A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome

Trial Design:

STELLAR is a UK multi-centre trial for patients with newly-diagnosed Richter's Syndrome (RS), which is a rare and highly aggressive transformation of another blood cancer, chronic lymphocytic leukaemia (CLL). It has two parts: a randomised trial (the main component of the trial) which compares the current standard of care with an 'experimental' combination, and a platform for trialing single-arm studies investigating new drugs, or new combinations of drugs, for treating patients with newly-diagnosed Richter's Syndrome. The first novel treatment to be investigated in STELLAR is acalabrutinib which is a 'small molecule' drug that targets and blocks one of the pathways that causes the CLL (and by extension Richter's Syndrome) cancer cells to grow and multiply. Stopping the proliferation of cancer cells is a key aim of cancer treatments. There have been promising studies using acalabrutinib to treat patients with CLL and patients with Richter's Syndrome, but so far these are small and have not compared acalabrutinib, on its own or in a combination, with the current Standard of Care treatment for Richter's Syndrome: CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab). In the STELLAR trial we will investigate if adding acalabrutinib to CHOP-R gives a better outcome for patients than CHOP-R alone. The sample sizes described below have been calculated by biostatisticians and are based on the known rates of progression, survival, and response rates for patients with Richter's Syndrome. The sample sizes given below will enable us to answer the research questions with the appropriate number of patients with a strong confidence interval.

In the randomised component of STELLAR, 60 eligible patients will be randomised 1:1 between the current standard of care for Richter's Syndrome (CHOP-R) and the experimental treatment of CHOP-R plus acalabrutinib such that 30 patients are in each of these two sets. The trial is not blinded so participants, clinic staff, and trial staff will know which treatment they receive after the patient has been randomised. Participants will have frequent assessments, which includes assessments after 4 and 6 cycles of treatment to see if the treatment is working, and all patients will be followed up for a minimum of 2 years. The primary aim of the randomised component is to see if adding acalabrutinib to CHOP-R improves the rate of progression free survival (PFS) for RS patients, i.e. if they are in remission from Richter's Syndrome for a longer period of time. It is important that this component is randomised so that the comparison of the two treatments will be fair and unbiased.

In the platform study part of STELLAR, single-arm cohorts (not randomised) will receive treatment which will test the activity of novel combinations or treatment. The platform may be expanded to test other promising treatments if any are identified whilst the randomised trial is open to recruitment. In the first platform study there are two cohorts which will answer two different research questions. The platform arms are not randomised or blinded because they are not comparable; it is rather that they help us to determine whether these treatments may be possible candidates for future therapies.

• Cohort 1 (21-30 participants) will be made up of patients whose Richter's Syndrome has progressed (their disease has got worse) whilst being treated with CHOP-R (or CHOP + another immunotherapy treatment) alone or who have relapsed with Richter's Syndrome after completing treatment with CHOP-R. Entry to this cohort will be prioritised for patients who have taken part in the STELLAR randomised trial, but will be opened up to patients outside STELLAR if fewer than 21 patients from STELLAR take part. In this cohort we will investigate if giving acalabrutinib treatment on its own improves outcomes for patients who have got worse on or relapsed after the current standard of care (CHOP-R).
• Cohort 2 (up to 15 patients) are anthracycline-naïve (they haven't received CHOP-R before) Richter's Syndrome patients, who have been diagnosed whilst being treated with ibrutinib (defined as a diagnosis within 4 weeks of the last dose of ibrutinib). Ibrutinib is the same class of drug as acalabrutinib, though acalabrutinib is a newer drug. Ibrutinib is often used to treat CLL and it is not known if patients who have been treated with ibrutinib will respond to treatment with acalabrutinib if they have Richter's Syndrome. Ibrutinib is becoming a routine treatment for CLL, so it is important to find out if acalabrutinib will help patients who do not respond to ibrutinib. These patients are not included in the randomised trial so that we can determine if acalabrutinib will work in these ibrutinib-treated patients.

Participants:

Participants will be identified at specialist haemato-oncology centres around the UK through multidisciplinary team meetings and consultant referral from other centres. Patients will be approached by their consultant and other, trained, members of the clinic team to introduce and discuss the trial. Patients will receive a patient information sheet and will be given at least 24 hours to review the information and ask any additional questions they may have.

