinghausen, North Rhine-Westphalia, 45659, Germany
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Dresden, Saxony, 1307, Germany
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Halle, Saxony-Anhalt, 6120, Germany
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Berlin, 10967, Germany
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Athens, 106 76, Greece
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Athens, 11527, Greece
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Chaïdári, 12462, Greece
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Pátrai, 26500, Greece
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Chai Wan, 0, Hong Kong
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Hong Kong, MISSING, Hong Kong
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Budapest, 1083, Hungary
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Győr, 9024, Hungary
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Kaposvár, 7400, Hungary
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Pécs, 7623, Hungary
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Tatabánya, 2800, Hungary
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Dublin, D07R2WY, Ireland
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Dublin, D08NHY1, Ireland
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Galway, H91YR71, Ireland
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Udine, Friuli Venezia Giulia, 33038, Italy
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Genoa, Liguria, 16132, Italy
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Milan, Lombardy, 20133, Italy
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Florence, Tuscany, 50134, Italy
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Nagoya, Aichi-ken, 464-8681, Japan
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Nagoya, Aichi-ken, 466-8650, Japan
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Maebashi, Gunma, 371-8511, Japan
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Kobe, Hyōgo, 650-0047, Japan
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Nankoku, Kochi, 783-8505, Japan
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Sendai, Miyagi, 980-8574, Japan
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Ōmura, Nagasaki, 856-8562, Japan
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Kurashiki, Okayama-ken, 710-8602, Japan
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Hirakata, Osaka, 573-1191, Japan
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Izumo, Shimane, 693-8501, Japan
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Chuo-ku, Tokyo, 104-0045, Japan
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Aomori, 030-8553, Japan
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Fukuoka, 811-1395, Japan
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Kumamoto, 860-8556, Japan
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Niigata, 951-8566, Japan
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Osaka, 545-8586, Japan
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Yamagata, 990-9585, Japan
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Kaunas, LT-50009, Lithuania
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Cheras, 56000, Malaysia
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Kota Kinabalu, 88586, Malaysia
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Kuala Lumpur, 59100, Malaysia
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Kuala Selangor, 68000, Malaysia
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Perak, 30450, Malaysia
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Pulau Pinang, 10450, Malaysia
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Morelia, Michoacán, 58260, Mexico
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Monterrey, Nuevo León, 64460, Mexico
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Tauranga, 3112, New Zealand
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City of Taguig, 1102, Philippines
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Pasig, 1605, Philippines
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Gdansk, 80-214, Poland
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Gdynia, 81-519, Poland
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Krakow, 30-727, Poland
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Lublin, 20-090, Poland
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Porto, 4200-072, Portugal
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Porto, 4434-502, Portugal
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Brasov, 500152, Romania
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Bucharest, 10825, Romania
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Bucharest, 20125, Romania
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Bucharest, 22328, Romania
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Bucharest, 30171, Romania
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Cluj-Napoca, 400015, Romania
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Craiova, 200143, Romania
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Târgu Mureş, 540136, Romania
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Chelyabinsk, 454048, Russia
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Irkutsk, 664035, Russia
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Kazan', 420029, Russia
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Kemerovo, 650066, Russia
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Kirov, 610027, Russia
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Novosibirsk, 630087, Russia
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Omsk, 644013, Russia
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Saint Petersburg, 197022, Russia
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Volgograd, 400138, Russia
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Singapore, 119074, Singapore
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Singapore, 168583, Singapore
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Singapore, 169608, Singapore
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Poprad, 058 01, Slovakia
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George, Eastern Cape, 6530, South Africa
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Johannesburg, Gauteng, 2013, South Africa
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Seoul, Seoul Teugbyeolsi, 03722, South Korea
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Seoul, Seoul Teugbyeolsi, 05505, South Korea
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Seoul, Seoul Teugbyeolsi, 3080, South Korea
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Busan, 49201, South Korea
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Busan, 49241, South Korea
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Hwasun Gun, 58128, South Korea
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Seoul, 06351, South Korea
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Majadahonda, Madrid, 28222, Spain
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Málaga, Málaga, 20910, Spain
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Barcelona, 08003, Spain
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Barcelona, 08035, Spain
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Barcelona, 8041, Spain
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Madrid, 28041, Spain
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Salamanca, 37007, Spain
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Changhua, 50006, Taiwan
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Kaohsiung City, 833, Taiwan
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Tainan, 704, Taiwan
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Taipei, 100, Taiwan
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Taipei, 11217, Taiwan
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Chiang Mai, 50200, Thailand
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Pathum Thani, 10120, Thailand
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Ankara, 6100, Turkey (Türkiye)
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Istanbul, 34093, Turkey (Türkiye)
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Izmir, 35100, Turkey (Türkiye)
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Kayseri, 38039, Turkey (Türkiye)
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Trabzon, 61080, Turkey (Türkiye)
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Cherkasy, 18009, Ukraine
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Dnipro, 49102, Ukraine
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Kyiv, 03022, Ukraine
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Lviv, 79044, Ukraine
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Vinnitsa, 21029, Ukraine
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Hà Nội, 10000, Vietnam
Unknown Facility
Ho Chi Minh City, 70000, Vietnam
Related Publications (2)
Matasar MJ, Capra M, Ozcan M, Lv F, Li W, Yanez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor A, Bouabdallah K, Galiulin R, Uchida T, Soler LM, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):678-689. doi: 10.1016/S1470-2045(21)00145-5. Epub 2021 Apr 10.
PMID: 33848462RESULTMorcos PN, Moss J, Veasy J, Hiemeyer F, Childs BH, Garmann D. Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen. Clin Pharmacol Ther. 2024 May;115(5):1092-1104. doi: 10.1002/cpt.3173. Epub 2024 Jan 16.
PMID: 38226495DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Therapeutic Area Head
- Organization
- Bayer AG
Study Officials
- STUDY DIRECTOR
Bayer Study Director
Bayer
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- LTE60
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 12, 2015
First Posted
February 20, 2015
Study Start
August 3, 2015
Primary Completion
August 31, 2020
Study Completion
November 15, 2024
Last Updated
October 14, 2025
Results First Posted
January 4, 2022
Record last verified: 2025-09
Data Sharing
- IPD Sharing
- Will not share
Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.