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

Lymphoma, Non-Hodgkin Clinical Trial

— CHRONOS-4  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02626455
• Other study ID #: 17833
• Secondary ID: 2015-001088-38
• Status: Terminated
• Phase: Phase 3
• Start date: January 6, 2016
• Est. completion date: November 10, 2023

Study information

• Verified date: November 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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, 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 547
• Est. completion date: November 10, 2023
• Est. primary completion date: September 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

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.
• 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.
• 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.
• 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
• 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
• 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
• 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
• Prednisone
Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Eastern Health Integrated Renal Service	Box Hill
Australia	Ashford Cancer Centre Research Pty Ltd	Kurralta Park	South Australia
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	The Alfred Hospital	Prahran	Victoria
Australia	Calvary Mater Hospital Newcastle	Waratah	New South Wales
Belgium	Institut Jules Bordet/Jules Bordet Instituut	Bruxelles - Brussel
Belgium	UZ Gent	Gent
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHU de Liège	Liege
Brazil	Faculdade de Ciencias Medicas-Universidade Estadual Campinas	Campinas	Sao Paulo
Brazil	Centro Integrado de Oncologia de Curitiba	Curitiba	Parana
Brazil	Centro de Pesquisas Oncológicas	Florianópolis	Santa Catarina
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Irmandade Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto Nacional do Cancer Jose Alencar Gomes da Silva	Rio de Janeiro
Brazil	Centro Multidisciplinar de Estudos Clínicos EPP - Ltda.	Santo Andre	Sao Paulo
Brazil	Hospital Israelita Albert Einstein | Morumbi - Clinical Research Department	Sao Paulo
Brazil	Hospital das Clínicas da Faculdade de Medicina da USP	São Paulo	Sao Paulo
Brazil	IEP São Lucas	São Paulo	Sao Paulo
Bulgaria	UMHAT Sveti Georgi	Plovdiv
Bulgaria	SHATHD Spec. Hospi. for Active Treatm. of Haematol. Dis. EAD	Sofia
Bulgaria	University Multiprofile Hosp. for Active Treat. Sveti Ivan	Sofia
Bulgaria	Multiprofile Hospital for Active Treatment Hristo Botev AD	Vratsa
Canada	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Hopital de L'Enfant Jesus	Quebec City	Quebec
Canada	Centre Universitaire de Sante de l'Estrie	Sherbrooke	Quebec
Chile	Instituto Nacional del Cáncer	Santiago
Chile	Sociedad de Investigaciones Medicas Ltda	Temuco	Araucanía
Chile	Centro de Investigaciones Clínicas Vina del Mar Ltda.	Vina del Mar	Valparaíso
China	Beijing Friendship Hospital, Capital Medical University	Beijing
China	Fifth Medical Center, General Hospital of the Chinese People	Beijing
China	Jilin Cancer Hospital	Changchun	Jilin
China	West China Hospital Sichuan University	Chengdu	Sichuan
China	FuJian Medical University Union Hospital	Fuzhou	Fujian
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong
China	The 1st Affiliated Hospital of Zhejiang University	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Jiangsu Cancer Hospital	Nanjing	Jiangsu
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Fudan University Shanghai Cancer Center	Shanghai
China	Xinhua Hos Affiliated to SH Jiaotong Uni School of Medicine	Shanghai
China	Tumor Hospital of Hebei Province	Shijiazhuang	Hebei
China	1st Affiliated hospital of Soochow University	Suzhou	Jiangsu
China	Tianjin Medical University Cancer Institiute & Hospital	Tianjin
China	Tianjin Union Medicine Centre (People's Hospital of Tianjin)	Tianjin
China	Henan Cancer Hospital	Zhengzhou	Henan
Czechia	Fakultni Nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense OUH, Haematologisk afdeling	Odense C
