Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL) (CHRONOS-4)

A Phase III, Randomized, Double-blind, Controlled Multicenter Study of Intravenous PI3K Inhibitor Copanlisib in Combination With Standard Immunochemotherapy Versus Standard Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine [R-B] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone [R-CHOP]) is effective and safe, compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab-based immunochemotherapy and alkylating agents.

Study Overview

• Status: Terminated
• Conditions: Lymphoma, Non-Hodgkin
• Intervention / Treatment: Drug: Copanlisib (BAY80-6946); Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Bendamustine; Drug: Prednisone; Drug: Placebo

Detailed Description

Patients should be in need of and fit for immunochemotherapy and should not be resistant to rituximab (resistance defined as lack of response or progression within 6 months of the last date of rituximab administration, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody).

This study will be composed of two parts: Safety run-in and phase III part. The purpose of the safety run-in part of this study is to assess whether the drug being tested (copanlisib) in combination with standard immunochemotherapy (R-B or R-CHOP) is safe and at what dose level of the study drug (copanlisib - 45mg or 60 mg) patients are able to tolerate the study treatment combination. In addition to finding a safe and tolerable dose level for the phase III part of the study, efficacy will also be evaluated for patients that stay on the study treatment during the safety run-in. The phase III part of the study started with the determined recommended dose of copanlisib of 60 mg in combination with R-B. Combination treatment of copanlisib at the recommended/approved dose of 60 mg with R-B or R-CHOP was completed in April 2021.

A maximum of 24 patients will take part in the safety run-in part of this study. In the phase III part approximately 520 patients will be randomly assigned to blinded treatment arms of copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP. Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be administered for a maximum of 6 cycles (C1-C6). Copanlisib/placebo (study drug) monotherapy will be administered from C7 onwards.

