Copanlisib in Combination With Rituximab and CHOP Chemotherapy in Patients With Previously Untreated DLBCL

Prior treatment

• 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 Patients permanently withdrawn from study participation will not be allowed to re-enter the study.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).
• History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator)
• 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
• Concurrent diagnosis of pheochromocytoma
• 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
• Prior treatment with PI3K inhibitors

Other illness

• 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:
• 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
• Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated:
  • Cervical carcinoma in situ
  • Non-melanoma skin cancer
  • Superficial bladder cancer (Ta \[non-invasive tumor\], Tis \[carcinoma in situ\] and T1 \[tumor invades lamina propria\])
  • Localized prostate cancer
• Patients with seizure disorder requiring medication
• 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)
• 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
• Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent
• Known hypersensitivity to copanlisib or to any of the excipients of rituximab, cyclophosphamide, doxorubicine, vincristine, and/or prednisone

Lab values

• Type I or II diabetes mellitus with HbA1c \> 8.5% at screening or fasting plasma glucose \> 160 mg/dL at screening
• 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

Other

• Patients who meet any of the following criteria at the time of screening will be excluded.
• Known lymphoma involvement of the central nervous system
• CMV-PCR positive at baseline
• Patient is pregnant (β-HCG positive) or breast-feeding

• Histologically confirmed
  • DLBCL (NOS) or
  • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or
  • High-grade B-cell lymphoma (NOS)
  • Follicular lymphoma Grade 3B (primary diagnosis without history of indolent lymphoma) with a diagnostic biopsy performed within 3 months before study entry and with material available for central review and complimentary scientific analyses
• 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.