Lymphoma, Non-HodgkinPhase 3CHRONOS-4NCT02626455
Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)
A Phase 3 study testing Copanlisib (BAY80-6946), Rituximab and Cyclophosphamide in people with Lymphoma, Non-Hodgkin, run by Bayer at 201 sites in 35 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lymphoma, Non-Hodgkin
- What is being tested?
- Copanlisib (BAY80-6946), Rituximab and Cyclophosphamide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 551 participants
- Where
- 201 sitesin 35 countries
- Study dates
- 6 Jan 2016to 10 Nov 2023
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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%
Who cannot join
- 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
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- 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
Trial locations and contacts
201 sites in 35 countries.
201 sites in 35 countries
Japan20 sites
Hyogo Cancer Center
Akashi, Hyōgo, 673-8558
Aomori Prefectural Central Hospital
Aomori, 030-8553
National Cancer Center Hospital
Chuo-ku, Tokyo, 104-0045
National Hospital Organization Kyushu Cancer Center
Fukuoka, 811-1395
Saitama Medical University International Medical Center
Hidaka, Saitama, 350-1298
Hiroshima Red Cross & Atomic-bomb Survivors Hospital
Hiroshima, 730-8619
JCHO Kyushu Hospital
Kitakyushu, Fukuoka, 806-8501
Kobe University Hospital
Kobe, Hyōgo, 650-0017
National Hospital Organization Kumamoto Medical Center
Kumamoto, 860-0008
Kumamoto University Hospital
Kumamoto, 860-8556
Gunma University Hospital
Maebashi, Gunma, 371-8511
Aichi Cancer Center Hospital
Nagoya, Aichi-ken, 464-8681
Nagoya City University Hospital
Nagoya, Aichi-ken, 467-8602
Osaka Red Cross Hospital
Osaka, 543-8555
Osaka Metropolitan University Hospital
Osaka, 545-8586
Kindai University Hospital
Osakasayama-shi, Osaka, 589-8511
Tohoku University Hospital
Sendai, Miyagi, 980-8574
Tenri Hospital
Tenri, Nara, 632-8552
Yamagata University Hospital
Yamagata, 990-9585
Kanagawa Cancer Center
Yokohama, Kanagawa, 241-8515
China18 sites
Fifth Medical Center, General Hospital of the Chinese People
Beijing, 100000
Beijing Friendship Hospital, Capital Medical University
Beijing, 100050
Jilin Cancer Hospital
Changchun, Jilin, 130000
West China Hospital Sichuan University
Chengdu, Sichuan, 610041
FuJian Medical University Union Hospital
Fuzhou, Fujian, 350000
Guangdong Provincial People's Hospital
Guangzhou, Guangdong, 510000
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, 510000
The 1st Affiliated Hospital of Zhejiang University
Hangzhou, Zhejiang, 310000
Zhejiang Cancer Hospital
Hangzhou, Zhejiang, 310022
Tumor Hospital of Hebei Province
Hebei, Hebei, 050000
Jiangsu Cancer Hospital
Nanjing, Jiangsu, 210000
The Affiliated Hospital of Qingdao University
Shandong, Shandong, 266000
Fudan University Shanghai Cancer Center
Shanghai, 200000
Xinhua Hos Affiliated to SH Jiaotong Uni School of Medicine
Shanghai, 200092
1st Affiliated hospital of Soochow University
Suzhou, Jiangsu, 215000
Tianjin Medical University Cancer Institute & Hospital
Tianjin, 300000
Tianjin Union Medicine Centre (People's Hospital of Tianjin)
Tianjin, 300121
Henan Cancer Hospital
Zhengzhou, Henan, 450000
France12 sites
Centre Hospitalier Universitaire - Angers
Angers, 49933
Centre Hospitalier de la Durance - Avignon
Avignon, 84000
Centre Hospitalier Intercommunal de la Côte Basque-Bayonne
Bayonne, 64100
Centre Hospitalier Universite de Grenoble
Grenoble, 38043
Clinique Victor Hugo - Le Mans
Le Mans, 72015
Hôpital Dupuytren
Limoges, 87042
Hôpital Saint-Eloi
Montpellier, 34059
Hopital Hotel Dieu - Nantes
Nantes, 44000
Hôpital Saint Louis
Paris, 75010
Centre François Magendie - Pessac
Pessac, 33600
Hôpital de la Milétrie
Poitiers, 86021
Clinique Saint Anne
Strasbourg, 67000
United States10 sites
Gabrail Cancer Center
Canton, Ohio, 44718
Ironwood Physicians P.C. DBA Ironwood Cancer & Res. Ctr.
