A trial of copanlisib to treat non Hodgkin lymphoma (CHRONOS 4)

Please note - this trial is no longer recruiting patients. We hope to add results when they are available.

Cancer type:

Blood cancers
Non-Hodgkin lymphoma




Phase 3

This trial is open to people who have a non Hodgkin lymphoma that has come back after treatment (relapsed). It is for people with one of the following low grade (slow growing) types of non Hodgkin lymphoma (NHL) 

  • Follicular lymphoma  
  • Small lymphocytic lymphoma  
  • Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia
  • Marginal zone lymphoma

More about this trial

Chemotherapy and a biological therapy called rituximab are used to treat relapsed non Hodgkin’s lymphoma. 

Copanlisib is another type of biological therapy called a PI3K inhibitor. We know from research that copanlisib can help people with NHL that has relapsed. The trial team think adding copanlisib to rituximab and chemotherapy might be better for people with relapsed NHL. 

There are 2 parts in this trial. In part 1, researchers need to find the best dose of copanlisib to give with rituximab and chemotherapy. 

In the part 2 they will use the best dose of copanlisib with rituximab and chemotherapy. They want to find out if this combination is better than rituximab and chemotherapy. 

Who can enter

The following bullet points list the entry conditions for this trial. Talk to your doctor or the trial team if you are unsure about any of these. They will be able to advise you. 

You may be able to join this trial if you have one of the following low grade (slow growing) non Hodgkin lymphomas

  • Follicular lymphoma that is grade 1, 2 or 3a 
  • Small lymphocytic lymphoma  
  • Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia
  • Marginal zone lymphoma

And the following must apply

  • Your lymphoma has come back after having treatment with rituximab and a chemotherapy drug from the alkylating group
  • You must have at least 1 area of lymphoma that is measurable on a scan and hasn’t been treated with radiotherapy 
  • For those with Waldenstrom macrogobulinemia who don’t have an area of lymphoma that is measurable you must have a blood test result that shows a certain level of immunoglobulin M (IgM) paraprotein 
  • Your heart works well enough. Your doctor will test for you for this
  • You are well enough to be up and about for at least half the day (performance status 0, 1 or 2
  • You have satisfactory blood test results
  • You are willing to use reliable contraception during treatment and for a year afterwards for a woman and 6 months for a man if there is any chance you or your partner could become pregnant
  • You are at least 18 years old

You cannot join this trial if any of these apply

  • You have follicular lymphoma that is grade 3b 
  • You have lymphoma that has transformed from low grade to high grade
  • You have chronic lymphocytic leukaemia (CLL)
  • You have lymphoma in the brain or spinal cord 
  • Your lymphoma didn’t respond to previous treatment with rituximab or came back within 6 months of finishing treatment with rituximab 
  • You have had a total life time dose of an anthracycline chemotherapy drug such as doxorubicin
  • You have already had copanlisib
  • You have had idelalisib or a similar drug and your lymphoma stopped responding to it
  • You are taking, or have taken in the past 28 days, an experimental drug as part of a clinical trial 
  • You are taking any ongoing medication that affects your immune system apart from a dose of steroids less than 15mg a day, inhalers and creams 
  • You have had radiotherapy, immunotherapy or chemotherapy in the past 4 weeks
  • You have had radiotherapy with immunotherapy or an autologous bone marrow transplant in the past 3 months
  • You have had a drug, such as G-CSF, to stimulate the growth of blood cells within 2 weeks of starting treatment
  • You have had a blood transfusion or platelet transfusion within a week of starting treatment
  • You have had an allogenic bone marrow transplant or an organ transplant 
  • You have had major surgery or major trauma within 28 days of starting treatment
  • You have had surgery to remove a sample of your lymphoma within a week of starting treatment
  • You are taking medication to regulate your heart beat apart from beta blockers and digoxin
  • You have or had a lung disease that cause inflammation or scarring of the lungs
  • Your lungs aren’t working well enough
  • You have diabetes
  • You have HIV, hepatitis B or hepatitis C
  • Yu have a cytomeglavirus (CMV) infection
  • You have had another cancer in the past 5 years apart from successfully treated carcinoma in situ of the cervix, non melanoma skin cancer or an early cancer of the prostate or bladder
  • You have symptoms of congestive heart disease
  • You have been diagnosed with angina in the past 3 months or have unstable angina
  • You have had a heart attack in the past 6 months
  • You have high blood pressure that isn’t controlled with medication
  • You have had problems caused by blood clots such as a stroke or deep vein thrombosis (DVT) in the past 3 months
  • You have a moderate to severe problem with bleeding within 4 weeks of starting treatment in the trial
  • You have a wound that hasn’t healed, an ulcer or a bone fracture
  • You have an infection 
  • You have fits (seizures) and need medication to control them 
  • You still have moderate to severe side effects from previous treatment apart from hair loss
  • You take other medication that affects body substances called CYP enzymes
  • You are pregnant or breastfeeding

Trial design

This is an international trial. There are 2 parts to this trial. In both parts everyone has either 


  • Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)   

Which one you have depends on what treatment you have already had for your NHL. And for how long after the end of treatment you didn’t need further treatment for NHL. 