Finland	HUS, Meilahden sairaala	Helsinki
Finland	Oulun yliopistollinen sairaala	Oulu
Finland	Tampereen yliopistollinen sairaala, keskussairaala	Tampere
Finland	Turun yliopistollinen keskussairaala	Turku
France	Centre Hospitalier Universitaire - Angers	Angers
France	Centre Hospitalier de la Durance - Avignon	Avignon
France	Centre Hospitalier Intercommunal de la Côte Basque-Bayonne	Bayonne
France	Centre Hospitalier Universite de Grenoble	Grenoble
France	Clinique Victor Hugo - Le Mans	Le Mans Cedex 2
France	Hôpital Dupuytren	Limoges Cedex
France	Hôpital Saint-Eloi	Montpellier Cedex
France	Hopital Hotel Dieu - Nantes	Nantes Cedex
France	Hôpital Saint Louis	Paris
France	Centre François Magendie - Pessac	Pessac
France	Hôpital de la Milétrie	Poitiers
France	Clinique Saint Anne	Strasbourg
Germany	Gemeinschaftspraxis Dr.Heinrich/ Prof.Bangerter	Augsburg	Bayern
Germany	Med. Fakultät der Martin-Luther-Universität Halle-Wittenberg	Halle	Sachsen-Anhalt
Germany	Medizinische Hochschule Hannover (MHH)	Hannover	Niedersachsen
Germany	Marienhospital Herne Universitätsklinik	Herne	Nordrhein-Westfalen
Germany	Klinikum der Universität München Grosshadern	München	Bayern
Germany	Universitätsklinikum Münster (UKM)	Münster	Nordrhein-Westfalen
Germany	Stauferklinikum Schwäbisch-Gmünd	Mutlangen	Baden-Württemberg
Germany	Oncologianova GmbH	Recklinghausen	Nordrhein-Westfalen
Greece	EVANGELISMOS General Hospital of Athens	Athens
Greece	LAIKO General Hospital of Athens	Athens
Greece	University General Hospital of Athens "ATTIKON"	Chaidari
Greece	Univ. General Hospital of Larissa	Larissa
Greece	University General Hospital of Patras	Patras
Hong Kong	Prince of Wales Hospital Hong Kong	Shatin
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Semmelweis University	Budapest
Hungary	Semmelweis University	Budapest
Hungary	Somogy Varmegyei Kaposi Mor Oktato Korhaz	Kaposvar
Hungary	SzSzBMK es EOK Josa Andras Oktatokorhaz	Nyiregyhaza
Hungary	Pecsi Tudomanyegyetem Klinikai Kozpont	Pecs
Hungary	Komarom-Esztergom Varmegyei Szent Borbala Korhaz	Tatabanya
Ireland	Cork University Hospital	Cork
Ireland	Mater Misericordiae Hospital	Dublin
Israel	Rambam Health Corporation	Haifa
Israel	Hadassah Hebrew University Hospital Ein Kerem	Jerusalem
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Shamir Medical Center (Assaf Harofeh)	Zerifin
Italy	A.O.U. Ospedali Riuniti "Umberto I - G.M.Lancisi - G.Salesi"	Ancona	Marche
Italy	IRCCS Ospedale Policlinico San Martino	Genova	Liguria
Italy	Istituto Clinico Humanitas - Humanitas Mirasole S.p.A.	Milano	Lombardia
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia	Lombardia
Japan	Hyogo Cancer Center	Akashi	Hyogo
Japan	Aomori Prefectural Central Hospital	Aomori
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	Saitama Medical University International Medical Center	Hidaka	Saitama
Japan	Hiroshima Red Cross & Atomic-bomb Survivors Hospital	Hiroshima
Japan	JCHO Kyushu Hospital	Kitakyushu	Fukuoka
Japan	Kobe University Hospital	Kobe	Hyogo
Japan	Kumamoto University Hospital	Kumamoto
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto
Japan	Gunma University Hospital	Maebashi	Gunma
Japan	Aichi Cancer Center Hospital	Nagoya	Aichi
Japan	Nagoya City University Hospital	Nagoya	Aichi
Japan	Osaka Metropolitan University Hospital	Osaka
Japan	Osaka Red Cross Hospital	Osaka
Japan	Kindai University Hospital	Osakasayama	Osaka
Japan	Tohoku University Hospital	Sendai	Miyagi
Japan	Tenri Hospital	Tenri	Nara
Japan	Yamagata University Hospital	Yamagata
Japan	Kanagawa Cancer Center	Yokohama	Kanagawa
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Centro Especializado en Investigación Clínica S.C.	Boca del Río	Veracruz
Mexico	Hospital General de México SS	Ciudad de México	Distrito Federal
Mexico	Centro de Atencion e Investigacion Clinica en Oncologia SCP	Merida	Yucatán
Mexico	Hospital Universitario "José Eleuterio González"	Monterrey	Nuevo Leon
Mexico	Centro de Investigación Clínica Chapultepec S.A. de C.V.	Morelia	Michoacán