Chandler, Arizona, 85224
SCL Health Research at St Joseph's Hospital Denver CO
Denver, Colorado, 80218
Oncology Consultants
Houston, Texas, 77024-2645
Texas Oncology- McAllen
McAllen, Texas, 78503
Memorial Sloan Kettering Cancer Center- Bergen
New York, New York, 10021
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
New York Cancer and Blood Specialists
Port Jefferson Station, New York, 11776
Lewis Hall Singletary Oncology Center
Thomasville, Georgia, 31792
Brian J. LeBerthon, MD
West Covina, California, 91790
Brazil10 sites
Faculdade de Ciencias Medicas-Universidade Estadual Campinas
Campinas, São Paulo, 130839 970
Centro Integrado de Oncologia de Curitiba
Curitiba, Paraná, 80810-050
Centro de Pesquisas Oncológicas
Florianópolis, Santa Catarina, 88034-000
Irmandade da Santa Casa de Misericordia de Porto Alegre | Hospital Sao Francisco - Centro Medico Pesquisa Clinica Cardiologia
Porto Alegre, Rio Grande do Sul, 90020-090
Hospital de Clinicas de Porto Alegre | Clinical Research Center - Surgery Research Center
Porto Alegre, Rio Grande do Sul, 90035-903
Instituto Nacional do Cancer Jose Alencar Gomes da Silva
Rio de Janeiro, 20231-050
Centro Multidisciplinar de Estudos Clínicos EPP - Ltda.
São Bernardo do Campo, São Paulo, 09715-090
IEP São Lucas
São Paulo, São Paulo, 01234-030
Hospital das Clínicas da Faculdade de Medicina da USP
São Paulo, 05403-000
Hospital Israelita Albert Einstein | Morumbi - Clinical Research Department
São Paulo, 05651-901
Turkey (Türkiye)9 sites
Ankara Universitesi Tip Fakultesi Hastanesi
Ankara, 6100
Trakya Univ. Tip Fak.
Edirne, 22030
Istanbul Universitesi Istanbul Tip Fakultesi
Istanbul, 34093
Marmara Uni. Tip Fak. Pendik EAH Hematoloji BD
Istanbul, 34899
Dokuz Eylul Universitesi Tip Fakultesi
Izmir, 35100
Ege Universitesi Tip Fakultesi
Izmir, 35100
Erciyes Universitesi Tip Fakultesi
Kayseri, 38039
Ondokuz Mayis Uni Tip Fakultesi
Samsun, 55139
Karadeniz Teknik Universitesi Tip Fakultesi
Trabzon, 61080
Germany8 sites
Haematologie-Onkologie im Zentrum MVZ GmbH
Augsburg, Bavaria, 86150
Med. Fakultät der Martin-Luther-Universität Halle-Wittenberg
Halle, Saxony-Anhalt, 6120
Medizinische Hochschule Hannover (MHH)
Hanover, Lower Saxony, 30625
Marienhospital Herne Universitätsklinik
Herne, North Rhine-Westphalia, 44625
Klinikum der Universität München Grosshadern
München, Bavaria, 81377
Universitaetsklinikum Muenster
Münster, North Rhine-Westphalia, 48149
Stauferklinikum Schwäbisch-Gmünd
Mutlangen, Baden-Wurttemberg, 73557
Oncologianova GmbH
Recklinghausen, North Rhine-Westphalia, 45659
Romania8 sites
Sp. Judetean de Urgenta Dr. Constantin Opris Baia Mare
Baia Mare, 430031
Sc Onco Card Srl
Brasov, 500152
Spitalul Clinic Colentina
Bucharest, 20125
