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)
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.
Inclusion Criteria:
1. Histologically confirmed
1. DLBCL (NOS) or
2. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or
3. High-grade B-cell lymphoma (NOS)
4. 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
2. 18-80 years of age
3. International Prognostic Index (IPI) 2-5
4. Eastern Cooperative Oncology Group Performance status (ECOG) 0-2
5. Life expectancy of at least 3 months
6. 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:
7. 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)
8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x
ULN for patients with liver involvement by lymphoma)
9. Lipase ≤ 1.5 x ULN
10. 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.
11. INR and PTT ≤ 1.5 x ULN
12. Platelet count ≥ 75,000 /mm3.
13. Hemoglobin (Hb) ≥ 8 g/dL
14. Absolute neutrophil count (ANC) ≥ 1,500/mm3
15. Left ventricular ejection fraction ≥ 50%
16. No prior lymphoma therapy
17. 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.
1. Previous assignment to treatment during this study. Patients permanently withdrawn
from study participation will not be allowed to re-enter the study.
2. 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).
3. 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:
4. Type I or II diabetes mellitus with HbA1c > 8.5% at screening or fasting plasma
glucose > 160 mg/dL at screening
5. History or concurrent condition of interstitial lung disease and/or severely impaired
lung function (as judged by the investigator)
6. Known lymphoma involvement of the central nervous system
7. Human immunodeficiency virus (HIV) infection
8. 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
9. CMV-PCR positive at baseline
10. Previous or concurrent history of malignancies within 5 years prior to study treatment
except for curatively treated:
1. Cervical carcinoma in situ
2. Non-melanoma skin cancer
3. Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and
T1 [tumor invades lamina propria])
4. Localized prostate cancer
11. 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
12. Patients with seizure disorder requiring medication
13. 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
14. Concurrent diagnosis of pheochromocytoma
15. Congestive heart failure > New York Heart Association (NYHA) class 2
16. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months)
17. Myocardial infarction less than 6 months before start of test drug
18. 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
19. Non-healing wound, ulcer, or bone fracture
20. Active, clinically serious infections > CTCAE Grade 2
21. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure >
90 mmHg despite optimal medical management)
22. 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
23. Ongoing inflammatory bowel disease
24. History of, or current autoimmune disease
25. Prior treatment with PI3K inhibitors
26. Any other co-existing medical or psychological condition that will preclude
participation in the study or compromise ability to give informed consent
27. Patient is pregnant (β-HCG positive) or breast-feeding
28. Known hypersensitivity to copanlisib or to any of the excipients of rituximab,
cyclophosphamide, doxorubicine, vincristine, and/or prednisone
