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This is a prospective, multicenter, non-randomized, open-label, phase II study to describe the efficacy of R-CHOP plus copanlisib including a safety run-in phase in order to detect early and common unexpected toxicities caused by the addition of copanlisib to the standard immuno-chemotherapy R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL)
Full description
Patients diagnosed with DLBCL can be cured with a combined approach of CHOP chemotherapy and the anti-CD20 antibody rituximab in roughly 65% of cases. About one third of patients with DLBCL relapse or show primary progressive disease after modern first-line therapy. The outcome of these patients is poor in particular if first-line therapy contained rituximab. Novel therapeutic approaches are urgently warranted. Thus, it is the goal to further improve progression-free Survival (PFS) and overall Survival (OS) by combining R-CHOP with copanlisib. Copanlisib is a small molecule pan-class 1 PI3K inhibitor and approved by US FDA for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
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Inclusion criteria
Histologically confirmed
18-80 years of age
International Prognostic Index (IPI) 2-5
Eastern Cooperative Oncology Group Performance status (ECOG) 0-2
Life expectancy of at least 3 months
Women of childbearing potential 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 the last administration of study treatment. 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 (failure rate of less than 1%), e.g. intrauterine device, intrauterine hormone-releasing system, 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 baseline laboratory values collected no more than 7 days before starting study treatment:
Total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement or with biliary obstruction due to lymphoma)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement by lymphoma)
Lipase ≤ 1.5 x ULN
Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the CKD-EPI formula or by 24-hour sampling. If the later result is within acceptable range, it may be used to fulfill the inclusion criteria instead.
INR and PTT ≤ 1.5 x ULN
Platelet count ≥ 75,000 /mm3.
Hemoglobin (Hb) ≥ 8 g/dL
Absolute neutrophil count (ANC) ≥ 1,500/mm3
Left ventricular ejection fraction ≥ 50%
No prior lymphoma therapy
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.
Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
Previous (within 28 days or less than 5 half-lives of the drug before start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s).
Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent persons (e.g. employee or student of the investigational site).
Excluded medical conditions:
Type I or II diabetes mellitus with HbA1c > 8.5% at screening or fasting plasma glucose > 160 mg/dL at screening
History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator)
Known lymphoma involvement of the central nervous system
Human immunodeficiency virus (HIV) infection
Hepatitis B (HBV) and C (HCV) infection. Patients with serologic markers of HBV immunization due to vaccination (HBsAg negative, Anti-HBc negative and Anti-HBs positive) will be eligible
CMV-PCR positive at baseline
Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated:
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
Patients with seizure disorder requiring 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
Concurrent diagnosis of pheochromocytoma
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
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
Non-healing wound, ulcer, or bone fracture
Active, clinically serious infections > CTCAE Grade 2
Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
Known history of drug induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension
Ongoing inflammatory bowel disease
History of, or current autoimmune disease
Prior treatment with PI3K inhibitors
Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent
Patient is pregnant (β-HCG positive) or breast-feeding
Known hypersensitivity to copanlisib or to any of the excipients of rituximab, cyclophosphamide, doxorubicine, vincristine, and/or prednisone
Primary purpose
Allocation
Interventional model
Masking
62 participants in 1 patient group
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Central trial contact
Prof. Georg Lenz, MD
Data sourced from clinicaltrials.gov
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