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Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL) (CHRONOS-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02367040
Recruitment Status : Active, not recruiting
First Posted : February 20, 2015
Last Update Posted : February 5, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:
The purpose of this study is 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.

Condition or disease Intervention/treatment Phase
Lymphoma,Non-Hodgkin Drug: Copanlisib (BAY 80-6946) Drug: Placebo Drug: Rituximab Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 453 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Copanlisib in Combination With Rituximab in Patients With Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL) - CHRONOS-3
Actual Study Start Date : August 3, 2015
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : August 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Copanlisib + Rituximab
Combination of the Copanlisib and rituximab
Drug: Copanlisib (BAY 80-6946)
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.

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.

Placebo Comparator: Placebo + Rituximab
Combination of Copanlisib placebo and rituximab
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.

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.




Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: 59 months ]
    Progression free survival is defined as the time (in days) from randomization to Disease Progression or death from any cause (if no progression documented).


Secondary Outcome Measures :
  1. Objective tumor response [ Time Frame: 59 months ]
    Proportion of responders with best response either complete or partial response.

  2. Duration of response (DOR) [ Time Frame: 59 months ]
    Duration of response will only be defined for patients with at least one Complete Response or Partial Response. Patients without disease progression or death at the time of analysis will be censored at the date of their last tumor evaluation.

  3. Complete response [ Time Frame: 59 months ]
    Assessed in all patients up to the time of analysis of Progression-free survival.

  4. Time to progression (TTP) [ Time Frame: 59 months ]
    The time from randomization to Disease progression or death related to Disease Progression.

  5. Overall survival (OS) [ Time Frame: 59 months ]
    The time (in days) from randomization until death from any cause.

  6. Time to deterioration in DRS-P of at least 3 points as measured by the FLymSI-18 (Lymphoma Symptom Index -18)questionnaire [ Time Frame: 59 months ]
  7. Number of participants with adverse Events as a measure of safety and tolerability [ Time Frame: 59 months ]
  8. Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less [ Time Frame: 59 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02367040


