A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome
A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome
The STELLAR trial will assess the effect of acalabrutinib taken in combination with CHOP-R
 compared to taking CHOP-R alone in patients with newly diagnosed Richter's Syndrome (RS). It
 will also be a platform to test other new drugs that show potential for treating RS. Chronic
 lymphocytic Leukaemia (CLL) is the most common blood cancer in adults, usually in their 70s
 or older. In a few patients, CLL can transform from a slow-growing cancer into an aggressive
 lymphoma called Richter's Syndrome. RS is very difficult to treat and patients have a short
 life-expectancy - usually a few months after diagnosis. Treatment for Richter's Syndrome in
 the UK is CHOP (four chemotherapy drugs) plus rituximab ('R' - an antibody treatment). The
 CHOP-R treatment is given as a standard of care for RS but has limited benefit - it is often
 temporary to extend life. Richter's Syndrome returns in most patients who then die from this
 disease. The STELLAR trial will investigate if a new drug called acalabrutinib, which is
 effective used by itself in patients with relapsed CLL and also some with Richter's Syndrome,
 will improve outcomes for newly diagnosed patients with RS. Acalabrutinib blocks a protein in
 CLL which can stop the cancer growing.

 Participants who have Richter's Syndrome and are suitable for CHOP-R will be recruited by
 specialised hospitals across the UK. People with another cancer, heart problems, or recent
 stroke cannot take part. Participants will have a lymph node biopsy, 3-4 bone marrow
 biopsies, blood samples, and PET-CT and CT scans. CHOP-R is given in a hospital every three
 weeks up to 6 times. All participants will receive CHOP-R; half will also receive
 acalabrutinib. When treatment with CHOP-R ends the patients who had acalabrutinib can
 continue to take it; patients who had CHOP-R alone may have acalabrutinib if their Richter's
 Syndrome returns after CHOP-R.
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.
Entry criteria for randomised trial component (standard of care and experimental arms):

 Inclusion criteria for the randomised trial component:

 -  Suitable for anthracycline-containing chemo-immunotherapy.

 -  Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.

 -  ECOG performance status of 0, 1, 2 or 3.

 -  Age 16 years and over.

 -  Signed written informed consent prior to performing any study-specific procedures.

 Exclusion criteria for the randomised trial component:

 -  Prior therapy with CHOP or any anthracycline containing treatment at any time prior to
 randomisation. (Please note that pre-treatment with prednisolone up to 2mg/kg is
 allowed for up to 14 days prior to the start of treatment).

 -  Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks
 of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue
 ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop
 RS are not excluded from the randomised trial component).

 -  Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase
 (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted, with the
 exception of patients who have progressed on ibrutinib - see exclusion criterion
 above).

 -  Known central nervous system (CNS) involvement of CLL or DLBCL.

 -  Any other active malignancy that requires active treatment, with the exception of
 basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell
 carcinoma of the skin.

 -  Chronic or ongoing active infectious disease requiring systemic treatment such as, but
 not limited to, chronic renal infection, chronic chest infection with bronchiectasis,
 tuberculosis, and active hepatitis

 -  Positive serology for Hepatitis B (HB) defined as a positive test for HB surface
 antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb)
 positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be
 performed and if positive the patient will be excluded.

 -  Known human immunodeficiency virus (HIV) positive.

 -  Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von
 Willebrand disease).

 -  Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g.
 phenprocoumon).

 -  Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin
 time (APTT) > 2 x the upper limit of normal (ULN).

 -  Major surgery within 30 days prior to randomisation and/or inadequate recovery (at
 Investigators discretion) from any prior major surgery, toxicity or complications.

 -  Patients with malabsorption syndrome or medical conditions significantly affecting
 gastrointestinal function.

 -  Clinically significant cardiac disease including unstable angina, uncontrolled
 congestive heart failure, and unstable arrhythmias requiring therapy, with the
 exception of extra systoles or minor conduction abnormalities. Stable and controlled
 atrial fibrillation is not an exclusion.

 -  Significant concurrent, uncontrolled severe medical condition including, but not
 limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary,
 neurological, cerebral or psychiatric disease.

 -  History of significant cerebrovascular disease in the 6 months prior to randomisation,
 including intracranial haemorrhage.

 -  Known or suspected hypersensitivity to components of the investigational products

 -  Patients who have received treatment with any non-marketed drug substance or
 experimental therapy within 4 weeks prior to proposed start of treatment unless
 discussed and approved by the Chief Investigator or Clinical Coordinator via the
 Trials Office.

 -  Current participation in any other interventional clinical study.

 -  Patients known or suspected of not being able to comply with a study protocol (e.g.
 due to alcoholism, drug dependency or psychological disorder).

 -  Breast feeding women or women with a positive pregnancy test at screening.

 -  Women of childbearing potential and men not willing to use highly effective
 contraception during study and for 12 months after last dose of study therapy. Highly
 effective contraception is defined as abstinence, hormonal birth control, intrauterine
 devices, vasectomy/surgical sterilisation.

 Entry criteria for single-arm relapsed Cohort 1:

 Inclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy):

 -  Patients with relapsed/refractory RS who received anthracycline based chemotherapy
 with anti-CD20 monoclonal antibody If fewer than the expected number of patients from
 the randomised component enter into Cohort 1, patients from outside STELLAR with
 relapsed/refractory RS following chemo-immunotherapy (anthracycline based chemotherapy
 with anti-CD20 monoclonal antibody) will be able to join this cohort if they meet the
 eligibility criteria. The Trials Office will alert sites by email if any slots are
 released for patients outside of STELLAR, these must be booked with the Trials Office
 prior to registration.