Poland	Szpital Morski im. PCK	Gdynia
Poland	Malopolskie Centrum Medyczne	Krakow
Poland	Wojew. Szpital Specjalistyczny im. M. Kopernika	Lodz
Portugal	Centro Clinico Academico - Braga	Braga
Portugal	Centro Hospitalar Universitario do Porto	Porto
Portugal	IPO Porto	Porto
Portugal	Centro Hospitalar Vila Nova de Gaia/Espinho | Unit 1 - Clinical Research Office	Vila Nova de Gaia
Romania	Sp. Judetean de Urgenta Dr. Constantin Opris Baia Mare	Baia Mare
Romania	S.C. Policlinica de Diagnostic Rapid S.A.	Brasov
Romania	Fundeni Clinical Institute	Bucharest
Romania	Spitalul Clinic Coltea	Bucharest
Romania	Spitalul Clinic Colentina	Bucuresti
Romania	Spitalul Clinic Municipal Filantropia Craiova	Craiova
Romania	Institutul Regional de Oncologie Iasi	Iasi
Romania	Spitalul Clinic Judetean de Urgenta Sibiu	Sibiu
Russian Federation	Kemerovo Regional Clinical Hospital	Kemerovo
Russian Federation	Clinical Oncological Dispensary of Omsk Region	Omsk
Russian Federation	Research Institute of Oncology	Rostov-on-Don
Russian Federation	RSRI of Hematology and Transfusiology	Saint-Petersburg
Russian Federation	Oncology Dispensary #2	Sochi
Russian Federation	Siberian State Medical University	Tomsk
Russian Federation	Republican Clinical Oncology Dispensary Ufa	Ufa
Singapore	National Cancer Center Singapore	Singapore
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Slovakia	Narodny onkologicky ustav	Bratislava
South Africa	Constantiaberg Medi Clinic	Cape Town	Western Cape
South Africa	Outeniqua Cancercare Oncology Unit	George	Eastern Cape
South Africa	Cancercare Langenhoven	Port Elizabeth	Eastern Cape
South Africa	Albert Alberts Stem Cell Transplant Research Centre	Pretoria	Gauteng
Spain	Institut Català d'Oncologia Badalona	Badalona	Barcelona
Spain	Ciutat Sanitaria i Universitaria de la Vall d'Hebron	Barcelona
Spain	Institut Català d'Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario Clinica Puerta de Hierro	Majadahonda	Madrid
Spain	Hospital Regional de Malaga | Oncologia	Malaga	Málaga
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Chang Gung Memorial Hospital Kaohsiung	Kaohsiung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Thailand	Pramongkutklao Hospital	Bangkok
Thailand	Siriraj Hospital, Mahidol	Bangkok
Turkey	Ankara Universitesi Tip Fakultesi Hastanesi	Ankara
Turkey	Trakya Univ. Tip Fak.	Edirne
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul
Turkey	Marmara Uni. Tip Fakultesi Pendik Egitim ve Aras. Hastanesi	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Fakultesi	Izmir
Turkey	Ege Universitesi Tip Fakultesi	Izmir
Turkey	Erciyes Universitesi Tip Fakultesi	Kayseri
Turkey	Ondokuz Mayis Uni Tip Fakultesi	Samsun
Turkey	Karadeniz Teknik Universitesi Tip Fakultesi	Trabzon
Ukraine	CNE "Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of the Cherkasy Regional Council"	Cherkasy
Ukraine	Municipal Non-Profit Enterprise "City Clinical Hospital ¿4" of the Dnipro City Council	Dnipro
Ukraine	Governmental Noncommercial Institution "National Cancer Institute	Kyiv
Ukraine	State Institution - Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine	Lviv
Ukraine	CNE "Zaporizhzhia Regional Clinical Hospital" of Zaporizhzhia regional council	Zaporizhzhya
United Kingdom	Dorset County Hospital	Dorchester
United Kingdom	Royal Devon & Exeter Hospital	Exeter	Devon
United Kingdom	Northwick Park Hospital	Harrow	London
United Kingdom	St George's Hospital	London
United Kingdom	Singleton Hospital	Swansea
United States	Gabrail Cancer Center	Canton	Ohio
United States	Ironwood Physicians P.C. DBA Ironwood Cancer & Res. Ctr.	Chandler	Arizona
United States	SCL Health Research at St Joseph's Hospital Denver CO	Denver	Colorado
United States	Oncology Consultants	Houston	Texas
United States	Texas Oncology- McAllen	McAllen	Texas
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	New York Cancer and Blood Specialists	Port Jefferson Station	New York
United States	Lewis Hall Singletary Oncology Center	Thomasville	Georgia
United States	Brian J. LeBerthon, MD	West Covina	California

