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

NCT05864742 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 21/001
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

This is an open label, multi-centre, phase II study in which RR MCL patients will be genetically risk-stratified into Standard risk (no 9p21.1-24.3 loss, no SMARCA2 or SMARCA4 mut/del) and High risk (9p21.1-24.3 loss, SMARCA2 and/or SMARCA4 mut/del). Patients without the high-risk mutations will be treated with ibrutinib, rituximab and venetoclax. Patients with the high-risk mutations will be treated with ibrutinib, rituximab, venetoclax and navitoclax.

Conditions

Mantle Cell Lymphoma Refractory

Outcome Measures

Primary Outcomes (1)

• Depth of MCL response to venetoclax and ibrutinib in combination with rituximab as determined by MRD at 16 weeks.

  Standard risk MCL (no 9p21.1-24.3 loss, SMARCA2 or SMARCA4 mut/del): to evaluate the depth of response to venetoclax and ibrutinib in combination with rituximab in the treatment of patients with MCL, as determined by MRD clearance rate at 16 weeks.

  2.5 years

Study Arms (2)

Standard-Risk Cohort

EXPERIMENTAL

Patients 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.

Drug: Ibrutinib; Drug: Venetoclax; Drug: Rituximab

High-Risk Cohort

EXPERIMENTAL

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

Drug: Ibrutinib; Drug: Venetoclax; Drug: Navitoclax; Drug: Rituximab

Interventions

Ibrutinib DRUG

560 mg daily continuously

Also known as: imbruvica

High-Risk Cohort; Standard-Risk Cohort

Venetoclax DRUG

Oral daily. Dose escalation every 7 days (if no TLS) 20mg, 50mg, 100mg, 200mg and 400mg

Also known as: Venclexta

High-Risk Cohort; Standard-Risk Cohort

Navitoclax DRUG

Oral daily. Dose-escalation every 14 days (if plt \>75x10\^9/L) 50mg, 100mg, 150mg, and 200mg (target dose)

Also known as: ABT-263

High-Risk Cohort

Rituximab DRUG

375mg/m2, intravenous. To be given on day 1 of weeks 1, 2, 3, 4 of C1 and day 1 of C2-C8

Also known as: Rituxan

High-Risk Cohort; Standard-Risk Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be ≥ 18 years of age.
• 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.
• 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).
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2 .
• 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)
• 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
• 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

You may not qualify if:

• 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.
• Patient has active and uncontrolled autoimmune cytopenias (for 2 weeks), including autoimmune haemolytic anaemia and immune thrombocytopenic purpura.
• Patient has current central nervous system (CNS) involvement by MCL.
• 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.
• Patient has received the following within 30 days prior to the first dose of study drug:
• Monoclonal antibody given with anti-neoplastic intent
• 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
• Patient has received the following within 7 days prior to the first dose of study drug:
• Steroid therapy given with anti-neoplastic intent
• 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

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (3)

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Flinders Medical Centre

Bedford Park, South Australia, 5042, Australia

Location

Peter MacCallum Cancer Centre

Parkville, Victoria, 3000, Australia

Location

MeSH Terms

Interventions

ibrutinib; venetoclax; navitoclax; Rituximab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2023
• First Posted: May 18, 2023
• Study Start: September 7, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2029
• Last Updated: August 12, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)