 -  ECOG performance status of 0, 1, 2 or 3.

 -  Age 16 years and over.

 -  Signed written informed consent prior to performing any study-specific procedures.

 Exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy):

 -  Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase
 (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted).

 -  Known central nervous system (CNS) involvement of CLL or DLBCL.

 -  Any other active malignancy that requires active treatment, with the exception of
 basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell
 carcinoma of the skin.

 -  Chronic or ongoing active infectious disease requiring systemic treatment such as, but
 not limited to, chronic renal infection, chronic chest infection with bronchiectasis,
 tuberculosis, and active hepatitis

 -  Positive serology for Hepatitis B (HB) defined as a positive test for HB surface
 antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb)
 positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be
 performed and if positive the patient will be excluded.

 -  Known human immunodeficiency virus (HIV) positive.

 -  Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von
 Willebrand disease).

 -  Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g.
 phenprocoumon).

 -  Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin
 time (APTT) > 2 x the upper limit of normal (ULN).

 -  Major surgery within 30 days prior to registration and/or inadequate recovery (at
 Investigators discretion) from any prior major surgery, toxicity or complications.

 -  Patients with malabsorption syndrome or medical conditions significantly affecting
 gastrointestinal function.

 -  Clinically significant cardiac disease including unstable angina, uncontrolled
 congestive heart failure, and unstable arrhythmias requiring therapy, with the
 exception of extra systoles or minor conduction abnormalities. Stable and controlled
 atrial fibrillation is not an exclusion.

 -  Significant concurrent, uncontrolled severe medical condition including, but not
 limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary,
 neurological, cerebral or psychiatric disease.

 -  History of significant cerebrovascular disease in the 6 months prior to registration,
 including intracranial haemorrhage.

 -  Known or suspected hypersensitivity to components of the investigational products

 -  Patients who have received treatment with any non-marketed drug substance or
 experimental therapy within 4 weeks prior to proposed start of treatment unless
 discussed and approved by the Chief Investigator or Clinical Coordinator via the
 Trials Office.

 -  Current participation in any other interventional clinical study.

 -  Patients known or suspected of not being able to comply with a study protocol (e.g.
 due to alcoholism, drug dependency or psychological disorder).

 -  Breast feeding women or women with a positive pregnancy test at screening.

 -  Women of childbearing potential and men not willing to use highly effective
 contraception during study and for 12 months after last dose of study therapy. Highly
 effective contraception is defined as abstinence, hormonal birth control, intrauterine
 devices, vasectomy/surgical sterilisation.

 Entry criteria for single arm Cohort 2

 Inclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on
 ibrutinib):

 -  Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within
 four weeks of last dose of ibrutinib.

 -  No previous anthracycline treatment and suitable for anthracycline-containing
 chemo-immunotherapy.

 -  Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.

 -  ECOG performance status of 0, 1, 2 or 3.

 -  Age 16 years and over.

 -  Signed written informed consent prior to performing any study-specific procedures.

 Exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on
 ibrutinib):

 -  Prior therapy with CHOP or any anthracycline containing treatment at any time prior to
 registration. (Please note that pre-treatment with prednisolone up to 2mg/kg is
 allowed for up to 14 days prior to the start of treatment).

 -  Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase
 (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted)

 -  Known central nervous system (CNS) involvement of CLL or DLBCL.

 -  Any other active malignancy that requires active treatment, with the exception of
 basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell
 carcinoma of the skin.

 -  Chronic or ongoing active infectious disease requiring systemic treatment such as, but
 not limited to, chronic renal infection, chronic chest infection with bronchiectasis,
 tuberculosis, and active hepatitis

 -  Positive serology for Hepatitis B (HB) defined as a positive test for HB surface
 antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb)
 positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be
 performed and if positive the patient will be excluded.

 -  Known human immunodeficiency virus (HIV) positive.

 -  Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von
 Willebrand disease).

 -  Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g.
 phenprocoumon).

 -  Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin
 time (APTT) > 2 x the upper limit of normal (ULN).

 -  Major surgery within 30 days prior to registration and/or inadequate recovery (at
 Investigators discretion) from any prior major surgery, toxicity or complications.

 -  Patients with malabsorption syndrome or medical conditions significantly affecting
 gastrointestinal function.

 -  Clinically significant cardiac disease including unstable angina, uncontrolled
 congestive heart failure, and unstable arrhythmias requiring therapy, with the
 exception of extra systoles or minor conduction abnormalities. Stable and controlled
 atrial fibrillation is not an exclusion.

 -  Significant concurrent, uncontrolled severe medical condition including, but not
 limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary,
 neurological, cerebral or psychiatric disease.

 -  History of significant cerebrovascular disease in the 6 months prior to registration,
 including intracranial haemorrhage.

 -  Known or suspected hypersensitivity to components of the investigational products

 -  Patients who have received treatment with any non-marketed drug substance or
 experimental therapy within 4 weeks prior to proposed start of treatment unless
 discussed and approved by the Chief Investigator or Clinical Coordinator via the
 Trials Office.

 -  Current participation in any other interventional clinical study.

 -  Patients known or suspected of not being able to comply with a study protocol (e.g.
 due to alcoholism, drug dependency or psychological disorder).

 -  Breast feeding women or women with a positive pregnancy test at screening.

 -  Women of childbearing potential and men not willing to use highly effective
 contraception during study and for 12 months after last dose of study therapy. Highly
 effective contraception is defined as abstinence, hormonal birth control, intrauterine
 devices, vasectomy/surgical sterilisation.