ALEXANDER: a phase 1/2 trial testing AUTO3 CAR-T cells with pembrolizumab consolidation as treatment for people with diffuse large B-cell lymphoma (DLBCL) that has relapsed (come back) or was refractory (didn’t respond) to previous treatment

---

Purpose of trial

The aim of this trial is to find out more about a new type of treatment, AUTO3 CAR-T cells, in people with diffuse large B-cell lymphoma (DLBCL).

If DLBCL relapses (comes back), it might be treated with a stronger chemotherapy and a self (autologous) stem cell transplant, which uses your own stem cells to help your body recover after high doses of chemotherapy.  

Some people can’t have a stem cell transplant because the lymphoma does not respond sufficiently to their first chemotherapy. Some people relapse again, despite having a stem cell transplant. In both cases, treatment options are very limited. 

This trial is testing whether AUTO3 CAR-T cells are safe and effective for people whose DLBCL has come back or has not responded to stronger treatment. This trial is also testing whether a short course of pembrolizumab after AUTO3 CAR-T cell treatment can reduce the risk of the lymphoma relapsing. 

The trial aims to find out:

• if AUTO3 CAR-T cells are safe for people with DLBCL
• what the most effective, safe dose of AUTO3 CAR-T cells is (how many AUTO3 CAR-T cells you should be given)
• how effective this treatment is 
• whether taking pembrolizumab with AUTO3 CAR-T cell treatment can reduce the risk of the lymphoma coming back.

---

Treatments

This treatment uses your own immune system to try to destroy lymphoma cells. Your body produces a type of lymphocyte, called a T cell, to fight infections and diseases, including lymphoma. AUTO3 CAR-T cells are made from your own T cells. Your T cells are collected from your blood and genetically modified (changed) to have chimeric antigen receptors (CARs) on their surface. The genetically modified T cells (CAR-T cells) are grown in the laboratory until there are enough of them. They are then given back to you. The AUTO3 CAR-T cells can recognise and kill lymphoma cells with two proteins (called CD19 and CD22) on their surface. 

Pembrolizumab is an immune checkpoint inhibitor. It works by helping the immune system recognise and kill the lymphoma. It is already approved to treat some people with lymphoma and other cancers. In this trial it is being used as a consolidation treatment, which may help the modified CAR-T cells to kill some remaining cancer cells and reduce the risk of your lymphoma coming back.

Everyone in this trial receives AUTO3 CAR-T cells if they can be successfully manufactured. It is not always possible to modify the T cells or produce enough AUTO3 CAR-T cells. If this happens, your doctor can discuss alternative treatment options with you.

There are several treatment stages in this trial:

• Your lymphocytes are collected at the hospital so that the T lymphocytes (or T cells) can be modified at the sponsor’s manufacturing site. This collection process is called ‘leukapheresis’. The T cells are modified and grown in the manufacturing site until there are enough cells to make the treatment.
• The week before you have the AUTO3 CAR-T cells, you have chemotherapy with cyclophosphamide and fludarabine. This chemotherapy is called pre-conditioning. These drugs are given intravenously (into a vein). The pre-conditioning chemotherapy is given over 3 days the week before the AUTO3 CAR-T cell infusion.
• You have a single dose of AUTO3 CAR-T cells. The cells are given intravenously and usually take a few minutes to infuse.
• About 2 weeks after AUTO3 CAR-T cell treatment, or the day before treatment, you start pembrolizumab consolidation. You have pembrolizumab intravenously once every 3 weeks (which makes up a cycle of treatment). You have 3 cycles of pembrolizumab.

There are 2 parts in this study. You enter either part 1 or part 2.

• In part 1, up to four different doses of AUTO3 CAR-T cells are being tested. The first few participants have the lowest dose being tested. If this doesn’t cause troublesome problems, the next few people have a higher dose. If the higher dose doesn’t cause troublesome problems, the last few people have the highest dose. 
• In part 2, the safest and most effective dose from part 1 of the trial is tested in more people.

You are monitored carefully during and after the treatment. This is because some people have severe reactions to CAR-T cells and can get very unwell. Your medical team should discuss all the possible side effects of CAR T-cells with you.

You have regular blood tests after treatment to see how it is affecting your body and the lymphoma.

---

Who can enter

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

Approximately 150 people are needed for this trial.

You may be able to enter if:

• You have DLBCL or another type of large B-cell lymphoma.
• You have already had at least one course of chemotherapy and your lymphoma did not respond (refractory lymphoma), or
• You have already had two or more courses of treatment and your lymphoma has come back (relapsed), or 
• You have had a self (autologous) stem cell transplant and your lymphoma did not respond or has come back.
• Your lymphoma is measurable by the tests used in the trial.
• You are well enough to take part in the trial.
• Your blood and other health test results are satisfactory.
• You haven’t needed any growth factor (G-CSF) treatment in the last 10 days.
• You are willing to use reliable contraception during treatment and females are willing to continue to use contraception for at least 12 months after treatment.
• You are 18 or over.

You won’t be able to enter if:

• You have any health problems that your doctor thinks might make it unsafe for you to have the trial treatment, including heart problems, lung problems, serious autoimmune problems (where your body attacks itself), bleeding in your digestive system, or an active infection.
• Your lymphoma is in your central nervous system (CNS; brain and spinal cord) and has not been successfully treated or you have previously had any cancer in your CNS.
• You’ve ever had problems with your CNS, for example brain injuries, dementia or epilepsy.
• You’ve had a blood clot requiring blood thinning medicines in the last 3 months.
• You’ve had major surgery in the last 3 months.
• You’ve had another cancer unless you have been cured for at least 2 years or unless it is a localised cancer (your doctor can advise you if this applies to you). 
• You’ve been treated with similar treatments to pembrolizumab before.
• You’ve had a bad reaction to treatments targeting CD19 or CD22 before.
• You are taking certain medicines (ask your doctor for advice).
• You have had radiotherapy in the last 4–24 weeks depending how extensive the radiotherapy was.
• You are being treated with another experimental treatment or you are taking part in another clinical trial. 
• You are pregnant or breastfeeding.

---

Further information

More information about this trial is available at clinicaltrials.gov/ct2/show/NCT03287817.