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

Study Overview
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Brief Summary
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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)

Detailed Description
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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.

Official Title
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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)

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Drug: Copanlisib
* Drug: R-CHOP Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib and R-CHOP chemotherapy<br>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. | Drug: Copanlisib<br>* Copanlisib vials 60 mg<br>Drug: R-CHOP Chemotherapy<br>* Immunochemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year progression-free survival | Length of time that a patient lives without disease progression or relapse. | From the day of inclusion into the study until event (disease progression, relapse, death due to any other cause) occurs, assessed up to 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The percentage of patients in this study who are still alive. | From the day of inclusion into the study to death due to any cause, assessed up to 4 years. | 
| Event-free survival | Length of time that a patient remains free of certain events (disease progression, start of additional, unplanned antitumor therapy, relapse, death due to any other cause). | From the day of inclusion into the study until event (disease progression, start of additional, unplanned anti-tumor therapy, relapse, death due to any other cause) occurs, assessed up to 4 years. | 
| Rate of complete remission | Rate of complete remission measured as number of complete remissions divided by the number of patients included. | From the day of inclusion into the study until date of complete remission, assessed up to 4 years. | 
| Rate of partial remission | Rate of partial remission measured as number of partial remissions divided by the number of patients included. | From the day of inclusion into the study until date of partial remission, assessed up to 4 years. | 
| Overall response rate | Overall response rate measured as number of complete and partial remissions divided by the number of patients included. | From the day of inclusion into the study until date of complete or partial remission, assessed up to 4 years. | 
| Progression rate | Progression rate measured as number of progressions divided by the number of patients included. | From the day of inclusion into the study until date of progression during therapy or within 2 months after last treatment course. | 
| Relapse rate | Relapse rate measured as number of relapses divided by the number of patients included. | From the day of inclusion into the study until date of relapse during therapy or within 2 months after last treatment course. | 
| Duration of response | The time between the initial response to therapy and subsequent disease progression or relapse. | From documentation of tumor response to relapse, assessed up to 4 years. | 
| Adverse events and serious adverse events | Frequency of adverse events and serious adverse events | The documentation of adverse events, including serious adverse events, starts with first study treatment after patient inclusion and ends 100 days after the last application of copanlisib or any component of R-CHOP | 
| Rate of treatment-related deaths | The number of deaths during therapy or up to 2 months after the end of therapy divided by the number of patients included. | From the start of therapy up to 2 months after the end of therapy. | 
| Therapy cycles (number) | Number of therapy cycles | From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years. | 
| Therapy cycles (duration) | Duration of therapy cycles | From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years. | 
| Used drugs | Cumulative doses of R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) and copanlisib. | From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years. | 
| Outcome according to lymphoma biology | Lymphoma tissue from all patients will be characterized. | From the start of study until the end of study, assessed up to 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copanlisib