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: 22 April 2024
• Main ID: EUCTR2015-001088-38-PL
• Date of registration: 16/02/2016
• Prospective Registration: Yes
• Primary sponsor: Bayer 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: 05/04/2016
• Target sample size: 520
• 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: yes 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

Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czech Republic, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Contacts

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

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer 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 study entry
o Lymphoplasmacytic lymphoma/ Waldenström macroglobulinemia
(LPL/WM)
o 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 rituximabbased
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 can be considered a
previous regimen in the case the patient responded to it); at least 2
consecutive cycles of polychemotherapy; autologous transplant;
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 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%.
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 260
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 260

Exclusion criteria:
- 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 date of rituximab
administration, including rituximab maintenance).
- 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 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 SOC.
- Congestive heart failure > New York Heart Association (NYHA) class 2.
- Uncontrolled hypertension despite optimal medical management (per
investigator's assessment).


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 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: BAY 80-6946
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)

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 at least one, but at most three lines of treatment, including rituximab-based immunochemotherapy and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option

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 280 PFS events in the FAS are observed.

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 256 PFS events in the FAS are observed.

Secondary Outcome(s)

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).

Timepoint(s) of evaluation of this end point: All secondary efficacy endpoints will be analyzed in the FAS at the time
of the analysis of the primary efficacy endpoint. Depending on study
success in the primary efficacy variable in the FAS, the secondary
efficacy variables ORR, time to deterioration and time to improvement in
DRS-P subscale of FLymSI-18 of at least 3 points will be tested
hierarchically in the FAS.
ORR will be tested first and, if successful, will be followed by time to
deterioration in DRS-P, and finally, if all previous tests are successful,
will be followed by time to improvement of DRS-P.

Secondary ID(s)

BAY80-6946/17833

2015-001088-38-FI

BAY80-6946

Source(s) of Monetary Support

Bayer HealthCare AG

Ethics review

Status: Approved
Approval date: 02/03/2016
Contact: