Status: Open
Specialty: Lymphoma
Date Opened: 25/10/2021
Planned Close Date: 16/09/2023
Sponsor: University Hospital Southampton
Principal Investigator: Dr Macheta
Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin’s lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP a type of immunochemotherapy), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in
DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL.
The main aims of this randomised phase II clinical study are:
- To determine if combining Acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL.
- To compare progression-free survival, overall survival, event free survival, disease free survival, time to progression, response duration and overall response rate between both treatment and molecular groups.
- To assess differences in toxicity between the assigned treatments
- To assess differences in quality of life in different treatment arms
- To explore correlation of molecular characterists in tumour material to clinical outcomes
- To explore correlation of baseline PET features including metabolic tuour characteristics in tumour material.
- To compare metablic response rates between molecular groups
UP to 558 patients (453 randomised) will be recruited to the clinical trial with 302 patients randomised to experiemental arm and 151 to the control arm in a 2:1 randomisation
1.Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to
HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO
classification of lymphoid neoplasms may be included:
• DLBCL, not otherwise specified (NOS)
• T-cell/histiocyte-rich large B-cell lymphoma
• Epstein-Barr virus positive DLBCL, NOS
• ALK-positive large B-cell lymphoma
• HHV8-positive DLBCL, NOS
• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma)
• High-grade B-cell lymphoma, NOS
2. At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest dimension as measured by CT
3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative
intent
4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter >7.5cm) to stage
IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be
eligible.
5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma.
6. Adequate bone marrow function with platelets >100x109/L; neutrophils >1.0x109/L at study entry, unless lower
figures are attributable to lymphoma.
7. Measured or calculated creatinine clearance >30mls/min, (calculated using the formula of Cockcroft and Gault
[(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (μmolL)]).
8. Serum bilirubin <35μmol/L and transaminases <1.5x upper limit of normal at time of study entry.
9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is
required to establish baseline LVEF equal to or greater than institutional normal range.
10. No concurrent uncontrolled medical condition.
11. Life expectancy .3 months
12. Aged 16 years or above
13. Willing and able tto participate in all required evaluations and procedures in this study protocol including swalling capsules without difficulty
13. Ability to understand the purpose and risks of the study and provide signed and dated informed consent
1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have
small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible.
2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible.
3. Diagnosis of primary mediastinal lymphoma.
4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement.
5. History of stroke or intracranial haemorrhage in preceding 6 months.
6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease).
7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient
components).
8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of
first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible,
as will those receiving direct oral anticoagulants.
9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk
inhibitors) or BCL-2 inhibitor (e.g. ABT-199).
10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole,
rabeprazole, or pantoprazole).
12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)).
13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
14. Major surgery in the preceding 4 weeks of first dose of study drug.
15. Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom
control. Patients receiving corticosteroid treatment with <30 mg/day of prednisone or equivalent must be documented
to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently
required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be
given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during
the screening phase to control symptoms.
16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or
myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York
Heart Association Functional Classification.
17. Serological positivity for Hepatitis B, C, or known HIV infection.
a. Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with
occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who
have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible.
b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
18. Women who can bear children must agree to use two highly effective forms of contraception or abstinence during
the study and for 12 months after the last treatment dose.
19. Breastfeeding or pregnant women.
20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or
abstinence during the study and for 12 months after the last treatment dose.
21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose.
22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give
informed consent.
23. Prior malignancy (other than DLBCL), except for adequately treated basal cell or sqamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥2 years or which will not limit survival to <2 years.
24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of
the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as
gastric bypass that would limit absorption of oral medication.
25. Any immunotherapy within 4 weeks of 1st dose.
26. Concurrent participation in another therapeutic clinical trial.
Research Nurse: Nicola Slawson (Ext No. 53062) Nicola.Slawson@nhs.net
Administrator: Tamaryn Louw
Link to EDGE