Patients who have enrolled on STELLAR who are offered entry into Cohort 1 because their disease has worsened when treated with CHOP-R alone, will already be familiar with the trial processes and systems. They will need to know all of the new information about acalabrutinib (the treatment for Cohort 1) and will be provided with a separate patient information sheet, clinicians will aim to give patients at least 24 hours to review the information. Because these patients are already familiar with the trial and will need urgent treatment they may be permitted to consent on the same day that they have received the patient information sheet if they have all their questions answered and are happy to proceed.

Treatment:

Participants randomised to the standard of care arm will receive up to 6 cycles of CHOP-R where each cycle is 21 days. Participants will be treated in a hospital day unit on day 1 of each cycle and will have tablets to take at home on days 2 to 5. All participants will be formally assessed after 4 and 6 cycles of treatment. Participants who have achieved a response may continue on to a stem cell transplant if they are suitable. Participants who do not achieve a response will be offered entry in to the platform Cohort 1 to receive acalabrutinib monotherapy if they are eligible. Entry into Cohort 1 is not mandatory; the participant's doctor will discuss all possible treatment options with them.

Participants who consent and are registered to Cohort 1 will take 100 mg twice-daily of acalabrutinib at home as oral tablets. Treatment is continuous until disease progression, unacceptable toxicity or patient choice. Participants will be formally assessed at weeks 12 and 24 to determine if they are responding to treatment.

Participants randomised to the experimental arm of STELLAR and registered to Cohort 2 will receive up to 6 cycles of CHOP-R where each cycle is 21 days. Participants will be treated in a hospital day unit on day 1 of each cycle and will have tablets to take at home on days 2 to 5. Patients will then take 100 mg twice daily of acalabrutinib oral tablets at home on days 6-21. All participants will be formally assessed after 4 and 6 cycles of treatment. Participants who have achieved a response will continue to take acalabrutinib at home at 100 mg twice daily, continuously until disease progression, unacceptable toxicity or patient choice. These participants may continue on to a stem cell transplant if they are suitable. If these patients do not achieve a response, they will discontinue trial treatment.

In all cases, if patients do not respond to treatment or wish to withdraw from the trial they will be counselled by their medical team on the options available to them.

Assessments and visits:

Participants in the STELLAR trial will have frequent assessments in the first 4 to 6 months of the study so that they are monitored for toxicity and response to treatment. Most of the assessments for participants receiving CHOP-R (with or without acalabrutinib) would be done as part of their standard of care. Before entering the study each potential participant will undergo screening assessments in the 4 weeks before trial entry (date of randomisation or registration).

Screening assessments:

A physical and medical assessment by their doctor to record their: age, medical history, blood pressure, pulse, weight, any symptoms of their Richter's Syndrome, ECG (heart trace), and any other relevant information. Women who are could become pregnant have to have a pregnancy test. Blood samples are taken for local assessments (blood count and other haematology tests, biochemistry, virology, immunology) and also for research (these are 'extra' samples that are not standard of care). Patients will also have a bone marrow assessment, a PET-CT scan, and a lymph node biopsy; these assessments would be done as part of the patients' standard of care.

Assessments during the trial:

All patients will have local assessments carried out whilst they receive CHOP-R, most of these assessments are standard of care. Patients will have extra assessments that will help us to answer the exploratory questions posed in the trial. Most of these extra assessments will be done at the same time as local assessments so that patients don't have lots of extra visits to the hospital. Patients in all cohorts will have: a physical assessment by their doctor to record their blood pressure, pulse, weight, and any symptoms or side effects they may have; blood samples are taken for local assessments, patients receiving acalabrutinib will have more blood samples taken for research at the same time as the local ones.

All patients will have a lymph node biopsy, bone marrow biopsy and PET-CT scan as part of their screening assessments. Some patients may have a bone marrow biopsy at the end of cycle 6 (or week 24 for Cohort 1) which would be part of their standard of care. All patients will have a CT scan at the end of cycle 4 (week 12 for Cohort 1) and a PET-CT at the end of cycle 6 (week 24 for Cohort 1). If a patient has disease progression they will have another PET-CT scan and lymph node biopsy, and some patients will have a bone marrow biopsy. All of these scans and biopsies would be part of the patient's standard of care.

As well as medical assessments, patients will complete validated Quality of Life questionnaires at trials visits. There are three multi item scales on fatigue, treatment side effects and disease symptoms, infection and social activities and future health worries. These questionnaires will be completed at clinic visits.

Follow Up:

All STELLAR patients will be followed-up for disease status and survival for at least 2 years from trial entry to determine the long-term effectiveness of the therapy.