Clinical trial NCT02367040: Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma,Non-Hodgkin
Keywords: Clinical trial, Phase III
Phosphatidylinositol-3-kinase
Non-Hodgkin's lymphoma
Indolent B-cell non-Hodgkin's lymphoma
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2015-02-20
Enrollment: 458
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Progression Free Survival (PFS) Based on Independent Central Review.
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Complete Response Rate (CRR)
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Duration of Response (DOR)
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Disease Control Rate (DCR)
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Time to Progression (TTP)
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Overall Survival (OS)
timeFrame: From randomization up to approximately 7 years of follow-up.
measure: Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire.
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire.
timeFrame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date.
timeFrame: Up to 30 days after end of treatment with study drug, data reporting cut-off at 5 years from the first participant randomization date
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date.
timeFrame: Up to 30 days after end of treatment with study drug, data reporting cut-off at 7 years from the first participant randomization date
Other outcomes:
Locations:
city: West Covina
country: United States
state: California
city: Ashland
country: United States
state: Kentucky
city: Louisville
country: United States
state: Kentucky
city: Bethesda
country: United States
state: Maryland
city: Las Vegas
country: United States
state: Nevada
city: New Jersey
country: United States
facility: MSK Basking Ridge
state: New Jersey
city: New Jersey
country: United States
facility: MSK Bergen
state: New Jersey
city: New Jersey
country: United States
facility: MSK Monmoth
state: New Jersey
city: Harrison
country: United States
facility: MSK Westchester
state: New York
city: Long Island City
country: United States
facility: MSK Commack
state: New York
city: Long Island City
country: United States
facility: MSK Rockville Centre
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Canton
country: United States
state: Ohio
city: Salt Lake City
country: United States
state: Utah
city: Spokane
country: United States
state: Washington
city: Buenos Aires
country: Argentina
state: Ciudad Auton. De Buenos Aires
city: Rosario
country: Argentina
state: Santa Fe
city: San Miguel de Tucumán
country: Argentina
state: Tucuman
city: Córdoba
country: Argentina
city: Ballarat
country: Australia
state: Victoria
city: Nedlands
country: Australia
city: Graz
country: Austria
state: Steiermark
city: Wien
country: Austria
city: Wien
country: Austria
city: Ottignies
country: Belgium
city: Passo Fundo
country: Brazil
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
state: Rio Grande Do Sul
city: Barretos/SP
country: Brazil
state: Sao Paulo
city: Jaú
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Temuco
country: Chile
state: Araucanía
city: Fuzhou
country: China
state: Fujian
city: Guangzhou
country: China
state: Guangdong
city: Guangzhou
country: China
state: Guangdong
city: Wuhan
country: China
state: Hubei
city: Nanjing
country: China
state: Jiangsu
city: Suzhou
country: China
state: Jiangsu
city: Nanchang
country: China
state: Jiangxi
city: Changchun City
country: China
state: Jilin
city: Shengyang
country: China
state: Liaoning
city: Chengdu
country: China
state: Sichuan
city: Urumqi
country: China
state: Xinjiang
city: Hangzhou
country: China
state: Zhejiang
city: Hangzhou
country: China
state: Zhejiang
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Chongqing
country: China
city: Chongqing
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Tianjin
country: China
city: Tianjin
country: China
city: Medellin
country: Colombia
state: Antioquia
city: Bogota
country: Colombia
state: Cundinamarca
city: Montería
country: Colombia
state: Córdoba
city: Cali
country: Colombia
state: Valle Del Cauca
city: Bayonne
country: France
city: Brest
country: France
city: Metz Cedex 03
country: France
city: Nice Cedex 2
country: France
city: Pessac
country: France
city: Poitiers
country: France
city: Saint-Herblain
country: France
city: München
country: Germany
state: Bayern
city: Recklinghausen
country: Germany
state: Nordrhein-Westfalen
city: Halle
country: Germany
state: Sachsen-Anhalt
city: Dresden
country: Germany
state: Sachsen
city: Berlin
country: Germany
city: Athens
country: Greece
city: Athens
country: Greece
city: Chaidari
country: Greece
city: Patras
country: Greece
city: Chai Wan
country: Hong Kong
city: Hong Kong
country: Hong Kong
city: Budapest
country: Hungary
city: Gyor
country: Hungary
city: Kaposvar
country: Hungary
city: Pecs
country: Hungary
city: Tatabanya
country: Hungary
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Galway
country: Ireland
city: Udine
country: Italy
state: Friuli-Venezia Giulia
city: Genova
country: Italy
state: Liguria
city: Milano
country: Italy
state: Lombardia
city: Firenze
country: Italy
state: Toscana
city: Nagoya
country: Japan
state: Aichi
city: Nagoya
country: Japan
state: Aichi
city: Maebashi
country: Japan
state: Gunma
city: Kobe
country: Japan
state: Hyogo
city: Nankoku
country: Japan
state: Kochi
city: Sendai
country: Japan
state: Miyagi
city: Omura
country: Japan
state: Nagasaki
city: Kurashiki
country: Japan
state: Okayama
city: Hirakata
country: Japan
state: Osaka
city: Izumo
country: Japan
state: Shimane
city: Chuo-ku
country: Japan
state: Tokyo
city: Aomori
country: Japan
city: Fukuoka
country: Japan
city: Kumamoto
country: Japan
city: Niigata
country: Japan
city: Osaka
country: Japan
city: Yamagata
country: Japan
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Busan
country: Korea, Republic of
city: Busan
country: Korea, Republic of
city: Hwasun Gun
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Kaunas
country: Lithuania
city: Cheras
country: Malaysia
city: Kota Kinabalu
country: Malaysia
city: Kuala Lumpur
country: Malaysia
city: Perak
country: Malaysia
city: Pulau Pinang
country: Malaysia
city: Selangor
country: Malaysia
city: Morelia
country: Mexico
state: Michoacán
city: Monterrey
country: Mexico
state: Nuevo Leon
city: Tauranga
country: New Zealand
city: Pasig city
country: Philippines
city: Taguig City
country: Philippines
city: Gdansk
country: Poland
city: Gdynia
country: Poland
city: Krakow
country: Poland
city: Lublin
country: Poland
city: Porto
country: Portugal
city: Porto
country: Portugal
city: Brasov
country: Romania
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Cluj-Napoca
country: Romania
city: Craiova
country: Romania
city: Targu Mures
country: Romania
city: Chelyabinsk
country: Russian Federation
city: Irkutsk
country: Russian Federation
city: Kazan
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Kirov
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Omsk
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Poprad
country: Slovakia
city: George
country: South Africa
state: Eastern Cape
city: Johannesburg
country: South Africa
state: Gauteng
city: Majadahonda
country: Spain
state: Madrid
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Salamanca
country: Spain
city: Changhua
country: Taiwan
city: Kaohsiung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Chiangmai
country: Thailand
city: Pathumthani
country: Thailand
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Kayseri
country: Turkey
city: Trabzon
country: Turkey
city: Cherkasy
country: Ukraine
city: Dnipro
country: Ukraine
city: Kyiv
country: Ukraine
city: Lviv
country: Ukraine
city: Vinnitsa
country: Ukraine
city: Ha Noi
country: Vietnam
city: Ho Chi Minh City
country: Vietnam
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.