Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Study Overview
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Brief Summary
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The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine [R-B] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone [R-CHOP]) is effective and safe, compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab-based immunochemotherapy and alkylating agents.

Detailed Description
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Patients should be in need of and fit for immunochemotherapy and should not be resistant to rituximab (resistance defined as lack of response or progression within 6 months of the last date of rituximab administration, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody). This study will be composed of two parts: Safety run-in and phase III part. The purpose of the safety run-in part of this study is to assess whether the drug being tested (copanlisib) in combination with standard immunochemotherapy (R-B or R-CHOP) is safe and at what dose level of the study drug (copanlisib - 45mg or 60 mg) patients are able to tolerate the study treatment combination. In addition to finding a safe and tolerable dose level for the phase III part of the study, efficacy will also be evaluated for patients that stay on the study treatment during the safety run-in. The phase III part of the study started with the determined recommended dose of copanlisib of 60 mg in combination with R-B. Combination treatment of copanlisib at the recommended/approved dose of 60 mg with R-B or R-CHOP was completed in April 2021. A maximum of 24 patients will take part in the safety run-in part of this study. In the phase III part approximately 520 patients will be randomly assigned to blinded treatment arms of copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP. Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be administered for a maximum of 6 cycles (C1-C6). Copanlisib/placebo (study drug) monotherapy will be administered from C7 onwards.

Official Title
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A Phase III, Randomized, Double-blind, Controlled Multicenter Study of Intravenous PI3K Inhibitor Copanlisib in Combination With Standard Immunochemotherapy Versus Standard Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Copanlisib (BAY80-6946)
* Drug: Placebo
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Bendamustine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of B lymphocyte antigen CD20 positive iNHL with histological subtype limited to: Follicular lymphoma G1-2-3a Small lymphocytic lymphoma with absolute lymphocyte count <5x10E9/L at study entry Lymphoplasmacytoid lymphoma / Waldenström macroglobulinemia (LPL / WM) Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) Patients must have relapsed (recurrence after complete response or presented progression after partial response) or progressed after at least one but at most three prior lines of therapy, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody (e.g. obinutuzumab) -based immunochemotherapy and alkylating agents (if given concomitantly is considered one line of therapy). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy with single agent rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody can be considered a previous regimen in the case the patient responded to it); at least 2 consecutive cycles of polychemotherapy; autologous transplant; or radioimmunotherapy. Previous exposure to other PI3K Inhibitors (except copanlisib) is acceptable provided there is no resistance (resistance defined as no response (response defined as partial response [PR] or complete response [CR]) at any time during therapy, or progressive disease (PD) after any response (PR/CR) or after stable disease within 6 months from the end of the therapy with a PI3K inhibitor. Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal and positive immunofixation test. Male or female patients ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Life expectancy of at least 3 months Availability of fresh tumor tissue and/or archival tumor tissue at Screening Adequate baseline laboratory values as assessed within 7 days before starting study treatment. Left ventricular ejection fraction ≥ 50% Exclusion Criteria Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of transformed disease, a fresh biopsy is recommended. Rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last date of rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody administration, including maintenance with these drugs). HbA1c > 8.5% at screening History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator) Known lymphomatous involvement of the central nervous system Known history of human immunodeficiency virus (HIV) infection Hepatitis B (HBV) or hepatitis C (HCV) infection. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA. Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will not be eligible.CMV PCR test is considered positive if, the result can be interpreted as a CMV viremia according to local standard of care. Uncontrolled hypertension despite optimal medical management (per investigator´s assessment) Congestive heart failure > New York Heart Association (NYHA) class 2

