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

Learn more about:
Related Clinical Trial
Safety & Efficacy Study of Epcoritamab in Subjects With R/R Chronic Lymphocytic Leukemia and Richter’s Syndrome ALX148, Rituximab and Lenalidomide for the Treatment of Indolent and Aggressive B-cell Non-Hodgkin Lymphoma R-EPOCH in Combination With Ibrutinib for Patients With Classical RT of CLL Phase 1 Study VIP152 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome A Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax in Patients With Richter’s Syndrome; Study of Cosibelimab in Subjects With Relapsed or Refractory Lymphoma CD19-Directed CAR-T Cell Therapy for the Treatment of Relapsed/Refractory B Cell Malignancies Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory NHL, RT, MM, T-PLL, Acute Leukemia (AML, ALL), MDS, MDS/MPN, and MF Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter’s Transformation Autologous Stem Cell Transplant Followed by Polatuzumab Vedotin in Patients With B-cell Non-Hodgkin and Hodgkin Lymphoma Venetoclax in Combination With Ublituximab and Umbralisib (TGR-1202) in Patients With Relapsed or Refractory CLL/SLL Ex Vivo-activated Autologous Lymph Node Lymphocytes in Treating Patients With Chronic Lymphocytic Leukemia Allogeneic Stem Cell Transplant for CLL Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin’s Lymphomas Atezolizumab, Gemcitabine, Oxaliplatin, and Rituximab in Treating Patients With Relapsed or Refractory Transformed Diffuse Large B-Cell Lymphoma Atezolizumab, Obinutuzumab, and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Relapsed or Refractory Richter Syndrome Duvelisib and Nivolumab in Treating Patients With Richter Syndrome or Transformed Follicular Lymphoma Sotrastaurin Acetate in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, Prolymphocytic Leukemia, or Richter’s Transformation Registry of the German CLL Study Group Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (Btk) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia A Study of Acalabrutinib and Vistusertib in Subjects With Relapsed/Refractory B-cell Malignancies Study of Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone (CHOP) With Ofatumumab in Patients With Richter’s Syndrome PNT2258 for Treatment of Patients With Richter’s Transformation (Brighton) Study of Immunotherapy in Combination With Ublituximab and Umbralisib in Patients With Relapsed-refractory CLL or Richter’s Transformation Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation BLINAtumomab After R-CHOP Debulking Therapy for Patients With Richter Transformation Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter’s Transformation and Leukemias Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter`s Transformation Requiring Allogeneic Stem Cell Transplantation Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma or Relapsed or Refractory Richter Syndrome (MK-3475-170/KEYNOTE-170) Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL or RS Study of Blinatumomab in Richter Transformation Genomic and Proteomic Study of Richter Syndrome (CGPSR) CRC043: A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R for Patients With Richter’s Syndrome Study of Ibrutinib & Obinutuzumab With/Without CHOP for Richter’s Transformation or Richter’s Syndrome Patients Obinutuzumab, High Dose Methylprednisolone (HDMP), and Lenalidomide for the Treatment of Patients With Richter’s Syndrome A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter’s Syndrome Selinexor in Initial or Refractory and/or Relapsed Richter’s Transformation

Brief Title

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

Official Title

A Phase II, Randomised Study of CHOP-R in Combination With Acalabrutinib Compared to CHOP-R in Patients With Newly Diagnosed Richter's Syndrome and a Platform for Initial Investigations Into Activity of Novel Treatments in Relapsed/Refractory and Newly Diagnosed Richter's Syndrome.

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Randomised Component - Progression free survival (PFS)

Secondary Outcome

 Overall Survival

Condition

Richter Syndrome

Intervention

Acalabrutinib

Study Arms / Comparison Groups

 Standard of Care Arm (CHOP-R)
Description:  Arm in the randomised trial. CHOP-R chemoimmunotherapy will continue for up to 6 cycles (each cycle is 21 days), and will be given according to the following schedule:
Rituximab, 375 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Cyclophosphamide, 750 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Doxorubicin, 50 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Vincristine, 1.4 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Prednisolone, 40 mg/m2, PO, OD, 6 cycles, days of cycle: 1-5

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

105

Start Date

April 2019

Completion Date

December 2024

Primary Completion Date

April 2024

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, +44 (0)121 371 7867, [email protected]



Administrative Informations


NCT ID

NCT03899337

Organization ID

RG_17-194


Responsible Party

Sponsor

Study Sponsor

University of Birmingham

Collaborators

 Bloodwise

Study Sponsor

, , 


Verification Date

March 2019