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This is a multicentric single arm phase II trial, to investigate the efficacy (in terms of PFS) of the combination regimen rituximab-bendamustine in association with copanlisib in patients affected by relapsed/refractory DLBCL, not eligible to HDC and ASCT or relapsed after intensified regimens.
Full description
The primary objective of this study is to evaluate the efficacy, in terms of Progression Free Survival (12m-PFS) at 12 months, of a treatment with copanlisib in combination with a standard rituximab-bendamustine regimen in patients with relapsed-refractory DLBCL, who have received at least one, but no more than three lines of treatment, including rituximab-based immunochemotherapy, not eligible for high-dose chemotherapy and ASCT or T-cell CAR-T therapy, or relapsed after these treatments.
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Inclusion criteria
Histologically confirmed diagnosis of DLBCL (de-novo DLBCL or DLBCL transformed by indolent lymphoma) including:
Patients must have relapsed (recurrence after complete response or presented progression after partial response) or refractory after at least ≥ 1 (but < 4) prior lines of therapy, including rituximab-based immunochemotherapy.
A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy.
Patients must not be eligible to high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or relapsed after that.
Patients must not be eligible to CAR T-cell therapy or relapsed after that.
Patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the 2014 Lugano criteria.
Male or female patient ≥ 18 years of age.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to lymphoma disease.
Ann Arbor stage II-IV disease.
Life expectancy of at least 3 months.
Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 6 months after last administration of bendamustine or copanlisib or 12 months after last rituximab dose. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile.
Adequate liver, renal and bone marrow function, assessed by baseline laboratory values as assessed within 7 days before starting study treatment; as assessed by the following (ULN= upper level of normality):
Left ventricular ejection fraction ≥ 45%.
Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure.
Exclusion criteria
Patients who meet any of the following criteria at the time of screening will be excluded.
Excluded medical conditions:
Primary mediastinal B-cell Lymphoma (PMBCL)
DLBCL with concomitant HHV8 positivity or chronic inflammation
ALK positive DLBCL
Known lymphomatous involvement of the central nervous system
Congestive heart failure > New York Heart Association (NYHA) class 2
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
Myocardial infarction less than 6 months before start of test drug
Uncontrolled arterial hypertension despite optimal medical management
HbA1c> 8.5%
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication. Patients with venous thrombotic events related to lymphoma vascular infiltration or compressive disease are eligible providing no signs of pulmonary embolism
Non-healing wound, ulcer, or bone fracture
Active, clinically serious infections > CTCAE Grade 2
History of, or current autoimmune disease
Known history of Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
DLBCL with concomitant primitive or secondary immunodeficiency
Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg are excluded. Patients positive for 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
CMV PCR positive at baseline
Previous or concurrent history of malignancies other than DLBCL within 5 years prior to study treatment except for curatively treated:
Patients with seizure disorder requiring medication
Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein: creatinine ratio > 3.5 on a random urine sample
History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
Concurrent diagnosis of pheochromocytoma
Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
Patients who meet any of the following criteria at the time of screening will be excluded.
Excluded medical conditions:
Primary mediastinal B-cell Lymphoma (PMBCL)
DLBCL with concomitant HHV8 positivity or chronic inflammation
ALK positive DLBCL
Known lymphomatous involvement of the central nervous system
Congestive heart failure > New York Heart Association (NYHA) class 2
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
Myocardial infarction less than 6 months before start of test drug
Uncontrolled arterial hypertension despite optimal medical management
HbA1c> 8.5%
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication. Patients with venous thrombotic events related to lymphoma vascular infiltration or compressive disease are eligible providing no signs of pulmonary embolism
Non-healing wound, ulcer, or bone fracture
Active, clinically serious infections > CTCAE Grade 2
History of, or current autoimmune disease
Known history of Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
DLBCL with concomitant primitive or secondary immunodeficiency
Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg are excluded. Patients positive for 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
CMV PCR positive at baseline
Previous or concurrent history of malignancies other than DLBCL within 5 years prior to study treatment except for curatively treated:
Patients with seizure disorder requiring medication
Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein: creatinine ratio > 3.5 on a random urine sample
History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
Concurrent diagnosis of pheochromocytoma
Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia
Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study e.g., uncontrolled diabetes, uncontrolled dyslipidemia, etc.)
Excluded previous therapies and medications:
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37 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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