Fundeni Clinical Institute
Bucharest, 22328
Spitalul Clinic Coltea
Bucharest, 30171
Spitalul Clinic Municipal Filantropia Craiova
Craiova, 200143
Institutul Regional de Oncologie Iasi
Iași, 700483
Spitalul Clinic Judetean de Urgenta Sibiu
Sibiu, 550245
Russia7 sites
Kemerovo Regional Clinical Hospital
Kemerovo, 650066
Clinical Oncological Dispensary of Omsk Region
Omsk, 644013
Research Institute of Oncology
Rostov-on-Don, 344037
RSRI of Hematology and Transfusiology
Saint Petersburg, 191024
Oncology Dispensary #2
Sochi, 354057
Siberian State Medical University
Tomsk, 634050
Republican Clinical Oncology Dispensary
Ufa, 450054
Australia6 sites
Flinders Medical Centre
Bedford Park, South Australia, 5042
Eastern Health Integrated Renal Service
Box Hill, 3128
Ashford Cancer Centre Research Pty Ltd
Kurralta Park, South Australia, 5037
The Alfred Hospital
Melbourne, Victoria, 3004
Fiona Stanley Hospital
Murdoch, Western Australia, 6961
Calvary Mater Hospital Newcastle
Waratah, New South Wales, 2298
Hungary6 sites
Semmelweis University
Budapest, 1083
Orszagos Onkologiai Intezet
Budapest, 1122
Somogy Varmegyei Kaposi Mor Oktato Korhaz
Kaposvár, 7400
Szabolcs-Szatmar-Bereg Varmegyei Oktatokorhaz
Nyíregyháza, 4400
Pecsi Tudomanyegyetem Klinikai Kozpont
Pécs, 7623
Komarom-Esztergom Varmegyei Szent Borbala Korhaz
Tatabánya, 2800
Spain6 sites
Institut Català d'Oncologia Badalona
Badalona, Barcelona, 8916
Ciutat Sanitaria i Universitaria de la Vall d'Hebron
Barcelona, 08035
Institut Català d'Oncologia Hospitalet
L'Hospitalet de Llobregat, Barcelona, 08907
Hospital Universitario Clinica Puerta de Hierro
Majadahonda, Madrid, 28222
Hospital Regional de Malaga | Oncologia
Málaga, Málaga, 29010
Hospital Clínico Universitario Lozano Blesa
Zaragoza, 50009
United Kingdom6 sites
Dorset County Hospital
Dorchester, DT1 2JY
Royal Devon & Exeter Hospital
Exeter, Devon, EX2 5DW
Northwick Park Hospital
Harrow, London, HA1 3UJ
St George's Hospital
Kogarah, London, 2217
Royal Marsden Hospital (London)
London, SW3 6JJ
Singleton Hospital
Swansea, SA2 8QA
Greece5 sites
EVANGELISMOS General Hospital of Athens
Athens, 106 76
General Hospital of Athens LAIKO
Athens, 11527
University General Hospital of Athens "ATTIKON"
Chaïdári, 12462
Univ. General Hospital of Larissa
Larissa, 41110
University General Hospital of Patras
Pátrai, 26500
Mexico5 sites
Centro Especializado en Investigación Clínica S.C.
Boca del Río, Veracruz, 94290
Centro de Atencion e Investigacion Clinica en Oncologia SCP
Mérida, Yucatán, 97134
Hospital General de México SS
México, D. F., Mexico City, 6726
Hospital Universitario "José Eleuterio González"
Monterrey, Nuevo León, TBC
Centro de Investigación Clínica Chapultepec S.A. de C.V.
