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RecruitingLast updated: 8 November 2023

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

Clinical summary


Eligible participants will be allocated to one of two experimental treatment arms, depending on their level of risk.

People without the high-risk mutations (no 9p21.1-24.3 loss, no SMARCA2 or SMARCA4 mut/del) will be treated with ibrutinib, rituximab and venetoclax. 

People with high-risk mutations (9p21.1-24.3 loss, SMARCA2 and/or SMARCA4 mut/del) will be treated with ibrutinib, rituximab, venetoclax and navitoclax.

Ibrutinib will be given at a dose of 560mg daily, continuously. Venetoclax will be given orally daily, dose escalation every 7 days (20mg, 50mg, 100mg, 200mg, 400mg). Rituximab will be given at a dose of 375mg/m2 intravenously on Day 1 of Weeks 1, 2, 3, 4 of C1 and Day 1 of C2-8. Navitoclax will be given orally daily, dose escalatione very 14 days (50mg, 100mg, 150mg, and 200mg).


This trial is treating patients with relapsed/refractory mantle cell lymphoma


Blood Cancers Haematological





Trial Acronym


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Trial Identifiers

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Trial sponsor

Peter MacCallum Cancer Centre, Australia

Scientific Title

A 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



  1. Patient must be ≥ 18 years of age.
  2. Patient must have a confirmed diagnosis of MCL according to World Health Organisation ([WHO] 2008) criteria, and have received at least one prior line of systemic therapy for their disease. Patients recently commenced on ibrutinib (≤4 weeks) will be allowed to enrol as long as at the time of enrolment there is measurable disease and no disease progression.
  3. Patient requires treatment in the opinion of the investigator, and has at least one site of assessable disease not previously irradiated (such as lymph node with largest 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 support at screening as follows:

    • Absolute Neutrophil Count (ANC) ≥ 0.75 x 109/L (neutropenia due to marrow infiltration may be supported by growth factors)
    • Platelets ≥ 50 x 109/L (≥ 30 x 109/L if reduced counts due to marrow infiltration; entry platelet count must be independent of transfusion within 7 days)
  6. Patients must have adequate coagulation, renal, and hepatic function, per laboratory reference 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-Gault equation or a 24-hour urine collection (Appendix 2)
    • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3.0 × ULN of institution's normal range
    • Bilirubin ≤1.5 × ULN. Patients with documented Gilbert's Syndrome may have a bilirubin > 1.5 × ULN
  7. Female patients of childbearing potential and non-sterile male patients (with partner(s) of child bearing potential) must practice at least one of the following methods 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 the patient; 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 with spermicidal jellies or cream AND a condom)
    • Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration
  8. Female patients of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [B-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
  9. Male patients must agree to refrain from sperm donation, from initial study drug administration 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 consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.


  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.


  • You are able to swallow medication by mouth.
  • You have had treatment but your cancer has gotten worse or has not responded to the treatment you have been given.
  • You have had treatment, but your cancer has come back.


  • You have been diagnosed with a prior or secondary type of cancer.
  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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