• Study Type: Interventional
• Enrollment (Actual): 551
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
    • Eastern Health Integrated Renal Service
  • New South Wales
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Hospital Newcastle
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre Research Pty Ltd
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6961
      • Fiona Stanley Hospital
• Belgium
  • Bruxelles, Belgium, 1070
    • Institut Jules Bordet/Jules Bordet Instituut
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
  • Liege, Belgium, 4000
    • CHU de Liège
• Brazil
  • Rio de Janeiro, Brazil, 20231-050
    • Instituto Nacional do Cancer Jose Alencar Gomes da Silva
  • Sao Paulo, Brazil, 05403-000
    • Hospital das Clinicas da Faculdade de Medicina da USP
  • Sao Paulo, Brazil, 05651-901
    • Hospital Israelita Albert Einstein | Morumbi - Clinical Research Department
  • Parana
    • Curitiba, Parana, Brazil, 80810-050
      • Centro Integrado de Oncologia de Curitiba
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090
      • Irmandade da Santa Casa de Misericordia de Porto Alegre | Hospital Sao Francisco - Centro Medico Pesquisa Clinica Cardiologia
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre | Clinical Research Center - Surgery Research Center
  • Santa Catarina
    • Florianópolis, Santa Catarina, Brazil, 88034-000
      • Centro de Pesquisas Oncologicas
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 130839 970
      • Faculdade de Ciencias Medicas-Universidade Estadual Campinas
    • São Bernardo do Campo, Sao Paulo, Brazil, 09715-090
      • Centro Multidisciplinar de Estudos Clínicos EPP - Ltda.
    • São Paulo, Sao Paulo, Brazil, 01234-030
      • IEP São Lucas
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • UMHAT Sveti Georgi
  • Sofia, Bulgaria, 1756
    • SHATHD Spec. Hospi. for Active Treatm. of Haematol. Dis. EAD
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hosp. for Active Treat. Sveti Ivan
  • Vratsa, Bulgaria, 3000
    • Multiprofile Hospital for Active Treatment Hristo Botev AD
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, QC H4J 1C5
      • Hopital du Sacre-Coeur de Montreal
    • Quebec City, Quebec, Canada, G1J 1Z4
      • Hopital de L'Enfant Jesus
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Universitaire de Sante de l'Estrie
• Chile
  • Santiago, Chile, 838-0455
    • Instituto Nacional del Cancer
  • Araucanía
    • Temuco, Araucanía, Chile, 4810469
      • Sociedad de Investigaciones Medicas Ltda
  • Valparaíso
    • Vina del Mar, Valparaíso, Chile, 2540364
      • Centro de Investigaciones Clinicas Vina del Mar Ltda.
• China
  • Beijing, China, 100050
    • Beijing Friendship Hospital, Capital Medical University
  • Beijing, China, 100000
    • Fifth Medical Center, General Hospital of the Chinese People
  • Shanghai, China, 200092
    • Xinhua Hos Affiliated to SH Jiaotong Uni School of Medicine
  • Shanghai, China, 200000
    • Fudan University Shanghai Cancer Center
  • Tianjin, China, 300121
    • Tianjin Union Medicine Centre (People's Hospital of Tianjin)
  • Tianjin, China, 300000
    • Tianjin Medical University Cancer Institute & Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350000
      • Fujian Medical University Union Hospital
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Sun Yat-sen University Cancer Center
    • Guangzhou, Guangdong, China, 510000
      • Guangdong Provincial People's Hospital
  • Hebei
    • Hebei, Hebei, China, 050000
      • Tumor Hospital of Hebei Province
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Henan Cancer Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Jiangsu Cancer Hospital
    • Suzhou, Jiangsu, China, 215000
      • 1st Affiliated hospital of Soochow University
  • Jilin
    • Changchun, Jilin, China, 130000
      • Jilin Cancer Hospital
  • Shandong
    • Shandong, Shandong, China, 266000
      • The Affiliated Hospital of Qingdao University
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital Sichuan University
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital
    • Hangzhou, Zhejiang, China, 310000
      • The 1st Affiliated Hospital of Zhejiang University
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove
  • Praha 10, Czechia, 10034
    • Fakultni nemocnice Kralovske Vinohrady
• Denmark
  • København Ø, Denmark, 2100
    • Rigshospitalet - Hjertesygdomme
  • Odense C, Denmark, 5000
    • Odense Universitetshospital - Hæmatologisk afdeling
• Finland
  • Helsinki, Finland, FIN-00260
    • HUS, Meilahden sairaala
  • Oulu, Finland, 90220
    • Oulun Yliopistollinen Sairaala
  • Tampere, Finland, 33520
    • Tampereen yliopistollinen sairaala
  • Turku, Finland, 20520
    • Turun yliopistollinen keskussairaala
• France
  • Angers, France, 49933
    • Centre Hospitalier Universitaire - Angers
  • Avignon, France, 84000
    • Centre Hospitalier de la Durance - Avignon
  • Bayonne, France, 64100
    • Centre Hospitalier Intercommunal de la Côte Basque-Bayonne
  • Grenoble, France, 38043
    • Centre Hospitalier Universite de Grenoble
  • Le Mans Cedex 2, France, 72015
    • Clinique Victor Hugo - Le Mans
  • Limoges Cedex, France, 87042
    • Hopital Dupuytren
  • Montpellier Cedex, France, 34059
    • Hopital Saint-Eloi
  • Nantes, France, 44000
    • Hopital Hotel Dieu - Nantes
  • Paris, France, 75010
    • Hopital Saint Louis
  • Pessac, France, 33600
    • Centre François Magendie - Pessac
  • Poitiers, France, 86021
    • Hôpital de la Milétrie
  • Strasbourg, France, 67000
    • Clinique Saint Anne
• Germany
  • Baden-Württemberg
    • Mutlangen, Baden-Württemberg, Germany, 73557
      • Stauferklinikum Schwäbisch-Gmünd
  • Bayern
    • Augsburg, Bayern, Germany, 86150
      • Haematologie-Onkologie im Zentrum MVZ GmbH
    • München, Bayern, Germany, 81377
      • Klinikum der Universität München Großhadern
  • NRW
    • Herne, NRW, Germany, 44625
      • Marienhospital Herne Universitätsklinik
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover (MHH)
  • Nordrhein-Westfalen
    • Münster, Nordrhein-Westfalen, Germany, 48149
      • Universitaetsklinikum Muenster
    • Recklinghausen, Nordrhein-Westfalen, Germany, 45659
      • Oncologianova GmbH
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 6120
      • Med. Fakultät der Martin-Luther-Universität Halle-Wittenberg
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens Laiko
  • Athens, Greece, 106 76
    • Evangelismos General Hospital of Athens
  • Chaidari, Greece, 12462
    • University General Hospital of Athens "Attikon"
  • Larissa, Greece, 41110
    • Univ. General Hospital of Larissa
  • Patras, Greece, 26500
    • University General Hospital of Patras
• Hong Kong
  • Hong Kong, Hong Kong, MISSING
    • Prince of Wales Hospital
• Hungary
  • Budapest, Hungary, 1122
    • Orszagos Onkologiai Intezet
  • Budapest, Hungary, 1083
    • Semmelweis University
  • Kaposvar, Hungary, 7400
    • Somogy Varmegyei Kaposi Mor Oktato Korhaz
  • Nyiregyhaza, Hungary, 4400
    • Szabolcs-Szatmar-Bereg Varmegyei Oktatokorhaz
  • Pecs, Hungary, 7623
    • Pécsi Tudományegyetem Klinikai Központ
  • Tatabanya, Hungary, 2800
    • Komarom-Esztergom Varmegyei Szent Borbala Korhaz
• Ireland
  • Cork, Ireland, t12DC4A
    • Cork University Hospital
  • Dublin, Ireland, D07R2WY
    • Mater Misericordiae University Hospital
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Corporation
  • Jerusalem, Israel, 9112001
    • Hadassah Hebrew University Hospital Ein Kerem
  • Ramat Gan, Israel, 5262000
    • Chaim Sheba Medical Center
  • Zerifin, Israel, 7030000
    • Shamir Medical Center (Assaf Harofeh)
• Italy
  • Liguria
    • Genova, Liguria, Italy, 16132
      • IRCCS Ospedale Policlinico San Martino
  • Lombardia
    • Milano, Lombardia, Italy, 20089
      • Humanitas Mirasole S.p.A.
    • Pavia, Lombardia, Italy, 27100
      • Irccs Fondazione Policlinico San Matteo
  • Marche
    • Ancona, Marche, Italy, 60126
      • A.O.U. Ospedali Riuniti "Umberto I - G.M.Lancisi - G.Salesi"