Morelia, Michoacán, 58260
Taiwan5 sites
Changhua Christian Hospital
Changhua, 50006
Chang Gung Memorial Hospital Kaohsiung
Kaohsiung City, 833
National Cheng Kung University Hospital
Tainan, 704
National Taiwan University Hospital
Taipei, 100
Taipei Veterans General Hospital
Taipei, 11217
Ukraine5 sites
CNE "Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of the Cherkasy Regional Council"
Cherkasy, 18009
Municipal Non-Profit Enterprise "City Clinical Hospital ?4" of the Dnipro City Council
Dnipro, 49102
Clinic of National cancer institute - scientific and research department of pediatric oncology
Kyiv, 03022
State Institution - Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine
Lviv, 79044
CNE "Zaporizhzhia Regional Clinical Hospital" of Zaporizhzhia regional council
Zaporizhzhya, 69600
Belgium4 sites
Institut Jules Bordet/Jules Bordet Instituut
Brussels, 1070
UZ Gent
Ghent, 9000
UZ Leuven Gasthuisberg
Leuven, 3000
CHU de Liège
Liège, 4000
Bulgaria4 sites
UMHAT Sveti Georgi
Plovdiv, 4000
University Multiprofile Hosp. for Active Treat. Sveti Ivan
Sofia, 1431
SHATHD Spec. Hospi. for Active Treatm. of Haematol. Dis. EAD
Sofia, 1756
Multiprofile Hospital for Active Treatment Hristo Botev AD
Vratsa, 3000
Canada4 sites
Hopital Maisonneuve-Rosemont
Montreal, Quebec, H1T 2M4
Hopital du Sacre-Coeur de Montreal
Montreal, Quebec, QC H4J 1C5
Hopital de L'Enfant Jesus
Québec, Quebec, G1J 1Z4
Centre Universitaire de Sante de l'Estrie
Sherbrooke, Quebec, J1H 5N4
Finland4 sites
HUS, Meilahden sairaala
Helsinki, FIN-00260
Oulun yliopistollinen sairaala
Oulu, 90220
Tampereen yliopistollinen sairaala
Tampere, 33520
Turun yliopistollinen keskussairaala
Turku, 20520
Israel4 sites
Rambam Health Corporation
Haifa, 3109601
Hadassah Hebrew University Hospital Ein Kerem
Jerusalem, 9112001
Chaim Sheba Medical Center
Ramat Gan, 5262000
Shamir Medical Center (Assaf Harofeh)
Ẕerifin, 7030000
Italy4 sites
A.O.U. Ospedali Riuniti "Umberto I - G.M.Lancisi - G.Salesi"
Ancona, The Marches, 60126
IRCCS Ospedale Policlinico San Martino
Genoa, Liguria, 16132
Humanitas Mirasole S.p.A.
Milan, Lombardy, 20089
IRCCS Fondazione Policlinico San Matteo
Pavia, Lombardy, 27100
Portugal4 sites
Centro Clinico Academico Braga | Braga, Portugal
Braga, 4710-243
Centro Hospitalar Universitario do Porto
Porto, 4099-001
IPO Porto
Porto, 4200-072
Centro Hospitalar Vila Nova de Gaia e Espinho | Unit 1 - Clinical Research Center
Porto, 4434-502
South Africa4 sites
Constantiaberg Medi Clinic
Cape Town, Western Cape, 7800
Outeniqua Cancercare Oncology Unit
George, Eastern Cape, 6530
Cancercare Langenhoven
Port Elizabeth, Eastern Cape, 6045
Albert Alberts Stem Cell Transplant Research Centre
Pretoria, Gauteng, 44
South Korea4 sites
Seoul National University Hospital
Seoul, Seoul Teugbyeolsi, 3080
Severance Hospital, Yonsei University Health System
Seoul, 03722
Asan Medical Center
Seoul, 138-736
Samsung Medical Center
Seoul, 6351
Chile3 sites
Instituto Nacional del Cáncer
Santiago, 838-0455
Sociedad de Investigaciones Medicas Ltda
Temuco, Araucania, 4810469
Centro de Investigaciones Clínicas Vina del Mar Ltda.