Locations
Hide Hide 192 study locations
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United States, California
West Covina, California, United States, 91790
United States, Kentucky
Ashland, Kentucky, United States, 41101
Louisville, Kentucky, United States, 40207
United States, Maryland
Bethesda, Maryland, United States, 20817
United States, Nevada
Las Vegas, Nevada, United States, 89169
United States, New Jersey
Montvale, New Jersey, United States, 07645
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
United States, New York
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, 10065
United States, Ohio
Canton, Ohio, United States, 44718
United States, Utah
Salt Lake City, Utah, United States, 84106
United States, Washington
Spokane, Washington, United States, 99208-1129
Argentina
Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina, C1431FWO
Rosario, Santa Fe, Argentina
San Miguel de Tucumán, Tucuman, Argentina, T4000
Córdoba, Argentina, X5000AOQ
Australia, Victoria
Ballarat, Victoria, Australia, 3350
Australia
Nedlands, Australia, 6009
Austria
Graz, Steiermark, Austria, 8036
Landeskrankenhaus Rankweil
Rankweil, Vorarlberg, Austria, 6830
Wien, Austria, 1090
Wien, Austria, 1130
Belgium
Ottignies, Belgium, 1340
Brazil
Ijuí, Rio Grande Do Sul, Brazil, 98700-000
Passo Fundo, Rio Grande Do Sul, Brazil, 99010-260
Porto Alegre, Rio Grande Do Sul, Brazil, 90110-270
Barretos, Sao Paulo, Brazil, 14784-400
Jaú, Sao Paulo, Brazil, 17210-120
São Paulo, Sao Paulo, Brazil, 01236-030
São Paulo, Sao Paulo, Brazil, 08270-070
Brazil, Brazil
Sao Paulo, Brazil, 05651-901
Bulgaria
Plovdiv, Bulgaria, 4002
Sofia, Bulgaria, 1756
Varna, Bulgaria, 9010
Chile
Temuco, Araucanía, Chile, 4810469
Santiago, Chile
China, Fujian
Fuzhou, Fujian, China, 350001
China, Guangdong
Guangzhou, Guangdong, China, 510060
Guangzhou, Guangdong, China, 510260
China, Hubei
Wuhan, Hubei, China, 430079
China, Jiangsu
Nanjing, Jiangsu, China, 210009
Suzhou, Jiangsu, China, 215006
China, Jiangxi
Nanchang, Jiangxi, China, 330029
China, Jilin
Changchun, Jilin, China
China, Liaoning
Shengyang, Liaoning, China, 110042
China, Sichuan
Chengdu, Sichuan, China, 610041
China, Xinjiang
Urumqi, Xinjiang, China, 830011
China, Zhejiang
Hangzhou, Zhejiang, China, 310003
Hangzhou, Zhejiang, China, 310022
China
Beijing, China, 100021
Beijing, China, 100050
Beijing, China, 100071
Beijing, China, 100083
Beijing, China, 100730
China, China
Chongqing, China, 400030
Shanghai, China, 200025
Shanghai, China, 200030
Shanghai, China, 200032
Tianjin, China, 300121
Tianjin, China
Colombia
Medellín, Antioquia, Colombia, 050034
Bogotá, Cundinamarca, Colombia
Montería, Córdoba, Colombia, 230002
Cali, Valle Del Cauca, Colombia
France
Bayonne, France, 64100
Brest, France, 29470
Metz Cedex 03, France, 57085
Nantes, France, 44805
NICE Cedex 2, France, 06189
Pessac, France, 33600
Poitiers, France, 86021
Germany
München, Bayern, Germany, 81377
Recklinghausen, Nordrhein-Westfalen, Germany, 45659
Halle, Sachsen-Anhalt, Germany, 06120
Dresden, Sachsen, Germany, 01307
Berlin, Germany, 10967
Greece
Athens, Greece, 106 76
Athens, Greece, 115 26
Chaidari, Greece, 12462
Patras, Greece, 26500
Hong Kong
Chai wan, Hong Kong
Hong Kong, Hong Kong
Shatin, Hong Kong
Hungary
Budapest, Hungary, 1083
Gyor, Hungary, 9023
Kaposvar, Hungary, 7400
Pecs, Hungary, 7624
Tatabanya, Hungary, 2800
Ireland
Dublin, Ireland, 7
Dublin, Ireland
Galway, Ireland
Italy
Udine, Friuli-Venezia Giulia, Italy, 33100
Genova, Liguria, Italy, 16132
Milano, Lombardia, Italy, 20133
Firenze, Toscana, Italy, 50141
Japan
Nagoya, Aichi, Japan, 464-8681
Nagoya, Aichi, Japan, 466-8650
Maebashi, Gunma, Japan, 371-8511
Kobe, Hyogo, Japan, 650-0047
Nankoku, Kochi, Japan, 783-8505
Sendai, Miyagi, Japan, 980-8574
Omura, Nagasaki, Japan, 856-8562
Kurashiki, Okayama, Japan, 710-8602
Hirakata, Osaka, Japan, 573-1191
Izumo, Shimane, Japan, 693-8501
Chuo-ku, Tokyo, Japan, 104-0045
Aomori, Japan, 030-8553
Fukuoka, Japan, 811-1395
Kumamoto, Japan, 860-8556
Niigata, Japan, 951-8566
Osaka, Japan, 545-8586
Yamagata, Japan, 990-9585
Korea, Republic of
Busan, Korea, Republic of, 49201
Busan, Korea, Republic of, 49241
Jeollanam-do, Korea, Republic of, 519-763
Seoul, Korea, Republic of, 03722
Seoul, Korea, Republic of, 06351
Seoul National University Hospital
Seoul, Korea, Republic of, 110-744
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Lithuania
Kaunas, Lithuania, LT-50009
Malaysia
Ipoh, Malaysia
Kota Kinabalu, Malaysia, 88200
Kuala Lumpur, Malaysia, 5600
Kuala Lumpur, Malaysia, 59100
Pulau Pinang, Malaysia
Selangor, Malaysia, 68000
Mexico
Morelia, Michoacán, Mexico, 58260
Monterrey, Nuevo Leon, Mexico, 64460
New Zealand
Tauranga, New Zealand, 3112
Philippines
Pasig City, Philippines
Quezon City, Philippines
Poland
Gdansk, Poland, 80-214
Gdynia, Poland, 81-519
Krakow, Poland, 30-510
Lublin, Poland, 20-090
Portugal
Vila Nova de Gaia, Porto, Portugal, 4434-502
Porto, Portugal, 4200-072
Romania
Brasov, Romania, 500152
Bucharest, Romania, 030171
Bucuresti, Romania, 010825
Bucuresti, Romania, 020125
Bucuresti, Romania, 022328
Cluj-Napoca, Romania, 400015
Craiova, Romania, 200143
Targu-Mures, Romania, 540136
Russian Federation
Chelyabinsk, Russian Federation, 454048
Irkutsk, Russian Federation, 664035
Kazan, Russian Federation, 420029
Kemerovo, Russian Federation, 650066
Kirov, Russian Federation, 610027
Novosibirsk, Russian Federation, 630087
Omsk, Russian Federation, 644013
St. Petersburg, Russian Federation, 197022
Volgograd, Russian Federation, 400138
Singapore
Singapore, Singapore, 119228
Singapore, Singapore, 169608
Singapore, Singapore, 169610
Slovakia
Poprad, Slovakia, 085 01
South Africa
George, Eastern Cape, South Africa, 6530
Johannesburg, Gauteng, South Africa, 2013
Spain
Majadahonda, Madrid, Spain, 28222
Barcelona, Spain, 08003
Barcelona, Spain, 08025
Barcelona, Spain, 08035
Madrid, Spain, 28041
Málaga, Spain, 29010
Salamanca, Spain, 37007
Taiwan
Changhua, Taiwan, 500
Kaohsiung, Taiwan, 833
Tainan, Taiwan
Taipei, Taiwan, 10002
Taipei, Taiwan, 11217
Thailand
Chiang Mai, Thailand, 50200
Pathumthani, Thailand, 10120
Turkey
Ankara, Turkey, 06100
Istanbul, Turkey, 34093
Izmir, Turkey, 35100
Kayseri, Turkey, 38039
Trabzon, Turkey, 61080
Ukraine
Cherkasy, Ukraine, 18009
Dnipro, Ukraine, 49102
Kiev, Ukraine, 03022
Lviv, Ukraine, 79044
Vinnitsa, Ukraine, 21029
Vietnam
Ha Noi, Vietnam
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02367040    
Other Study ID Numbers: 17067
2013-003893-29 ( EudraCT Number )
First Posted: February 20, 2015    Key Record Dates
Last Update Posted: February 5, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Clinical trial, Phase III
Phosphatidylinositol-3-kinase
Non-Hodgkin's lymphoma
Indolent B-cell non-Hodgkin's lymphoma
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents