Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)

NCT ID: NCT02367040

Last Updated: 2025-10-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 458 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-03
• Study Completion Date: 2024-11-15

Brief Summary

The purpose of this study was to evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.

Conditions

Lymphoma,Non-Hodgkin

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Copanlisib + Rituximab

Combination of the Copanlisib and rituximab

Group Type: EXPERIMENTAL

Copanlisib (Aliqopa, BAY80-6946)

Intervention Type: 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. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.

Rituximab

Intervention Type: DRUG

Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

Placebo + Rituximab

Combination of Copanlisib placebo and rituximab

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.

Rituximab

Intervention Type: DRUG

Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

Interventions

Copanlisib (Aliqopa, 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. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.

Intervention Type: 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 on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.

Intervention Type: DRUG

Rituximab

Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed diagnosis of Indolent non-Hodgkin's lymphoma (iNHL) in CD20 positive patients, with histological subtype limited to:

• Follicular lymphoma(FL) grade1-2-3a
• Small lymphocytic lymphoma(SLL) with absolute lymphocyte count <5x10*9/L at study entry
• Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
• Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
• Patients must have relapsed (recurrence after complete response or presented progression after partial response) after the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K is acceptable (except to copanlisib) provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
• Non-WM must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL (Marginal-zone lymphoma) this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease.
• Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) and positive immunofixation test .
• Male or female patients ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Life expectancy of at least 3 months
• Availability of fresh tumor tissue and/or archival tumor tissue for central pathology(obtained within 5 years of the consent date) at Screening
• Adequate baseline laboratory values collected no more than 7 days before starting study treatment
• Left ventricular ejection fraction ≥ 45%
• Patients must either:

• have had a progression-free and treatment-free interval of at least 12 months after completion of the rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment OR
• be considered unfit to receive chemotherapy on reason of age, concomitant morbidities, and/or residual toxicity from previous treatments, or unwillingness to receive chemotherapy. These patients must also have had a progression-free and treatment-free interval of at least 6 months after completion of the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment. Patients in whom chemotherapy is contraindicated are defined by one of the following features:

• Age ≥ 80 years
• Age < 80 years and at least 1 of the following conditions:

• at least 3 grade 3 CIRS-G comorbidities OR
• at least 1 grade 4 CIRS-G comorbidity (if compatible to participation in the study).

Exclusion Criteria

• Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia
• Progression free interval or treatment free interval of less than 12 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing treatment(including maintenance with these drugs). For patients considered unwilling/unfit to receive chemotherapy : progression free interval or treatment free interval of less than 6 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment (including maintenance with these drugs), as assessed by the investigator
• History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
• Known lymphomatous involvement of the central nervous system
• Patients with HbA1c > 8.5% at Screening
• Known history of human immunodeficiency virus (HIV) infection
• Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti- HCV antibody will be eligible if they are negative for HCV-RNA
• Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors.
• Prior treatment with copanlisib
• Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will not be eligible.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

West Covina, California, United States

Ashland, Kentucky, United States

Louisville, Kentucky, United States

Bethesda, Maryland, United States

Las Vegas, Nevada, United States

Montvale, New Jersey, United States

MSK Basking Ridge

New Jersey, New Jersey, United States

MSK Bergen

New Jersey, New Jersey, United States

MSK Monmoth

New Jersey, New Jersey, United States

MSK Westchester

Harrison, New York, United States

MSK Commack

Long Island City, New York, United States

MSK Rockville Centre

Long Island City, New York, United States

New York, New York, United States

Canton, Ohio, United States

Salt Lake City, Utah, United States

Spokane, Washington, United States

Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina

Rosario, Santa Fe Province, Argentina

San Miguel de Tucumán, Tucumán Province, Argentina

Córdoba, , Argentina

Ballarat, Victoria, Australia

Nedlands, , Australia

Graz, Styria, Austria

Vienna, , Austria

Vienna, , Austria

Ottignies, , Belgium

Passo Fundo, Rio Grande do Sul, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

