A prospective multicenter phase 2 study of copanlisib in combination with rituximab and CHOP chemotherapy (COPA-R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Muenster AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 May 2020 → 3 May 2025

Decision date (initial)

2024-09-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bayer AG

External identifiers

EU CT number

2024-517166-42-00

EudraCT number

2018-003560-31

ClinicalTrials.gov

NCT04263584

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective with respect to safety is the rate of patients with dose-limiting toxicity during cycle 1 of R-CHOP and copanlisib. The primary efficacy objective is to estimate the 2-year PFS with 95% CI achieved with copanlisib in combination with R-CHOP in newly diagnosed DLBCL patients (18-80 years) and an IPI 2 - 5.

Secondary objectives 2

1. Secondary objectives for efficacy are to evaluate Overall survival (OS), Event-free survival (EFS), Complete remission (CR), partial remission (PR), overall response (OR=CR+PR), Primary progression (PD) rate, Rate of relapse an Duration of response. All objectives for efficacy will be evaluated in molecular subtypes of DLBCL
2. Secondary objectives for safety are to evaluate Rate of treatment-related death, Toxicity and protocol adherence of COPA-R-CHOP

Conditions and MedDRA coding

Diffuse large B-cell lymphoma (DLBCL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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) or Follicular lymphoma Grad 3B (primary diagnosis without history of indolent lymphoma)
2. 18-80 years of age
3. International Prognostic Index (IPI) 2-5
4. toxicity and response criteria of the eastern cooperative oncology group (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.
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. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement by lymphoma)
9. Lipase ≤ 1.5 x ULN
10. GFR ≥ 40 mL/min/1.73 m2 according to the CKD-EPI Creatinine Equation (2009)
11. INR and PTT ≤ 1.5 x ULN
12. Platelet count ≥ 75,000 /mm3.
13. Hemoglobin ≥ 8 g/dL
14. Absolute neutrophil count ≥ 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 28

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)
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. HIV infection
8. HBV and 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: 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
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, doxorubicin, vincristine, and/or prednisone

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety run-in part: The primary endpoint is the recommended phase 2 dose after analysis of the first 12 patients treated. All patients: 2-year PFS with 95% CI of all patients treated.

Secondary endpoints 2

1. Secondary endpoints for efficacy: OS, EFS, CR, PR, ORR, PD, DOR, rate of relapse, Outcome in molecular subtypes of DLBCL
2. Secondary endpoints for safety: Adverse events (AE), Serious AEs (SAE), Number of treatment related deaths, Incidence of secondary malignancies, Number and duration of therapy cycles, Cumulative doses of cyclophosphamide, doxorubicin, vincristine, rituximab and copanlisib

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Muenster AöR

Sponsor organisation

Universitaetsklinikum Muenster AöR

Address

Albert-Schweitzer-Campus 1, Sentrup Sentrup

City

Muenster

Postcode

48149

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Muenster AöR

Contact name

Central study office

Public contact point

Organisation

Universitaetsklinikum Muenster AöR

Contact name

Central study office

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications