A study investigating copanlisib in combination with standard treatment versus standard treatment alone in order to see if copanlisib improves the response to standard treatment in patients with relapsed indolent non-Hodgkin's lymphoma.

• Register: EUCTR
• Last refreshed on: 8 January 2024
• Main ID: EUCTR2015-001088-38-ES
• Date of registration: 05/11/2015
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG
• Public title: A study investigating copanlisib in combination with standard treatment versus standard treatment alone in order to see if copanlisib improves the response to standard treatment in patients with relapsed indolent non-Hodgkin's lymphoma.
• Scientific title: 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) - CHRONOS-4 - Phase III study of copanlisib with standard immunochemotherapy in relapsed iNHL
• Date of first enrolment: 12/01/2016
• Target sample size: 700
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001088-38
• 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: no 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, Canada, Chile, China, Colombia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Lithuania, Luxembourg, Mexico, New Zealand, Philippines, Poland, Portugal, Romania, Russian Federation, Saudi Arabia, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam

Contacts

• Name: Bayer Clin. Trials Contact CTP Team
• Affiliation: Bayer HealthCare AG

• Name: Bayer Clin. Trials Contact CTP Team
• Affiliation: Bayer HealthCare AG

Key inclusion & exclusion criteria

Inclusion criteria:
Main criteria for inclusion:
- Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to:
o Follicular lymphoma (FL) G1, G2, or G3a
o Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at the time of diagnosis and at study entry
o Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM)
o Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
- Patients must have relapsed after at least 1 prior line of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K inhibitors is acceptable provided there is no resistance (treatment stopped for other reasons than progressive disease).
- Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification.
- 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.
- 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%.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 600
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion criteria:
Main criteria for exclusion:
- Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3b or transformed disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of transformed disease, a fresh biopsy is recommended.
- Rituximab resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last course of treatment with a rituximab containing regimen).
- Type I or II diabetes mellitus with HbA1c > 8.5% 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 lymphomatous 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.
- Congestive heart failure > New York Heart Association (NYHA) class 2.
- Uncontrolled hypertension (systolic blood pressure > 150 mmHg or
diastolic pressure > 90 mmHg despite optimal medical management).


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

Health Condition(s) or Problem(s) studied

Patients with relapsed indolent non-Hodgkin's lymphoma
MedDRA version: 18.1 Level: PT Classification code 10029600 Term: Non-Hodgkin's lymphoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

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 DIHYDROCHLORID 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

Primary Outcome(s)

Primary end point(s): The primary completion event for this study is PFS (progression assessed by central review or death from any cause if death occurs before progression). The analysis will be performed when approximately 273 PFS events in FL patients occur.

Secondary Objective: Safety run-in part
The secondary objectives are to evaluate (for patients that stay on treatment after Cycle 1):
Radiological and clinical indicators of treatment efficacy
Safety and tolerability of copanlisib in combination with R-B/R-CHOP

Phase III part (randomized, controlled trial)
Secondary objectives are to evaluate:
Other radiological and clinical indicators of treatment efficacy (objective response rate (ORR), duration of response (DOR), complete response rate (CRR), time to progression (TTP), time to next antilymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in diseaserelated symptoms - physical)
Safety and tolerability of copanlisib in combination with R-B/R-CHOP

Timepoint(s) of evaluation of this end point: The analysis will be performed when approximately 273 PFS events in FL patients occur.

Main Objective: Safety run-in part
Primary objective is to determine:
The recommended phase III dose (RP3D) of copanlisib in combination with standard immunochemotherapy (rituximab and bendamustine [RB] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]) to be used in the subsequent phase III part of the study

Phase III part (randomized, controlled trial)
Primary objective is:
To evaluate whether copanlisib in combination with standard immunochemotherapy, is superior to standard immunochemotherapy in prolonging progression-free survival (PFS), in patients with relapsed indolent non-Hodgkin?s lymphoma, who have received one or more lines of treatment, including rituximab and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: The analysis will be performed when approximately 273 PFS events in FL patients occur.

Secondary end point(s): Secondary efficacy variables are objective response rate (ORR), duration of response (DOR), complete response rate (CRR), time to progression (TTP), time to next anti-lymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in disease-related symptoms - physical (disease-related symptoms - physical (DRS-P)) of at least 3 points of lymphoma as measured by the FLymSI-18 questionnaire (FLymSI = NCCN-FACT Lymphoma Symptom Index).

Secondary ID(s)

BAY80-6946

2015-001088-38-FI

BAY80-6946/17833

Source(s) of Monetary Support

Bayer HealthCare AG

Ethics review

Status: Approved
Approval date: 23/11/2015
Contact: