| Eligibility |
Inclusion Criteria:
1. Men and women = 60 years of age.
2. Pathologically confirmed MCL, with documentation of monoclonal B cells that have a
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1.
3. Stage II-IV MCL and requiring treatment in the opinion of the treating clinician.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 (
5. One or more of the following:
- Age 80 years or more
- Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score 6 or greater
- Left ventricular ejection fraction (LVEF) less than or equal to 50% as assessed
by echocardiogram or multi-gated coronary angiography (MUGA)
- Significant co-morbidities or cardiac risk factors making
anthracycline-containing chemotherapy inadvisable
- Heart failure clinically determined by the presence of New York Heart Association
(NYHA) failure grade II due to a cause other than MCL
- Impaired respiratory function with DLCO and/or FVC/FEV1 ratio less than 75% of
predicted due to a cause other than MCL
- Significant respiratory illness e.g., moderate or severe COPD / bronchiectasis
- Other co-morbidities that in the Investigator's opinion which would preclude the
use of standard immuno-chemotherapy (to be discussed on a case-by-case basis with
the TMG, via UCL CTC)
6. Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty.
7. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP).
8. Willing to comply with the contraceptive requirements of the trial (see section
6.3.4).
9. Written informed consent.
Exclusion Criteria:
1. Any prior therapy (including targeted inhibitors) for MCL (other than prior localised
radiotherapy, a 10-day pulse of high dose steroids or ongoing continuous prednisolone
above 20mg od for symptom control).
2. Patients considered fit enough to receive standard, full dose cytotoxic
immunochemotherapy as treatment for non-transplant eligible MCL e.g., full dose
R-CHOP, VR-CAP, R-DHAP, R-Bendamustine, R-FC.
3. Prior malignancy (or any other malignancy requiring active treatment), except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
localised prostate cancer or other cancer from which the subject has been disease free
for = 2 years or which will not limit survival to < 5 years.
4. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, or
myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac
disease as defined by the New York Heart Association (NYHA) Functional Classification,
or corrected QT interval (QTc) > 480 msec at screening.
5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel that is likely to affect absorption,
symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or
gastric restrictions and bariatric surgery, such as gastric bypass.
6. Known history of infection with HIV or any uncontrolled active systemic infection
(e.g., bacterial, viral or fungal).
7. Known history of drug-specific hypersensitivity or anaphylaxis to any study drug
(including active product or excipient components).
8. Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand
disease.
9. Uncontrolled AIHA (autoimmune haemolytic anaemia) or ITP (idiopathic thrombocytopenic
purpura).
10. Known presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months
before screening.
11. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug.
13. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) > 2 x upper
limit of normal (ULN).
14. Requires treatment with proton pump inhibitors (e.g. omeprazole, esomeprazole,
lansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors
who switch to H2-receptor antagonists or antacids are eligible for enrolment to this
study.
15. History of significant cerebrovascular disease/event, including stroke or intracranial
haemorrhage, within 6 months before the first dose of study drug.
16. Major surgical procedure within 28 days of first dose of study drug. Note: If a
subject had major surgery, they must have recovered adequately from any toxicity
and/or complications from the intervention before the first dose of study drug.
17. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB
core) positive and who are surface antigen negative will need to have a negative
polymerase chain reaction (PCR) test. Those who are hepatitis B surface antigen
(HbsAg) positive or hepatitis B PCR positive will be excluded. Those who are hepatitis
C antibody or PCR positive will be excluded (those who are hepatitis C antibody
positive and PCR negative will not be excluded).
18. Absolute neutrophil count <1.0 x 109/L (or requires growth factor support to maintain
absolute neutrophil count >1.0 x 109/L) and/or platelets <75 x109/L independent of
growth factor support, unless related to bone marrow infiltration or splenomegaly due
to underlying MCL (where platelets between 50-75 x109/L are acceptable)
19. Total bilirubin > 1.5 x ULN, unless due to Gilbert's syndrome or of non-hepatic
origin.
20. AST and/or ALT > 3 x ULN.
21. Calculated creatinine clearance <30 mL/min.
22. Breastfeeding or pregnant.
23. Concurrent participation in another therapeutic clinical trial.
24. Live vaccine within 28 days of first study dose
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