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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02626455




Registration number
NCT02626455
Ethics application status
Date submitted
3/11/2015
Date registered
10/12/2015
Date last updated
4/07/2019

Titles & IDs
Public title
Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)
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)
Secondary ID [1] 0 0
2015-001088-38
Secondary ID [2] 0 0
17833
Universal Trial Number (UTN)
Trial acronym
CHRONOS-4
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphoma, Non-Hodgkin 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Copanlisib (BAY80-6946)
Treatment: Drugs - Placebo
Treatment: Drugs - Rituximab
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Vincristine
Treatment: Drugs - Bendamustine
Treatment: Drugs - Prednisone

Experimental: Copanlisib + R-B or R-CHOP / Arm 1 - 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)

Placebo Comparator: Placebo + R-B or R-CHOP / Arm 2 - Combination of placebo and R-B or R-CHOP (phase III only)


Treatment: Drugs: Copanlisib (BAY80-6946)
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. Copanlisib will be administered before rituximab followed by cyclophosphamide, doxorubicin and vincristine infusions. Prednisone/prednisolone tablets to be taken for 5 days.

Treatment: Drugs: Placebo
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.

Treatment: Drugs: Rituximab
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.

Treatment: Drugs: Cyclophosphamide
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

Treatment: Drugs: Doxorubicin
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

Treatment: Drugs: Vincristine
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

Treatment: Drugs: Bendamustine
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

Treatment: Drugs: Prednisone
Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
At Cycle 1: 21 days or 28 days
Primary outcome [2] 0 0
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).
Timepoint [2] 0 0
Up to 52 months
Secondary outcome [1] 0 0
Safety run-in_Best Overall Response (BOR)
Timepoint [1] 0 0
After Cycle 1: Up to 12 months
Secondary outcome [2] 0 0
Safety run-in_Number of participants with treatment-emergent adverse events
Timepoint [2] 0 0
Up to 13 months
Secondary outcome [3] 0 0
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), very good partial response (VGPR), partial response (PR) or minor response (MR).
Timepoint [3] 0 0
Up to 52 months
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Up to 52 months
Secondary outcome [5] 0 0
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).
Timepoint [5] 0 0
Up to 52 months
Secondary outcome [6] 0 0
Phase III_Time to tumor progression (TTP) - Time from randomization to PD or death related to PD, whichever is earlier.
Timepoint [6] 0 0
Up to 52 months
Secondary outcome [7] 0 0
Phase III_Time to next anti-lymphoma treatment (TTNT) - Time from stop of study medication to start of new anti-lymphoma therapy.
Timepoint [7] 0 0
Up to 52 months
Secondary outcome [8] 0 0
Phase III_Overall survival (OS) - The time (in days) from randomization until death from any cause.
Timepoint [8] 0 0
Up to 5 years after last patient´s first treatment
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Up to 52 months
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
Up to 52 months
Secondary outcome [11] 0 0
Phase III_Number of participants with treatment-emergent adverse events
Timepoint [11] 0 0
Up to 52 months

Eligibility
Key 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-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 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%
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 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 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Kinghorn Cancer Centre - Darlinghurst
Recruitment hospital [2] 0 0
Calvary Mater Hospital Newcastle - Waratah
Recruitment hospital [3] 0 0
Pindara Private Hospital - Benowa
Recruitment hospital [4] 0 0
Royal Brisbane & Women's Hospital - Brisbane
Recruitment hospital [5] 0 0
Flinders Medical Centre - Adelaide
Recruitment hospital [6] 0 0
Ashford Cancer Centre Pty Ltd - Kurralta Park
Recruitment hospital [7] 0 0
Frankston Hospital - Frankston
Recruitment hospital [8] 0 0
The Alfred Hospital - Prahran
Recruitment hospital [9] 0 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [10] 0 0
Eastern Health Integrated Renal Service - Box Hill
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2298 - Waratah
Recruitment postcode(s) [3] 0 0
4217 - Benowa
Recruitment postcode(s) [4] 0 0
4029 - Brisbane
Recruitment postcode(s) [5] 0 0
5042 - Adelaide
Recruitment postcode(s) [6] 0 0
5037 - Kurralta Park
Recruitment postcode(s) [7] 0 0
3199 - Frankston
Recruitment postcode(s) [8] 0 0
3181 - Prahran
Recruitment postcode(s) [9] 0 0
6150 - Murdoch
Recruitment postcode(s) [10] 0 0
3128 - Box Hill
Recruitment outside Australia
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Marche
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Nara
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Osaka
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Shimane
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Tochigi
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Tokyo
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Aomori
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Hiroshima
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Kumamoto
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Kyoto
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Niigata
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Yamagata
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Gdynia
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Krakow
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Lodz
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Braga
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Porto
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Portugal
State/province [150] 0 0
Vila Nova de Gaia
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Omsk
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Ho Chi Minh City

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Bayer
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02626455
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bayer Study Director
Address 0 0
Bayer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Bayer Clinical Trials Contact
Address 0 0
Country 0 0
Phone 0 0
(+)1-888-84 22937
Fax 0 0
Email 0 0
clinical-trials-contact@bayer.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02626455