Part 1
In this part the researchers are looking at 2 different doses of copanlisib to find which would be the best to use in part 2. 

For this part the team need 12 to 24 people to join. 

The first people to join have a low dose of copanlisib. Depending on the side effects the next people might have the low dose or a higher dose. 

The recommended dose will depend on how many people have side effects and how serious they are. 

Your doctor might recommend you continue treatment as part of the trial. This will depend on which dose of copanlisib you had.

Part 2
Part 2 is a phase 3 trial. The researchers need 520 people to join worldwide.

This part is a randomised trial. The people taking part are put into 1 of 2 treatment groups by a computer. Neither you nor your doctor will be able to decide which group you are in. And neither of you will know which group you are in. This is called a double blind trial

The 2 groups are

  • copanlisib with R-B or R-CHOP
  • dummy drug (placebo) with R-B or R-CHOP

Diagram showing trial design for CHRONOS 4

You have all the drugs in R-B and R-CHOP, apart from prednisolone, as a drip into a vein. Prednisolone is a tablet. Your doctor will tell you how often you have the drugs and how to take prednisolone. 

R-B is given over a 4 week period and R-CHOP is given over a 3 week period. Each 3 and 4 week period is called a cycle of treatment. You have a maximum of 6 cycles. 

You have copanlisib or the dummy drug as a drip into a vein. 

  • For those having R-B you have it once a week for the first 3 weeks of every cycle
  • For those having R-CHOP you have it in the 1st and 2nd week of each cycle

After finishing R-B or R-CHOP you continue to have copanlisib or the dummy drug once a week for 3 weeks and then a week of not having it. This is the cycle of treatment.

You can have copanlisib or the dummy drug, with the other drugs or by themselves, for a maximum of 12 months. 

Tissue and blood samples
The researchers will ask for a sample of your cancer that was removed when you had a biopsy. 

You must have a new biopsy taken if the previous biopsy isn’t available or can’t be used. You need to agree to this to take part in the trial. 

As a part of the trial the researchers ask for extra blood samples to find out what happens to copanlisib in the body.  

They also use these samples to look for substances (biomarkers) that might tell them how well copanlisib is working. 

The team will ask you to take part in a phamacogenetic research project. You don’t have to agree to this. You can still take part in the trial. 

Quality of life 
For people in the 2nd part the trial team will ask you to fill out a questionnaire 

  • before you start treatment 
  • every 4 weeks during treatment
  • at the end of treatment 
  • a month after you finish treatment
  • every 3 months for years 1 and  2
  • every 6 months for years 3, 4 and 5

The questionnaire will ask about side effects and how you’ve been feeling.
This is called a quality of life study.

Please Note
There are certain foods, such as grapefruit, grapefruit juice, Seville oranges and starfruit, you can’t have while taking part in the trial. This is because these foods can affect how copanlisib works.

Hospital visits

You see the doctor to have some tests before you take part. These tests include

At the beginning of each cycle of treatment you see the doctor for a physical examination and blood tests. You have regular heart scans and heart traces during treatment. You have a CT scan or MRI scan every 3 months. 

Copanlisib can cause an increase in your blood sugar. This will be closely monitored during treatment. If your blood sugar levels go up you will be taught how to check them at home. 

At the end of treatment you see the doctor for the same tests you had at the start. 

You only have another bone marrow test if the results of the test at the beginning showed there was lymphoma in your bone marrow.  

Once treatment finishes you see the doctor every 3 months. 

Those who stopped treatment early for some reason and their lymphoma isn’t getting worse see the doctor 

  • every 3 months for up to 2 years
  • every 6 months for another 3 years

Side effects

Copanlisib is a new drug and there might be side effects we don’t know about yet. The most common side effects include

We have information on the side effects of 

Your doctor will talk to about the side effects of all the treatment used in this trial before you agree to take part.

Recruitment start:

Recruitment end:

How to join a clinical trial

Please note: In order to join a trial you will need to discuss it with your doctor, unless otherwise specified.

Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Chief Investigator

Dr Ruth Pettengell

Supported by


Freephone 0808 800 4040

Last review date

CRUK internal database number:


Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

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