Genetically Risk-Stratified Venetoclax, Ibrutinib, Rituximab (± Navitoclax) in Relapsed/Refractory Mantle Cell Lymphoma

Inclusion Criteria:

1. Patient must be ≥ 18 years of age.

2. Patient must have a confirmed diagnosis of MCL according to World HealthOrganisation ([WHO] 2008) criteria, and have received at least one prior line ofsystemic therapy for their disease. Patients recently commenced on ibrutinib (≤4weeks) will be allowed to enrol as long as at the time of enrolment there ismeasurable disease and no disease progression.

3. Patient requires treatment in the opinion of the investigator, and has at least onesite of assessable disease not previously irradiated (such as lymph node withlargest diameter ≥1.5cm, or unequivocal hepatomegaly/splenomegaly).

4. Patient has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2 .

5. Patient must have adequate bone marrow function independent of growth factor supportat screening as follows:

• Absolute Neutrophil Count (ANC) ≥ 0.75 x 109/L (neutropenia due to marrowinfiltration may be supported by growth factors)

• Platelets ≥ 50 x 109/L (≥ 30 x 109/L if reduced counts due to marrowinfiltration; entry platelet count must be independent of transfusion within 7days)

6. Patients must have adequate coagulation, renal, and hepatic function, per laboratoryreference range at screening as follows:

• Activated partial thromboplastin time (aPTT) and prothrombin time (PT) ≤1.5 ×the upper limit of normal (ULN)

• Calculated creatinine clearance of at least 30 mL/min using the Cockcroft-Gaultequation or a 24-hour urine collection (Appendix 2)

• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3.0 × ULNof institution's normal range

• Bilirubin ≤1.5 × ULN. Patients with documented Gilbert's Syndrome may have abilirubin > 1.5 × ULN

7. Female patients of childbearing potential and non-sterile male patients (withpartner(s) of child bearing potential) must practice at least one of the followingmethods of birth control with partner(s) from initial study drug administration to 90 days after the last dose of study drug:

• Total abstinence from sexual intercourse as the preferred life style of thepatient; periodic abstinence is not acceptable

• Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy,bilateral tubal ligation, bilateral oophorectomy or hysterectomy

• Intrauterine device

• Double-barrier method (contraceptive sponge, diaphragm or cervical cap withspermicidal jellies or cream AND a condom)

• Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 monthsprior to study drug administration

8. Female patients of childbearing potential must have a negative serum (beta-humanchorionic gonadotropin [B-hCG]) or urine pregnancy test at screening. Women who arepregnant or breastfeeding are ineligible for this study.

9. Male patients must agree to refrain from sperm donation, from initial study drugadministration until 90 days after the last dose of study drug.

10. Patient is able to swallow whole tablets.

11. Patient (or their legally acceptable representatives) must sign an informed consentdocument indicating that they understand the purpose of and procedures required forthe study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

1. Patient has undergone an allogeneic stem cell transplant within the last 6 months orcurrently has active graft-vs-host disease requiring the use of immunosuppressants.

2. Patient has active and uncontrolled autoimmune cytopenias (for 2 weeks), includingautoimmune haemolytic anaemia and immune thrombocytopenic purpura.

3. Patient has current central nervous system (CNS) involvement by MCL.

4. Patient currently receiving ibrutinib for >4 weeks or previously received a Bruton'styrosine kinase (BTK) inhibitor or B-cell lymphoma 2 (bcl-2) inhibitor.

5. Patient has received the following within 30 days prior to the first dose of studydrug:

• Monoclonal antibody given with anti-neoplastic intent

6. Patient has received any of the following within 14 days prior to the first dose ofstudy drug, or has not recovered to less than CTCAE grade 2 clinically significantadverse effect(s)/toxicity(s) of the previous therapy:

• Any anti-cancer therapy including chemotherapy, or radiotherapy

• Investigational therapy, including targeted small molecule agents

7. Patient has received the following within 7 days prior to the first dose of studydrug:

• Steroid therapy given with anti-neoplastic intent

8. Patients requires ongoing therapy with:

• Potent CYP3A inhibitors (such as indinavir, ketoconazole, and clarithromycin)

• Potent CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine or St. John'sWort)

• Warfarin, or equivalent vitamin K antagonist

• Antiretroviral medications.

9. Patient has consumed the following within 3 days prior to the first dose of studydrug:

• Grapefruit, or

• Grapefruit products, or

• Seville oranges (including marmalade containing Seville oranges), or

• Star fruit

10. Patient has clinically significant cardiovascular disease such as uncontrolledarrhythmias, congestive heart failure, or myocardial infarction within 6 months ofscreening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as definedby the New York Heart Association Functional Classification

11. Patient has a life-threatening illness, medical condition, or organ systemdysfunction which, in the investigator's opinion, could compromise the patient'ssafety, interfere with the absorption or metabolism of oral drugs, or put the studyoutcomes at undue risk:

• Specifically, a patient with history of stroke or intracranial haemorrhage within 6 months prior to enrolment is excluded

12. Patient has a history of other active malignancies other than MCL within the past 2years prior to study entry, with the exception of:

• Adequately treated in situ carcinoma of the cervix uteri

• Adequately treated basal cell carcinoma of the skin or localised squamous cellcarcinoma of the skin

• Previous malignancy confined and surgically resected (or treated with othermodalities) with curative intent

13. Patient has active Hepatitis C Virus (HCV) or active Hepatitis B Virus (HBV)infection or known history of human immunodeficiency virus (HIV) or any uncontrolledactive systemic infection requiring intravenous (IV) antibiotics.

14. Received live, attenuated vaccines within 4 weeks prior to the first dose of studydrug.

15. Major surgery within 4 weeks prior to the first dose of study drug.