• Japan
  • Aomori, Japan, 030-8553
    • Aomori Prefectural Central Hospital
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
  • Hiroshima, Japan, 730-8619
    • Hiroshima Red Cross & Atomic-bomb Survivors Hospital
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Kumamoto, Japan, 860-0008
    • National Hospital Organization Kumamoto Medical Center
  • Osaka, Japan, 543-8555
    • Osaka Red Cross Hospital
  • Osaka, Japan, 545-8586
    • Osaka Metropolitan University Hospital
  • Yamagata, Japan, 990-9585
    • Yamagata University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Aichi Cancer Center Hospital
    • Nagoya, Aichi, Japan, 467-8602
      • Nagoya City University Hospital
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 806-8501
      • JCHO Kyushu Hospital
  • Gunma
    • Maebashi, Gunma, Japan, 371-8511
      • Gunma University Hospital
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Hyogo Cancer Center
    • Kobe, Hyogo, Japan, 650-0017
      • Kobe University Hospital
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 241-8515
      • Kanagawa cancer center
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
  • Nara
    • Tenri, Nara, Japan, 632-8552
      • Tenri Hospital
  • Osaka
    • Osakasayama-shi, Osaka, Japan, 589-8511
      • Kindai University Hospital
  • Saitama
    • Hidaka, Saitama, Japan, 350-1298
      • Saitama Medical University International Medical Center
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 6351
    • Samsung Medical Center
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 3080
      • Seoul National University Hospital
• Mexico
  • Distrito Federal
    • México, D. F., Distrito Federal, Mexico, 6726
      • Hospital General de México SS
  • Michoacán
    • Morelia, Michoacán, Mexico, 58260
      • Centro de Investigación Clínica Chapultepec S.A. de C.V.
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, TBC
      • Hospital Universitario "José Eleuterio González"
  • Veracruz
    • Boca del Río, Veracruz, Mexico, 94290
      • Centro Especializado en Investigación Clínica S.C.
  • Yucatán
    • Merida, Yucatán, Mexico, 97134
      • Centro De Atencion E Investigacion Clinica En Oncologia SCP
• Poland
  • Gdynia, Poland, 81-519
    • Szpital Morski Im. Pck
  • Krakow, Poland, 30-727
    • Pratia MCM Krakow
  • Lodz, Poland, 93-513
    • Wojew. Szpital Specjalistyczny im. M. Kopernika
• Portugal
  • Braga, Portugal, 4710-243
    • Centro Clinico Academico Braga | Braga, Portugal
  • Porto, Portugal, 4200-072
    • IPO Porto
  • Porto, Portugal, 4099-001
    • Centro Hospitalar Universitario do Porto
  • Porto, Portugal, 4434-502
    • Centro Hospitalar Vila Nova de Gaia e Espinho | Unit 1 - Clinical Research Center
• Romania
  • Baia Mare, Romania, 430031
    • Sp. Judetean de Urgenta Dr. Constantin Opris Baia Mare
  • Brasov, Romania, 500152
    • Sc Onco Card Srl
  • Bucuresti, Romania, 20125
    • Spitalul Clinic Colentina
  • Bucuresti, Romania, 30171
    • Spitalul Clinic Coltea
  • Bucuresti, Romania, 22328
    • Fundeni Clinical Institute
  • Craiova, Romania, 200143
    • Spitalul Clinic Municipal Filantropia Craiova
  • Iasi, Romania, 700483
    • Institutul Regional de Oncologie Iasi
  • Sibiu, Romania, 550245
    • Spitalul Clinic Judetean de Urgenta Sibiu
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Kemerovo Regional Clinical Hospital
  • Omsk, Russian Federation, 644013
    • Clinical Oncological Dispensary of Omsk Region
  • Rostov-on-Don, Russian Federation, 344037
    • Research Institute of Oncology
  • Saint-Petersburg, Russian Federation, 191024
    • RSRI of Hematology and Transfusiology
  • Sochi, Russian Federation, 354057
    • Oncology Dispensary #2
  • Tomsk, Russian Federation, 634050
    • Siberian State Medical University
  • Ufa, Russian Federation, 450054
    • Republican Clinical Oncology Dispensary
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 119074
    • National University Hospital
  • Singapore, Singapore, 168583