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib + R-B or R-CHOP / Arm 1<br>Combination of copanlisib with standard immunochemotherapy (rituximab and bendamustine) [R-B] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP] (safety run-in and phase III) | Drug: Copanlisib (BAY80-6946)<br>* Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. For patients on R-B dosing of copanlisib will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered and then rituximab followed by bendamustine. For patients on R-CHOP dosing of copanlisib will be administered on Days 1 and 8 of each 21-day cycle. Treatment with copanlisib/placebo will be continued up to 12 months. Copanlisib will be administered before rituximab followed by cyclophosphamide, doxorubicin and vincristine infusions. Prednisone/prednisolone tablets to be taken for 5 days.<br>Drug: Rituximab<br>* Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Doxorubicin<br>* Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Vincristine<br>* Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Bendamustine<br>* Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B<br>Drug: Prednisone<br>* Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP<br>|
| Placebo Comparator: Placebo + R-B or R-CHOP / Arm 2<br>Combination of placebo and R-B or R-CHOP (phase III only) | Drug: Placebo<br>* Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered as per copanlisib described above. Applies to the phase III part of the study only.<br>Drug: Rituximab<br>* Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Doxorubicin<br>* Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Vincristine<br>* Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP<br>Drug: Bendamustine<br>* Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B<br>Drug: Prednisone<br>* Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in_Determination of the recommended Phase-III dose (RP3D) of copanlisib in combination with standard immunochemotherapy assessed by the occurrence of dose-limiting toxicities / adverse events |  | At Cycle 1: 21 days or 28 days | 
| Phase III_Evaluation whether copanlisib in combination with standard immunochemotherapy is superior to placebo and standard immunochemotherapy assessed by the prolongation of progression free survival (PFS) | Progression free survival is defined as the time (in days) from randomization to disease progression or death from any cause (if no progression documented). | Up to 52 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in_Best Overall Response (BOR) |  | After Cycle 1: Up to 12 months | 
| Safety run-in_Number of participants with treatment-emergent adverse events |  | Up to 13 months | 
| Phase III_Objective tumor response rate (ORR) | Proportion of patients who have a best overall response over the whole duration of the study (i.e. up to time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia a best overall response of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria. | Up to 52 months | 
| Phase III_Duration of tumor response (DOR) | Time (in days) from first observed tumor response (complete response [CR], very good partial response [VGPR], partial response [PR], or minor response [MR]) until PD or death from any cause, whichever is earlier. DOR will only be analyzed for patients with at least one CR, VGPR, PR, or MR. | Up to 52 months | 
| Phase III_Complete tumor response rate (CRR) | Proportion of patients who have a best overall response of CR during the study (i.e., up to time of analysis of PFS). | Up to 52 months | 
| Phase III_Time to tumor progression (TTP) | Time from randomization to PD or death related to PD, whichever is earlier. | Up to 52 months | 
| Phase III_Time to next anti-lymphoma treatment (TTNT) | Time from stop of study medication to start of new anti-lymphoma therapy. | Up to 52 months | 
| Phase III_Overall survival (OS) | The time (in days) from randomization until death from any cause. | Up to 5 years after last patient´s first treatment | 
| Phase III_Time to improvement in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire | Time to improvement in disease-related physical symptoms (DRS-P) is defined as time from randomization to first increase in DRS-P score of at least 3 points from baseline before tumor progression. Will be evaluated for patients with a baseline DRS-P score of 30 points or less. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma. | Up to 52 months | 
| Phase III_Time to deterioration in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire | Time to deterioration in disease-related physical symptoms (DRS-P) is defined as time (in days) from randomization to the earliest occurrence of 1) first reduction of DRS-P score from baseline ≥ 3 points, or 2) radiological progression or biochemical progression for Waldenström macroglobulinemia patients without lesions evaluable by imaging, or 3) death from any cause. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma. | Up to 52 months | 
| Phase III_Number of participants with treatment-emergent adverse events |  | Up to 52 months | 
| Phase III_Disease control rate (DCR) | Proportion of patients who have a best response rating of CR, VGPR, PR, MR, or stable disease (SD) (excluding unconfirmed early SD) that is achieved during treatment or within 35 days after termination of study treatment. | Up to 52 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical trial, Phase III, Phosphatidylinositol-3-kinase, Non-Hodgkin's lymphoma, Indolent B-cell non-Hodgkin's lymphoma