AIM2: This study is evaluating the effectiveness of combination targeted therapy in people with relapsed and refractory mantle cell lymphomaA Phase II Study of Genetically Risk-Stratified Combination of Venetoclax, Ibrutinib and Rituximab (With and Without Navitoclax) in Patients With Relapsed and Refractory Mantle Cell Lymphoma

Exclusion

1. Patient has undergone an allogeneic stem cell transplant within the last 6 months or currently has active graft-vs-host disease requiring the use of immunosuppressants.
2. Patient has active and uncontrolled autoimmune cytopenias (for 2 weeks), including autoimmune 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's tyrosine 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 study drug:

   • Monoclonal antibody given with anti-neoplastic intent

6. Patient has received any of the following within 14 days prior to the first dose of study drug, or has not recovered to less than CTCAE grade 2 clinically significant adverse 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 study drug:

   • 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's Wort)
   • Warfarin, or equivalent vitamin K antagonist
   • Antiretroviral medications.

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

   • Grapefruit, or
   • Grapefruit products, or
   • Seville oranges (including marmalade containing Seville oranges), or
   • Star fruit
10. Patient has clinically significant cardiovascular disease such as uncontrolled arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification

11. Patient has a life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of oral drugs, or put the study outcomes 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 2 years 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 cell carcinoma of the skin
    • Previous malignancy confined and surgically resected (or treated with other modalities) 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 uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
14. Received live, attenuated vaccines within 4 weeks prior to the first dose of study drug.
15. Major surgery within 4 weeks prior to the first dose of study drug.