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

NCT ID: NCT04263584

Last Updated: 2024-01-05

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-19
• Study Completion Date: 2025-04-30

Brief Summary

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)

Detailed 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.

Conditions

Diffuse Large B Cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Copanlisib and R-CHOP chemotherapy

All patients will receive 6 cycles of R-CHOP immunochemotherapy every two weeks with the following doses per cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/ m², vincristine 1.4 mg/m² (dose capped at 2 mg or 1 mg for individuals above 60 years of age), prednisolone 500 mg. In addition, copanlisib at a dose of 60 mg will be administered on days 1 and 8 of each 21-day cycle of R-CHOP in the first 6 patients. If dose limiting toxicity (DLT) occurs in no more than one out of these 6 patients during cycle 1, additional 6 patients at 60 mg will be enrolled and treated for at least 1 cycle before opening the phase II portion of the study. If a DLT is observed in 2 or more of the first 6 patients during cycle 1 the dose of copanlisib will be reduced to 45 mg on days 1 and 8 for the next 6 patients. The data of the safety run-in analysis (first 12 patients) will be presented to the Data Safety Monitoring Board and the recommended phase 2 dose will be determined.

Group Type: EXPERIMENTAL

Copanlisib

Intervention Type: DRUG

Copanlisib vials 60 mg

R-CHOP Chemotherapy

Intervention Type: DRUG

Immunochemotherapy

Interventions

Copanlisib

Copanlisib vials 60 mg

Intervention Type: DRUG

R-CHOP Chemotherapy

Immunochemotherapy

Intervention Type: DRUG

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

University Hospital Muenster

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Prof. Georg Lenz, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Muenster

Locations

University Hospital RWTH Aachen

Aachen, , Germany

Klinikum-Bremen-Mitte

Bremen, , Germany

St.-Johannes-Hospital Dortmund

Dortmund, , Germany

Onkozentrum Dresden

Dresden, , Germany

University Hospital Halle

Halle, , Germany

Westpfalz-Klinikum

Kaiserslautern, , Germany

ÜBAG MVZ Dr. Vehling-Kaiser GmbH

Landshut, , Germany

University Hospital Leipzig

Leipzig, , Germany

Hospital of the Ludwig-Maximilians-University (LMU) Munich

Munich, , Germany

University Hospital Muenster

Münster, , Germany

Hospital Stuttgart - Stuttgart Cancer Center

Stuttgart, , Germany

University Hospital Ulm

Ulm, , Germany

Countries

Germany

Other Identifiers

UKM18-0021

Identifier Type: -

Identifier Source: org_study_id