    • National Cancer Center Singapore
• Slovakia
  • Bratislava, Slovakia, 833 10
    • Narodny Onkologicky Ustav
• South Africa
  • Eastern Cape
    • George, Eastern Cape, South Africa, 6530
      • Outeniqua Cancercare Oncology Unit
    • Port Elizabeth, Eastern Cape, South Africa, 6045
      • Cancercare Langenhoven
  • Gauteng
    • Pretoria, Gauteng, South Africa, 44
      • Albert Alberts Stem Cell Transplant Research Centre
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7800
      • Constantiaberg Medi Clinic
• Spain
  • Barcelona, Spain, 08035
    • Ciutat Sanitaria i Universitaria de la Vall d'Hebron
  • Zaragoza, Spain, 50009
    • Hospital Clinico Universitario Lozano Blesa
  • Barcelona
    • Badalona, Barcelona, Spain, 8916
      • Institut Català d'Oncologia Badalona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Institut Catala d'Oncologia Hospitalet
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Clinica Puerta de Hierro
  • Málaga
    • Malaga, Málaga, Spain, 29010
      • Hospital Regional de Malaga | Oncologia
• Taiwan
  • Changhua, Taiwan, 50006
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan, 833
    • Chang Gung Memorial Hospital Kaohsiung
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• Thailand
  • Bangkok, Thailand, 10400
    • Phramongkutklao Hospital
  • Bangkok, Thailand, 10700
    • Siriraj Hospital, Mahidol
• Turkey
  • Ankara, Turkey, 6100
    • Ankara Universitesi Tip Fakultesi Hastanesi
  • Edirne, Turkey, 22030
    • Trakya Univ. Tip Fak.
  • Istanbul, Turkey, 34093
    • Istanbul Universitesi Istanbul Tip Fakultesi
  • Istanbul, Turkey, 34899
    • Marmara Uni. Tip Fak. Pendik EAH Hematoloji BD
  • Izmir, Turkey, 35100
    • Ege Universitesi Tip Fakultesi
  • Izmir, Turkey, 35100
    • Dokuz Eylul Universitesi Tip Fakultesi
  • Kayseri, Turkey, 38039
    • Erciyes Universitesi Tip Fakultesi
  • Samsun, Turkey, 55139
    • Ondokuz Mayis Uni Tip Fakultesi
  • Trabzon, Turkey, 61080
    • Karadeniz Teknik Universitesi Tip Fakultesi
• Ukraine
  • Cherkasy, Ukraine, 18009
    • CNE "Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of the Cherkasy Regional Council"
  • Dnipro, Ukraine, 49102
    • Municipal Non-Profit Enterprise "City Clinical Hospital ?4" of the Dnipro City Council
  • Kyiv, Ukraine, 03022
    • Clinic of National cancer institute - scientific and research department of pediatric oncology
  • Lviv, Ukraine, 79044
    • State Institution - Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine
  • Zaporizhzhya, Ukraine, 69600
    • CNE "Zaporizhzhia Regional Clinical Hospital" of Zaporizhzhia regional council
• United Kingdom
  • Dorchester, United Kingdom, DT1 2JY
    • Dorset County Hospital
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital (London)
  • Swansea, United Kingdom, SA2 8QA
    • Singleton Hospital
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon & Exeter Hospital
  • London
    • Harrow, London, United Kingdom, HA1 3UJ
      • Northwick Park Hospital
    • Kogarah, London, United Kingdom, 2217
      • St George's Hospital
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Physicians P.C. DBA Ironwood Cancer & Res. Ctr.
  • California
    • West Covina, California, United States, 91790
      • Brian J. LeBerthon, MD
  • Colorado
    • Denver, Colorado, United States, 80218
      • SCL Health Research at St Joseph's Hospital Denver CO
  • Georgia
    • Thomasville, Georgia, United States, 31792
      • Lewis Hall Singletary Oncology Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center- Bergen
    • Port Jefferson Station, New York, United States, 11776
      • New York Cancer and Blood Specialists
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center
  • Texas
    • Houston, Texas, United States, 77024-2645
      • Oncology Consultants
    • McAllen, Texas, United States, 78503
      • Texas Oncology- McAllen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of B lymphocyte antigen CD20 positive iNHL with histological subtype limited to:

