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CHRONOS-3: 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 lymphoma

Description

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

Status

Accepting new patients

Primary Study Objective(s)

The primary objective 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 indolent non-Hodgkin lymphoma, who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of more than 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy or for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including male or female patients older than 18, who have:

  • A histologically confirmed diagnosis of indolent non-Hodgkin lymphoma in CD20 positive patients, with histological subtype limited to:
    • Follicular lymphoma Grade1-2-3a
    • Small lymphocytic lymphoma with absolute lymphocyte count <5x10*9/L at study entry
    • Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia
    • Marginal zone lymphoma (splenic, nodal, or extra-nodal)
  • 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 two months of single-agent therapy [less than two months of therapy is allowed for patients who responded to single-agent rituximab]; at least two 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.)
  • Not been diagnosed with Waldenström macroglobulinemia and have at least one bi-dimensionally measurable lesion, which has not been previously irradiated, according to the Lugano Classification (For patients with splenic marginal-zone lymphoma this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease.)
  • Been affected by Waldenström macroglobulinemia, 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
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • A life expectancy of at least three months
  • Available fresh tumor tissue and/or archival tumor tissue obtained within five years of the consent date at screening
  • Adequate baseline laboratory values collected no more than seven days before starting study treatment
  • A left ventricular ejection fraction ≥ 45%
  • A progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing treatment or are 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 six months after completion of the last rituximab-containing treatment.)

Patients in whom chemotherapy is contraindicated are defined by one of the following features:

  • Older than 80 years
  • Younger than 80 and at least one of the following conditions: At least three Grade 3 CIRS-G comorbidities or at least one Grade 4 CIRS-G comorbidity (if compatible to participation in the study)

Excluding patients who have:

  • A histologically confirmed diagnosis of follicular lymphoma Grade 3b or transformed disease, or chronic lymphocytic leukemia
  • A 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: a progression free interval or treatment free interval of less than six months since the last rituximab containing treatment, including rituximab maintenance, as assessed by the investigator.)
  • A 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
  • HbA1c > 8.5% at screening
  • A known history of human immunodeficiency virus (HIV) infection
  • Hepatitis B or hepatitis C (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
  • Had prior treatment with copanlisib
  • Cytomegalovirus (CMV) infection (Patients who are CMV PCR positive at baseline will not be eligible.)