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

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ClinicalTrials.gov Identifier: NCT02367040
Recruitment Status : Recruiting
First Posted : February 20, 2015
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE February 12, 2015
First Posted Date  ICMJE February 20, 2015
Last Update Posted Date August 8, 2019
Actual Study Start Date  ICMJE August 3, 2015
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2016)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2015)
Progression free survival (PFS) [ Time Frame: 51 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).
Change History Complete list of historical versions of study NCT02367040 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 25, 2016)
  • Objective tumor response [ Time Frame: 59 months ]
    Proportion of responders with best response either complete or partial response.
  • 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.
  • Complete response [ Time Frame: 59 months ]
    Assessed in all patients up to the time of analysis of Progression-free survival.
  • Time to progression (TTP) [ Time Frame: 59 months ]
    The time from randomization to Disease progression or death related to Disease Progression.
  • Overall survival (OS) [ Time Frame: 59 months ]
    The time (in days) from randomization until death from any cause.
  • 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 ]
  • Number of participants with adverse Events as a measure of safety and tolerability [ Time Frame: 59 months ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2015)
  • Objective tumor response [ Time Frame: 51 months ]
    Proportion of responders with best response either complete or partial response
  • Duration of response (DOR) [ Time Frame: 51 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.
  • Complete response [ Time Frame: 51 months ]
    Assessed in all patients up to the time of analysis of Progression-free survival
  • Time to progression (TTP) [ Time Frame: 51 months ]
    The time from randomization to Disease progression or death related to Disease Progression
  • Overall survival (OS) [ Time Frame: 51 months ]
    The time (in days) from randomization until death from any cause
  • Time to deterioration in DRS-P of at least 3 points as measured by the FLymSI-18 (Lymphoma Symptom Index -18)questionnaire [ Time Frame: 51 months ]
  • Number of participants with adverse Events as a measure of safety and tolerability [ Time Frame: 51 months ]
  • 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: 51 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Lymphoma,Non-Hodgkin
Intervention  ICMJE
  • 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: 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.
Study Arms  ICMJE
  • Experimental: Copanlisib + Rituximab
    Combination of the Copanlisib and rituximab
    Interventions:
    • Drug: Copanlisib (BAY 80-6946)
    • Drug: Rituximab
  • Placebo Comparator: Placebo + Rituximab
    Combination of Copanlisib placebo and rituximab
    Interventions:
    • Drug: Placebo
    • Drug: Rituximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 2, 2018)
450
Original Estimated Enrollment  ICMJE
 (submitted: February 13, 2015)
567
Estimated Study Completion Date  ICMJE August 28, 2020
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 last rituximab-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); 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 (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 last rituximab-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-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 containing treatment (including rituximab maintenance). For patients considered unwilling/unfit to receive chemotherapy : progression free interval or treatment free interval of less than 6 months since the last rituximab containing treatment (including rituximab maintenance), 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bayer Clinical Trials Contact (+)1-888-84 22937 clinical-trials-contact@bayer.com
Contact: For trial location information (Phone Menu Options '3' or '4') (+)1-888-84 22937
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belarus,   Belgium,   Brazil,   Bulgaria,   Chile,   China,   Colombia,   Denmark,   France,   Germany,   Greece,   Hong Kong,   Hungary,   Ireland,   Italy,   Japan,   Korea, Republic of,   Lithuania,   Luxembourg,   Malaysia,   Mexico,   New Zealand,   Philippines,   Poland,   Portugal,   Romania,   Russian Federation,   Singapore,   Slovakia,   South Africa,   Spain,   Sweden,   Taiwan,   Thailand,   Turkey,   Ukraine,   United States,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02367040
Other Study ID Numbers  ICMJE 17067
2013-003893-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP