CHRONOS-4: a randomised phase 3 trial testing the targeted treatment copanlisib in combination with rituximab and chemotherapy for people with relapsed or refractory low-grade non-Hodgkin lymphoma

This trial is testing a new drug in combination with standard treatment for people with low-grade (slow-growing) non-Hodgkin lymphoma (NHL) who have been treated before but need more treatment.

Purpose of trial

The aim of the trial is to see if adding copanlisib to standard chemo-immunotherapy (rituximab with chemotherapy) can improve outcomes for people with low-grade NHL that has relapsed (come back) or was refractory (didn’t respond) to previous treatment.

The trial treatment is being tested in people with:


Copanlisib is a cell signal blocker. It blocks signals that encourage cancer cells to grow.

Rituximab is a monoclonal antibody. The combinations of chemotherapy (bendamustine or CHOP) with rituximab are widely used as treatments for relapsed or refractory low-grade non-Hodgkin lymphoma.

This is a randomised trial. Participants are put into one of the following groups at random:

  • copanlisib with rituximab and chemotherapy
  • placebo (a dummy treatment) with rituximab and chemotherapy.

You can’t choose which group you are in and neither can your doctor. Neither you nor your doctor will know whether you are having copanlisib or placebo.

The chemotherapy you have is either bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). Your doctor can decide which you have depending on your personal circumstances, for example what treatment you had before and how you responded it. They can give you information about the chemotherapy they recommend and what it involves.

All of the drugs are given intravenously (into a vein) except for prednisolone (the ‘P’ in CHOP), which is taken as tablets.

You have up to 6 cycles of treatment. You have treatment on some days followed by a rest period for your body to recover before the next cycle begins. When you have finished the 6 cycles of combination treatment, you continue to have copanlisib or placebo alone for up to another 6 cycles. If you are having bendamustine with rituximab and copanlisib or placebo, each cycle is 3 weeks. If you are having CHOP with rituximab and copanlisib or placebo, each cycle is 4 weeks.

Who can enter

Your consultant can give you advice on whether this trial might be suitable for you.

Around 676 people are needed for this trial.

You may be able to enter if

  • You have follicular lymphoma (grade 1, 2 or 3a), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinaemia, lymphoplasmacytic lymphoma, or marginal zone lymphoma (splenic, nodal or MALT).
  • A sample of the lymphoma is available for tests or you are willing to have a fresh sample taken.
  • You have had 1–3 previous courses of treatment, with at least 1 course including rituximab and chemotherapy drugs known as alkylating agents.
  • Your lymphoma is measurable with the tests used in the trial.
  • You are well enough to have the trial treatments.
  • Your blood and health test results are satisfactory.
  • You and your partner are willing to use reliable contraception if there is any chance of you or your partner becoming pregnant.
  • You are 18 or over.

You will not be able to enter if

  • Your follicular lymphoma is grade 3b.
  • Your lymphoma has transformed (changed) into a faster-growing type of lymphoma.
  • You have chronic lymphocytic leukaemia (CLL).
  • You had resistance to rituximab at any time in your past treatment or your lymphoma progressed (got worse) within 6 months of your last treatment containing rituximab.
  • You had resistance to idelalisib or a similar drug in the past.
  • Your lymphoma is affecting your central nervous system (CNS; brain and spinal cord).
  • You have significant heart or lung problems or uncontrolled high blood pressure.
  • You have diabetes.
  • You have HIV, hepatitis B or hepatitis C.

Further information

More information about this trial is available at and Cancer Research UK.