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  China,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Poland,  Portugal,  Romania,  Russian Federation,  Singapore,  Slovakia,  South Africa,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety run-in_Determination of the recommended Phase-III dose (RP3D) of copanlisib in combination with standard immunochemotherapy assessed by the occurrence of dose-limiting toxicities / adverse events		At Cycle 1: 21 days or 28 days
Primary	Phase III_Evaluation whether copanlisib in combination with standard immunochemotherapy is superior to placebo and standard immunochemotherapy assessed by the prolongation of progression free survival (PFS)	Progression free survival is defined as the time (in days) from randomization to disease progression or death from any cause (if no progression documented).	Up to 52 months
Secondary	Safety run-in_Best Overall Response (BOR)		After Cycle 1: Up to 12 months
Secondary	Safety run-in_Number of participants with treatment-emergent adverse events		Up to 13 months
Secondary	Phase III_Objective tumor response rate (ORR)	Proportion of patients who have a best overall response over the whole duration of the study (i.e. up to time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia a best overall response of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria.	Up to 52 months
Secondary	Phase III_Duration of tumor response (DOR)	Time (in days) from first observed tumor response (complete response [CR], very good partial response [VGPR], partial response [PR], or minor response [MR]) until PD or death from any cause, whichever is earlier. DOR will only be analyzed for patients with at least one CR, VGPR, PR, or MR.	Up to 52 months
Secondary	Phase III_Complete tumor response rate (CRR)	Proportion of patients who have a best overall response of CR during the study (i.e., up to time of analysis of PFS).	Up to 52 months
Secondary	Phase III_Time to tumor progression (TTP)	Time from randomization to PD or death related to PD, whichever is earlier.	Up to 52 months
Secondary	Phase III_Time to next anti-lymphoma treatment (TTNT)	Time from stop of study medication to start of new anti-lymphoma therapy.	Up to 52 months
Secondary	Phase III_Overall survival (OS)	The time (in days) from randomization until death from any cause.	Up to 5 years after last patient´s first treatment
Secondary	Phase III_Time to improvement in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire	Time to improvement in disease-related physical symptoms (DRS-P) is defined as time from randomization to first increase in DRS-P score of at least 3 points from baseline before tumor progression. Will be evaluated for patients with a baseline DRS-P score of 30 points or less.; The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma.	Up to 52 months
Secondary	Phase III_Time to deterioration in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire	Time to deterioration in disease-related physical symptoms (DRS-P) is defined as time (in days) from randomization to the earliest occurrence of 1) first reduction of DRS-P score from baseline = 3 points, or 2) radiological progression or biochemical progression for Waldenström macroglobulinemia patients without lesions evaluable by imaging, or 3) death from any cause.; The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma.	Up to 52 months
Secondary	Phase III_Number of participants with treatment-emergent adverse events		Up to 52 months
Secondary	Phase III_Disease control rate (DCR)	Proportion of patients who have a best response rating of CR, VGPR, PR, MR, or stable disease (SD) (excluding unconfirmed early SD) that is achieved during treatment or within 35 days after termination of study treatment.	Up to 52 months

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