Viña del Mar, Valparaiso, 2540364
Poland3 sites
Szpital Morski im. PCK
Gdynia, 81-519
Pratia McM Kraków
Krakow, 30-727
Wojew. Szpital Specjalistyczny im. M. Kopernika
Lodz, 93-513
Singapore3 sites
National University Hospital
Singapore, 119074
National Cancer Center Singapore
Singapore, 168583
Singapore General Hospital
Singapore, 169608
Czechia2 sites
Fakultni Nemocnice Hradec Kralove
Hradec Králové, 500 05
Fakultni nemocnice Kralovske Vinohrady
Prague, 10034
Denmark2 sites
Rigshospitalet - Hjertesygdomme
København Ø, 2100
Odense Universitetshospital - Hæmatologisk afdeling
Odense C, 5000
Ireland2 sites
Cork University Hospital
Cork, T12DC4A
Mater Misericordiae University Hospital
Dublin, D07R2WY
Thailand2 sites
Phramongkutklao Hospital
Bangkok, 10400
Siriraj Hospital, Mahidol
Bangkok, 10700
About this study
Official title: 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.
Read the 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.
- Conditions
- Lymphoma, Non-Hodgkin
- Being tested
- Copanlisib (BAY80-6946), Placebo, Rituximab, Cyclophosphamide, Doxorubicin
- Keywords
- Clinical trial, Phase III, Phosphatidylinositol-3-kinase, Non-Hodgkin's lymphoma, Indolent B-cell non-Hodgkin's lymphoma
- Medical subject headings
- Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Copanlisib (BAY80-6946)Drug
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.
PlaceboDrug
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.
RituximabDrug
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.
CyclophosphamideDrug
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
DoxorubicinDrug
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
VincristineDrug
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
BendamustineDrug
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
PrednisoneDrug
Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP
| Study group | Role | What they receive |
|---|---|---|
| Copanlisib + R-B or R-CHOP / Arm 1 | Experimental | 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) Receives: Drug: Copanlisib (BAY80-6946); Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Bendamustine; Drug: Prednisone |
| Placebo + R-B or R-CHOP / Arm 2 | Placebo comparator | Combination of placebo and R-B or R-CHOP (phase III only) Receives: Drug: Placebo; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Bendamustine; Drug: Prednisone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: Approximately 6 years 4 months
Secondary outcomes (17)
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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Approximately 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2015 (estimated)
- Study start6 Jan 2016
- Primary completion15 Sep 2023
- Study completion10 Nov 2023
Why it stopped: Company decided to terminate this study due to study did not meet the primary endpoint.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Lymphoma, Non-HodgkinStudies of the same condition, open and under way.
- More trials run by BayerThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 551 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bayer
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bayer Study Director, Study director, Bayer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02626455
- Sponsor's protocol ID
- 17833
- Other IDs
- 2015-001088-38, 2015
- Acronym
- CHRONOS-4
- Status last verified
- Nov 2024
- First submitted
- 3 Nov 2015
- Last updated
- 11 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: 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.
Publications
Zinzani PL, Wang H, Feng J, Kim TM, Tao R, Zhang H, Fogliatto L, Maluquer Artigal C, Ozcan M, Yanez E, Kim WS, Kirtbaya D, Kriachok I, Maciel F, Xue H, Bouabdallah K, Phelps C, Chaturvedi S, Weispfenning A, Morcos PN, Odongo F, Buvaylo V, Childs BH, Dreyling M, Matasar M, Ghione P. CHRONOS-4: phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma. Blood Adv. 2024 Sep 24;8(18):4866-4876. doi: 10.1182/bloodadvances.2024013236.
PubMed 39058951Matasar 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.
PubMed 34389273