A study investigating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma.

• Register: EUCTR
• Last refreshed on: 3 August 2020
• Main ID: EUCTR2013-003893-29-IE
• Date of registration: 05/03/2015
• Prospective Registration: Yes
• Primary sponsor: Bayer AG
• Public title: A study investigating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma.
• Scientific title: A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin’s lymphoma (iNHL) - CHRONOS-3 - Copanlisib and rituximab in relapsed iNHL
• Date of first enrolment: 25/06/2015
• Target sample size: 450
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003893-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, China, Colombia, Denmark, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Republic of, Lithuania, Luxembourg, Malaysia, Mexico, New Zealand, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Taiwan, Thailand, Turkey, Ukraine, United States, Vietnam

Contacts

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Ability to understand and willingness to sign written ICF. Signed ICF must be obtained before any study specific procedure.
2. Histologically confirmed diagnosis of iNHL in CD20 positive patients, with histological subtype limited to: -Follicular lymphoma (FL) grade 1-2-3a, -Small lymphocytic lymphoma (SLL) with absolute monoclonal lymphocyte count <5x109/L at study entry, -Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), -Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
3. Patients must have relapsed (recurrence after complete response or presented progression after partial response) after the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of following: at least 2 mths of single-agent therapy (less than 2 mths of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of polychemotherapy; acceptable provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
4. Non-WM patients must have at least one bi-dimensionally measurable lesion (not been previously irradiated) according to 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.
5. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in baseline radiologic assessment must have measurable disease, defined as presence of IgM paraprotein with a minimum IgM level =2 x upper limit of normal and positive immunofixation test
6. Male/female patients =18 yrs of age
7. ECOG performance status =2
8. Life expectancy at least 3 mths
9. Availability of fresh tissue and/or archival tumor tissue for central pathology (obtained within 5 yrs of the consent date) at Screening
10. Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for time period between signing of ICF and 12 mths (for WOCBP) and 5 mths (for men) after last administration of study treatment. A high FSH level in postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator/a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. IUD, IUS, bilateral tubal occlusion, vasectomized partner and sexual abstinence. Use of condoms by male patients required unless female partner permanently sterile
11. 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-Meulengracht syndrome or for patients with cholestasis due to compressive adenopathies of the hepatic hilum), -ALT and AST =2.5 x ULN (=umm5 x ULN for patients with liver involvement by lymphoma), -Lipase =1.5 x ULN, -GFR =30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula, -International normalized ratio (INR) =1.5 and partial thromboplastin time (PTT) =1.5 x ULN. PT can be used instead of INR if =1.5 x ULN, -Platelet count =75,000/mm3. For patients with confir
Exclusion criteria:
1. Previous assignment to treatment during this study
2. Close affiliation with site
3. FL grade 3b or transformed disease, or CLL
4. Progression free interval or treatment free interval of less than 12 mths since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) containing treatment (including maintenance with these drugs). For patients considered unwilling/unfit to receive chemotherapy: progression free interval or treatment free interval of less than 6 mths since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody containing treatment (including maintenance with these drugs), as assessed by the investigator
5. Previous/concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL (as described in Inc. criteria 2)within 5 yrs prior to treatm start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis & T1), and asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for =1 yr prior to randomization
6. Known lymphomatous involvement of central nervous system
7. Congestive heart failure > NYHA class 2
8. Unstable angina, new-onset angina. Myocardial infarction less than 6 mths before start of test drug
9. Uncontrolled arterial Hypertension despite optimal medical management
10. Patients with HbA1c >8.5% at Screening
11. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, DVT or pulmonary embolism within 3 mths before start of study treatment
12. Non-healing wound, ulcer, or bone fracture
13. Active, clinically serious infections >CTCAE Grade 2
14. Known history of HIV infection
15. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start. Patients positive for HBsAg or HBcAb will be eligible if negative for HBV-DNA, these patients should receive prophylactic antiviral therapy; patients positive for anti-HCV antibody will be eligible if negative for HCV-RNA
16. seizure disorder requiring medication
17. evidence or history of bleeding diathesis. Any hemorrhage or bleeding event =CTCAE Grade 3 within 4 wks prior to start of study treatm
19. Proteinuria of CTCAE Grade 3
20. History/concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
21. Concurrent diagnosis of pheochromocytoma
22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a max of 7 days before start of treatm and negative result must be documented before start of treatm
23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters
24. Known hypersensitivity to any of test drugs, test drug classes, or excipients in formulation
25. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of study results
26. Any illness or medical conditions that are unstable or could jeopardize safety of patients and compliance in study
28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatm.
29

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Patients with relapsed indolent B-cell non-Hodgkin's lymphoma
MedDRA version: 23.0 Level: PT Classification code 10029600 Term: Non-Hodgkin's lymphoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: Copanlisib
Product Code: BAY84-1236
Pharmaceutical Form: Lyophilisate for solution for infusion
INN or Proposed INN: Copanlisib
Current Sponsor code: BAY 84-1236
Other descriptive name: BAY 80-6946 (as dihydrochloride BAY 84-1236)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Lyophilisate for solution for infusion
Route of administration of the placebo: Intravenous use

Product Name: Rituximab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Time (in days) from randomization to PD or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will be censored at Day 1.

Main Objective: The primary objective of this study is:
- To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of =12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.

Primary end point(s): Progression free survival (PFS)

Secondary Objective: The secondary objectives of this study are to evaluate:
• The following characteristics of disease-related symptoms: “time to deterioration” and “time to improvement”
• Other radiological and clinical indicators of treatment efficacy
• Safety and tolerability of copanlisib

The other objectives of this study are to evaluate:
- Pharmacokinetics
- Biomarkers
- Quality of life

Secondary Outcome(s)

Secondary end point(s): - Objective tumor response rate (ORR)
- Duration of response (DOR)
- Complete response rate (CRR)
- Time to progression (TTP)
- Overall survival (OS)
- Time to deterioration in DRS-P
- Time to improvement in DRS-P

Timepoint(s) of evaluation of this end point: - ORR - assessed in all patients up to the time of analysis of PFS.
- DOR: time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until PD or death from any cause, whichever is earlier
- CRR: assessed in all patients up to the time of analysis of PFS.
- TTP: time from randomization to PD or death related to PD, whichever is earlier
- OS: time (in days) from randomization until death from any cause.
- Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire.
- Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less.

Secondary ID(s)

BAY80-6946/17067

BAY80-6946

Source(s) of Monetary Support

Bayer AG

Ethics review

Status: Approved
Approval date: 25/06/2015
Contact: