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

NCT03899337 | Recruiting Phase 2 DMC

• 1 other identifier: RG_17-194
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 16

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.

Conditions

Richter Syndrome

Keywords

Chronic Lymphocytic Leukaemia; Richter's Transformation; Richter's Syndrome; CHOP-R; Acalabrutinib; Diffuse Large B Cell Lymphoma; non-Hodgkin Lymphoma

Outcome Measures

Primary Outcomes (3)

• Randomised Component - Progression free survival (PFS)

  Progression free survival (PFS) defined as the time from randomisation to the date of progression or death from any cause. Progression will be defined by the modified Cheson criteria (Appendix 1). Patients who are alive and progression free at the time of analysis will be censored at date last seen. Any participants who withdraw or are lost to follow-up will also be censored at date last seen.

  Time from randomisation to the date of progression or death from any cause, whichever came first, assessed up to 24 months..

• Registration Arm - Cohort 1 - Overall Response

  Overall response after 24 weeks of treatment based on the modified Cheson criteria (Appendix 1). Complete response (CR) and partial response (PR) are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 6 month assessment or do not have the 6 month assessment will be considered non responders.

  Response assessed at 24 weeks of treatment

• Registration Arm - Cohort 2 - Overall Response

  Overall response after 6 cycles of treatment, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.

  Response assessed after 6 cycles of treatment. Each cycle is 21 days.

Secondary Outcomes (7)

• Overall Survival

  Time from trial entry to the date of death from any cause, whichever came first, assessed up to 24 months.

• Overall Response after 6 cycles

  Response assessed after 6 cycles of treatment. Each cycle is 21 days.

• Overall Response after 12 weeks

  Response assessed after 12 weeks of treatment

• Progression Free Survival

  Time from date of registration to date of progression or death from any cause, whichever came first, assessed up to 24 months.

• Quality of Life Questionnaire Outcomes

  Analysed at the end of cycles 4 (week 12) and 6 (week 24)

Study Arms (4)

Standard of Care Arm (CHOP-R)

ACTIVE COMPARATOR

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

Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisolone; Drug: Rituximab

Experimental Arm (CHOP-R + Acalabrutinib)

EXPERIMENTAL

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 Acalabrutinib 100 mg, PO, BD will be taken on days 6-21, of each cycle - up to cycle 6. Acalabrutinib treatment will be continuous thereafter until disease progression toxicity, patient choice or death.

Drug: Acalabrutinib; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisolone; Drug: Rituximab

Cohort 1 - Acalabrutinib Monotherapy - Platform Trial

EXPERIMENTAL

Registration arm in platform study. Patients registered to Cohort 1 will receive 100 mg acalabrutinib monotherapy, twice daily, continuously from day 1 until disease progression, toxicity, patient choice or death.

Drug: Acalabrutinib

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial

EXPERIMENTAL

Registration arm in platform study. 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 Acalabrutinib 100 mg, PO, BD will be taken on days 6-21, of each cycle - up to cycle 6. Acalabrutinib treatment will be continuous thereafter until disease progression toxicity, patient choice or death.

Drug: Acalabrutinib; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisolone; Drug: Rituximab

Interventions

Acalabrutinib DRUG

100mg capsule, PO, BD

Cohort 1 - Acalabrutinib Monotherapy - Platform Trial; Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib)

Cyclophosphamide DRUG

750mg/m\^2, IV bolus

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib); Standard of Care Arm (CHOP-R)

Doxorubicin DRUG

50mg/m\^2, IV bolus

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib); Standard of Care Arm (CHOP-R)

Vincristine DRUG

1.4mg/m\^2, IV infusion

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib); Standard of Care Arm (CHOP-R)

Prednisolone DRUG

40mg/m\^2, PO, OD

Also known as: Pevanti

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib); Standard of Care Arm (CHOP-R)

Rituximab DRUG

375mg/m\^2, IV infusion

Also known as: Mabthera

Cohort 2 - CHOP-R + Acalabrutinib - Platform Trial; Experimental Arm (CHOP-R + Acalabrutinib); Standard of Care Arm (CHOP-R)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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.
• 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

Sponsors & Collaborators

• University of Birmingham: lead
• Bloodwise: collaborator
• Acerta Pharma, LLC: collaborator

Study Sites (16)

Belfast City Hospital

Belfast, United Kingdom

RECRUITING

Royal Bournemouth Hospital

Bournemouth, United Kingdom

RECRUITING

University Hospital of Wales

Cardiff, United Kingdom

RECRUITING

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

RECRUITING

St James's University Hospital

Leeds, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, United Kingdom

RECRUITING

King's College Hospital

London, United Kingdom

RECRUITING

St Bartholomew's Hospital

London, United Kingdom

RECRUITING

University College London Hospital

London, United Kingdom

RECRUITING

Christie Hospital

Manchester, United Kingdom

RECRUITING

Norfolk and Norwich University Hospital

Norwich, United Kingdom

RECRUITING

Nottingham City Hospital

Nottingham, United Kingdom

RECRUITING

Churchill Hospital

Oxford, United Kingdom

RECRUITING

Derriford Hospital

Plymouth, United Kingdom

RECRUITING

Royal Hallamshire Hospital

Sheffield, United Kingdom

RECRUITING

Southampton General Hospital

Southampton, United Kingdom

RECRUITING

Related Publications (2)

• Klintman J, Appleby N, Stamatopoulos B, Ridout K, Eyre TA, Robbe P, Pascua LL, Knight SJL, Dreau H, Cabes M, Popitsch N, Ehinger M, Martin-Subero JI, Campo E, Mansson R, Rossi D, Taylor JC, Vavoulis DV, Schuh A. Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia. Blood. 2021 May 20;137(20):2800-2816. doi: 10.1182/blood.2020005650.

  PMID: 33206936 DERIVED

• Appleby N, Eyre TA, Cabes M, Jackson A, Boucher R, Yates F, Fox S, Rawstron A, Hillmen P, Schuh A. The STELLAR trial protocol: a prospective multicentre trial for Richter's syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease. BMC Cancer. 2019 May 20;19(1):471. doi: 10.1186/s12885-019-5717-y.

  PMID: 31109313 DERIVED

MeSH Terms

Conditions

Leukemia, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin

Interventions

acalabrutinib; Cyclophosphamide; Doxorubicin; Vincristine; Prednisolone; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Lymphoma

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Anna Schuh, PhD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joseph Rogers, MSc

CONTACT

+44 (0)121 371 7867; STELLAR@trials.bham.ac.uk

Francesca Yates, PhD

CONTACT

+44 (0)121 371 7867; STELLAR@trials.bham.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2019
• First Posted: April 2, 2019
• Study Start: July 23, 2019
• Primary Completion: October 31, 2025
• Study Completion (Estimated): May 31, 2027
• Last Updated: January 9, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (16)