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

Lymphoma,Non-Hodgkin Clinical Trial

— CHRONOS-3  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02367040
• Other study ID #: 17067
• Secondary ID: 2013-003893-29
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 3, 2015
• Est. completion date: May 31, 2024

Study information

• Verified date: April 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 458
• Est. completion date: May 31, 2024
• Est. primary completion date: August 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma,Non-Hodgkin

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
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	MSK Basking Ridge	New Jersey	New Jersey
United States	MSK Bergen	New Jersey	New Jersey
United States	MSK Monmoth	New Jersey	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

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

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) Based on Independent Central Review.	Progression-free survival (PFS) was defined as the time from randomization to progressive disease (PD) or death due to any cause, whichever was earlier according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section).	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	Objective Response Rate (ORR)	Objective response rate (ORR) was defined as the percentage of participants who have a best response rating over the whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria (kindly refer to the links in the Protocol section).	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	Complete Response Rate (CRR)	Complete response rate (CRR) was defined as the percentage of participants who had a best response rating over the whole duration of the study (i.e., until the time of analysis of PFS) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of Complete Response according to the Owen Criteria (kindly refer to the links in the Protocol section).	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	Duration of Response (DOR)	Duration of response (DOR) was defined as the time (in days) from first observed tumor response Complete Response (CR), Very good partial response (VGPR), Partial Response (PR) or Minor Response (MR) until progression or death from any cause, whichever occurred earlier according to the Owen Criteria (kindly refer to the links in the Protocol section). Only patients with response in FAS were included in the analysis.	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	Disease Control Rate (DCR)	Disease control rate was defined as the percentage of participants who had a best response rating as Complete Response (CR), Partial Response (PR) or stable disease (SD) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) as a response rating of CR, very good partial response (VGPR), PR, minor response (MR) or stable disease (SD) according to the Owen Criteria (kindly refer to the links in the Protocol section).	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	Time to Progression (TTP)	Time to progression (TTP) was defined as the time (days) from date of randomization to date of first observed disease progression according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section).	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	Overall Survival (OS)	Overall survival was defined as the time (in days) from randomization until death from any cause.	From randomization up to approximately 7 years of follow-up.
Secondary	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.	Time to deterioration in DRS-P (Disease-Related Symptoms - Physical) of at least three points was defined as the time (in days) from randomization to DRS-P decline, progression, or death due to any reason, whichever occurred earlier. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.	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	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.	Time to improvement in DRS-P (Disease-Related Symptoms - Physical) was defined as the time (in days) from randomization to DRS-P improvement of at least three points. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.	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	Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date.	Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.	Up to 30 days after end of treatment with study drug, data reporting cut-off at 5 years from the first participant randomization date
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date.	Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.	Up to 30 days after end of treatment with study drug, data reporting cut-off at 7 years from the first participant randomization date

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