  • Follicular lymphoma G1-2-3a
  • Small lymphocytic lymphoma with absolute lymphocyte count <5x10E9/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) or progressed after at least one but at most three prior lines of therapy, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody (e.g. obinutuzumab) -based immunochemotherapy and alkylating agents (if given concomitantly is considered one line of therapy). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy with single agent rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody can be considered a previous regimen in the case the patient responded to it); at least 2 consecutive cycles of polychemotherapy; autologous transplant; or radioimmunotherapy. Previous exposure to other PI3K Inhibitors (except copanlisib) is acceptable provided there is no resistance (resistance defined as no response (response defined as partial response [PR] or complete response [CR]) at any time during therapy, or progressive disease (PD) after any response (PR/CR) or after stable disease within 6 months from the end of the therapy with a PI3K inhibitor.
• Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL 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 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 at Screening
• Adequate baseline laboratory values as assessed within 7 days before starting study treatment.
• Left ventricular ejection fraction ≥ 50%

Exclusion Criteria

• Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of transformed disease, a fresh biopsy is recommended.
• Rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last date of rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody administration, including maintenance with these drugs).
• HbA1c > 8.5% at screening
• History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator)
• Known lymphomatous involvement of the central nervous system
• Known history of human immunodeficiency virus (HIV) infection
• Hepatitis B (HBV) or hepatitis C (HCV) infection. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
• Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will not be eligible.CMV PCR test is considered positive if, the result can be interpreted as a CMV viremia according to local standard of care.
• Uncontrolled hypertension despite optimal medical management (per investigator´s assessment)
• Congestive heart failure > New York Heart Association (NYHA) class 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Copanlisib + R-B or R-CHOP / Arm 1; Combination of copanlisib with standard immunochemotherapy (rituximab and bendamustine) [R-B] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP] (safety run-in and phase III)	Drug: Copanlisib (BAY80-6946); 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. For patients on R-B dosing of copanlisib will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered and then rituximab followed by bendamustine. For patients on R-CHOP dosing of copanlisib will be administered on Days 1 and 8 of each 21-day cycle. Treatment with copanlisib/placebo will be continued up to 12 months. Copanlisib will be administered before rituximab followed by cyclophosphamide, doxorubicin and vincristine infusions. Prednisone/prednisolone tablets to be taken for 5 days.; Drug: Rituximab; Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.; Drug: Cyclophosphamide; Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Doxorubicin; Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Vincristine; Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Bendamustine; Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B; Drug: Prednisone; Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP
Placebo Comparator: Placebo + R-B or R-CHOP / Arm 2; Combination of placebo and R-B or R-CHOP (phase III only)	Drug: Rituximab; Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.; Drug: Cyclophosphamide; Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Doxorubicin; Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Vincristine; Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP; Drug: Bendamustine; Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B; Drug: Prednisone; Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP; Drug: Placebo; 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 as per copanlisib described above. Applies to the phase III part of the study only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SRI: Occurrence of Dose-limiting Toxicities (DLT)	Dose-limiting toxicity is defined as any of the following occurring during Cycle 1 at a given dose level and regarded by the investigator and/or the sponsor to be possibly, probably, or definitely related to copanlisib given in combination with R-B or R-CHOP. General: any grade 5 hematologic or non-hematologic toxicity or any delay of >2 weeks of Cycle 2 due to study treatment-related toxicity; Non-hematologic DLT: any non-hematologic toxicity grade ≥ 3; Hematologic DLT: grade 4 absolute neutrophil count decrease lasting >7 days, or grade 4 febrile neutropenia, or grade 4 platelet count decreased or grade 3 platelet count decreased with serious bleeding, or signs of serious bleeding and/or international normalized ratio (INR) increased or partial thromboplastin time (PTT) prolonged of grade 3.	At Cycle 1: 28 days for Copa+R-B or 21 days for Copa+R-CHOP
Phase 3: Progression-free Survival (PFS) by Independent Central Review	PFS is defined as the time from randomization to progressive disease (PD) or death from any cause (if no progression is documented).	Approximately 6 years 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SRI: Best Overall Response	Best overall response is defined as the best response achieved during the treatment and active follow-up periods; prior to end of study or start of new anti-tumor treatment, whichever occurs first.	Approximately 7 years 8 months
SRI: Number of Subjects With Treatment-emergent Adverse Event (TEAE)	A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.	Approximately 4 years 10 months
Phase 3: Objective Tumor Response Rate (ORR)-Independent Central Review	ORR, as assessed by independent central review, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).	Up to 6 years 4 months
Phase 3: ORR-Investigator Assessment	ORR, as assessed by investigator, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).	Up to 6 years 4 months
Phase 3: Duration of Tumor Response (DOR)-Independent Central Review	DOR, as assessed by independent central review, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.	Approximately 6 years 4 months
Phase 3: DOR-Investigator Assessment	DOR, as assessed by investigator, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.	Approximately 6 years 4 months
Phase 3: Complete Tumor Response Rate (CRR)-Independent Central Review	CRR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).	Approximately 6 years 4 months
Phase 3: CRR-Investigator Assessment	CRR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).	Approximately 6 years 4 months
Phase 3: Disease Control Rate (DCR)-Independent Central Review	DCR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).	Approximately 6 years 4 months
Phase 3: DCR-Investigator Assessment	DCR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).	Approximately 6 years 4 months
Phase 3: Time to Tumor Progression (TTP)-Independent Central Review	TTP, as assessed by independent central review, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of "other" as reason (which excludes PD).	Approximately 6 years 4 months
Phase 3: TTP-Investigator Assessment	TTP, as assessed by investigator, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of "other" as reason (which excludes PD).	Approximately 6 years 4 months
Phase 3: Time to Next Anti-lymphoma Treatment (TTNT)	A new anti-lymphoma therapy is any new systemic anticancer treatment or radiotherapy for lymphoma, with a consolidation intent. TTNT was defined as the time from the date of randomization to the start of new anti-lymphoma therapy, where the date of randomization was considered Day 1.	Approximately 6 years 4 months
Phase 3: Overall Survival (OS)	Overall survival is defined as the time from randomization until death from any cause. The OS for patients alive at the time of the database cut-off date was censored to the last date they were known to be alive. Deaths that occurred after the database cut-off date, reported during data cleaning, were considered for establishing the last known alive date at data cut-off.	Approximately 6 years 4 months
Phase 3: Time to Deterioration in Disease-related Symptoms-physical (DRS-P) of at Least 3 Points of Lymphoma	Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated in all patients. It is defined as the time from randomization to DRS-P decline, progression, or death from any reason, whichever occurred earlier.	Approximately 6 years 4 months
Phase 3: Time to Improvement in Disease-related Symptoms-physical (DRS-P) of at Least 3 Points of Lymphoma	Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated for all patients. It is defined as the time from randomization to DRS-P improvement of at least 3 points.	Approximately 6 years 4 months
Phase 3: Number of Subjects With Treatment-emergent Adverse Event (TEAE)	A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.	Approximately 4 years

Collaborators and Investigators

• Sponsor: Bayer
• Investigators: Study Director: Bayer Study Director, Bayer

Publications and helpful links

General Publications

• Matasar MJ, Dreyling M, Leppa S, Santoro A, Pedersen M, Buvaylo V, Fletcher M, Childs BH, Zinzani PL. Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2021 Nov;21(11):e886-e894. doi: 10.1016/j.clml.2021.06.021. Epub 2021 Jul 2.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards.

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2016
• Primary Completion (Actual): September 15, 2023
• Study Completion (Actual): November 10, 2023

Study Registration Dates

• First Submitted: November 3, 2015
• First Submitted That Met QC Criteria: December 8, 2015
• First Posted (Estimated): December 10, 2015

Study Record Updates

• Last Update Posted (Actual): December 11, 2024
• Last Update Submitted That Met QC Criteria: November 15, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Non-Hodgkin's lymphoma; Clinical trial, Phase III; Phosphatidylinositol-3-kinase; Indolent B-cell non-Hodgkin's lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Bendamustine Hydrochloride; Rituximab; Prednisone; Cyclophosphamide; Doxorubicin; Vincristine
• Other Study ID Numbers: 17833; 2015-001088-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No