Barretos/SP, São Paulo, Brazil

Jaú, São Paulo, Brazil

São Paulo, São Paulo, Brazil

São Paulo, São Paulo, Brazil

São Paulo, , Brazil

São Paulo, , Brazil

Plovdiv, , Bulgaria

Sofia, , Bulgaria

Varna, , Bulgaria

Temuco, Región de la Araucanía, Chile

Fuzhou, Fujian, China

Guangzhou, Guangdong, China

Guangzhou, Guangdong, China

Wuhan, Hubei, China

Nanjing, Jiangsu, China

Suzhou, Jiangsu, China

Nanchang, Jiangxi, China

Changchun, Jilin, China

Shengyang, Liaoning, China

Chengdu, Sichuan, China

Ürümqi, Xinjiang, China

Hangzhou, Zhejiang, China

Hangzhou, Zhejiang, China

Beijing, , China

Beijing, , China

Beijing, , China

Beijing, , China

Chongqing, , China

Chongqing, , China

Shanghai, , China

Shanghai, , China

Shanghai, , China

Tianjin, , China

Tianjin, , China

Medellín, Antioquia, Colombia

Bogota, Cundinamarca, Colombia

Montería, Departamento de Córdoba, Colombia

Cali, Valle del Cauca Department, Colombia

Bayonne, , France

Brest, , France

Metz, , France

Nice, , France

Pessac, , France

Poitiers, , France

Saint-Herblain, , France

München, Bavaria, Germany

Recklinghausen, North Rhine-Westphalia, Germany

Dresden, Saxony, Germany

Halle, Saxony-Anhalt, Germany

Berlin, , Germany

Athens, , Greece

Athens, , Greece

Chaïdári, , Greece

Pátrai, , Greece

Chai Wan, , Hong Kong

Hong Kong, , Hong Kong

Budapest, , Hungary

Győr, , Hungary

Kaposvár, , Hungary

Pécs, , Hungary

Tatabánya, , Hungary

Dublin, , Ireland

Dublin, , Ireland

Galway, , Ireland

Udine, Friuli Venezia Giulia, Italy

Genoa, Liguria, Italy

Milan, Lombardy, Italy

Florence, Tuscany, Italy

Nagoya, Aichi-ken, Japan

Nagoya, Aichi-ken, Japan

Maebashi, Gunma, Japan

Kobe, Hyōgo, Japan

Nankoku, Kochi, Japan

Sendai, Miyagi, Japan

Ōmura, Nagasaki, Japan

Kurashiki, Okayama-ken, Japan

Hirakata, Osaka, Japan

Izumo, Shimane, Japan

Chuo-ku, Tokyo, Japan

Aomori, , Japan

Fukuoka, , Japan

Kumamoto, , Japan

Niigata, , Japan

Osaka, , Japan

Yamagata, , Japan

Kaunas, , Lithuania

Cheras, , Malaysia

Kota Kinabalu, , Malaysia

Kuala Lumpur, , Malaysia

Kuala Selangor, , Malaysia

Perak, , Malaysia

Pulau Pinang, , Malaysia

Morelia, Michoacán, Mexico

Monterrey, Nuevo León, Mexico

Tauranga, , New Zealand

City of Taguig, , Philippines

Pasig, , Philippines

Gdansk, , Poland

Gdynia, , Poland

Krakow, , Poland

Lublin, , Poland

Porto, , Portugal

Porto, , Portugal

Brasov, , Romania

Bucharest, , Romania

Bucharest, , Romania

Bucharest, , Romania

Bucharest, , Romania

Cluj-Napoca, , Romania

Craiova, , Romania

Târgu Mureş, , Romania

Chelyabinsk, , Russia

Irkutsk, , Russia

Kazan', , Russia

Kemerovo, , Russia

Kirov, , Russia

Novosibirsk, , Russia

Omsk, , Russia

Saint Petersburg, , Russia

Volgograd, , Russia

Singapore, , Singapore

Singapore, , Singapore

Singapore, , Singapore

Poprad, , Slovakia

George, Eastern Cape, South Africa

Johannesburg, Gauteng, South Africa

Seoul, Seoul Teugbyeolsi, South Korea

Seoul, Seoul Teugbyeolsi, South Korea

Seoul, Seoul Teugbyeolsi, South Korea

Busan, , South Korea

Busan, , South Korea

Hwasun Gun, , South Korea

Seoul, , South Korea

Majadahonda, Madrid, Spain

Málaga, Málaga, Spain

Barcelona, , Spain

Barcelona, , Spain

Barcelona, , Spain

Madrid, , Spain

Salamanca, , Spain

Changhua, , Taiwan

Kaohsiung City, , Taiwan

Tainan City, , Taiwan

Taipei, , Taiwan

Taipei, , Taiwan

Chiang Mai, , Thailand

Pathum Thani, , Thailand

Ankara, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Kayseri, , Turkey (Türkiye)

Trabzon, , Turkey (Türkiye)

Cherkasy, , Ukraine

Dnipro, , Ukraine

Kyiv, , Ukraine

Lviv, , Ukraine

Vinnitsa, , Ukraine

Hà Nội, , Vietnam

Ho Chi Minh City, , Vietnam

Countries

United States; Argentina; Australia; Austria; Belgium; Brazil; Bulgaria; Chile; China; Colombia; France; Germany; Greece; Hong Kong; Hungary; Ireland; Italy; Japan; Lithuania; Malaysia; Mexico; New Zealand; Philippines; Poland; Portugal; Romania; Russia; Singapore; Slovakia; South Africa; South Korea; Spain; Taiwan; Thailand; Turkey (Türkiye); Ukraine; Vietnam

References

Matasar MJ, Capra M, Ozcan M, Lv F, Li W, Yanez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor A, Bouabdallah K, Galiulin R, Uchida T, Soler LM, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):678-689. doi: 10.1016/S1470-2045(21)00145-5. Epub 2021 Apr 10.

Reference Type: RESULT

PMID: 33848462 (View on PubMed)

Morcos PN, Moss J, Veasy J, Hiemeyer F, Childs BH, Garmann D. Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen. Clin Pharmacol Ther. 2024 May;115(5):1092-1104. doi: 10.1002/cpt.3173. Epub 2024 Jan 16.

Reference Type: DERIVED

PMID: 38226495 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.clinicaltrialsregister.eu/

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https://clinicaltrials.bayer.com/study/17067

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Other Identifiers

2013-003893-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

17067

Identifier Type: -

Identifier Source: org_study_id