Clinical Trials /

Clinical Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma

NCT04234061

Description:

This is an open label, multi-center, single-arm, phase II study investigating the efficacy and safety of the combination of ibrutinib and Tisagenlecleucel in twenty patients with relapsed or refractory Mantle Cell Lymphoma (MCL) or who had sub-optimal response to standard therapy in the presence of TP53 mutation.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Clinical Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma
  • Official Title: A Phase II, Open-Label, Single Arm Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 19/008
  • NCT ID: NCT04234061

Conditions

  • Mantle Cell Lymphoma Recurrent

Purpose

This is an open label, multi-center, single-arm, phase II study investigating the efficacy and safety of the combination of ibrutinib and Tisagenlecleucel in twenty patients with relapsed or refractory Mantle Cell Lymphoma (MCL) or who had sub-optimal response to standard therapy in the presence of TP53 mutation.

Trial Arms

NameTypeDescriptionInterventions
SingleExperimentalibrutinib and Tisagenlecleucel

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients must meet all the following criteria for study entry:
    
                   1. Written informed consent prior to screening procedures
    
                   2. Be ≥18 years of age on the day of signing informed consent
    
                   3. Have a confirmed diagnosis of MCL according to World Health Organization (2016)
                      criteria
    
                   4. Have sufficient fresh or archival material available for central review
    
                   5. At least one site of radiographically assessable disease not previously
                      irradiated (lymph node with largest diameter ≥1.5cm, or unequivocal evaluable
                      hepatomegaly/splenomegaly or marrow phase disease)
    
                   6. Meet at least one of the following disease criteria:
    
                        -  Have relapsed, or progressed following at least 1 prior line of systemic
                           chemoimmunotherapy for MCL (may include ibrutinib or other BTK-inhibitor in
                           combination)
    
                        -  Be refractory to at least one prior line of chemoimmunotherapy (refractory
                           is defined as less than a conventional PR following 2 cycles of
                           anthracycline or cytarabine-containing therapy)
    
                        -  Have achieved <CR on PET imaging following 2 cycles of anthracycline or
                           cytarabine-containing therapy in the presence of aberrations of p53; or <CR
                           post autologous stem cell transplantation
    
                        -  Failure to achieve CR following at least 6 months of an ibrutinib or BTK
                           inhibitor -containing front-line regimen, or failure to achieve PR following
                           8 weeks of a BTK inhibitor
    
                   7. Have a life expectancy of ≥ 3 months, as judged by the investigator
    
                   8. Have acceptable haematological function within 7 days prior to registration,
                      defined as:
    
                        -  Absolute neutrophil count ≥1x10^9/L (may be supported by growth)
    
                        -  Absolute lymphocyte count ≥0.3x10^9/L or absolute CD3+ fraction > 0.15x
                           10^9/L
    
                        -  Platelets >50x 10^9/L unless explained by lymphoma at the discretion of the
                           CPI
    
                        -  Haemoglobin ≥ 80 g/L (may be transfusion supported)
    
                   9. Have acceptable organ function within 7 days prior to registration, defined as:
    
                        -  Serum creatinine ≤1.5 x ULN, or a calculated creatinine clearance of at
                           least 50 mL/min using the Cockcroft-Gault equation (see appendix 1) or a
                           24-hour urine collection
    
                        -  AST or ALT ≤3.0 x ULN
    
                        -  Bilirubin ≤ 1.5 x ULN (with the exception of patients with Gilbert's
                           syndrome. Patients with Gilbert's syndrome may be included if their total
                           bilirubin is ≤3.0 x ULN and direct bilirubin ≤1.5 x ULN).
    
                        -  aPTT and PT ≤ 1.5x ULN
    
                        -  Adequate pulmonary function defined as:
    
              -  No or mild dyspnea (≤ grade 1)
    
              -  Oxygen saturation measured by pulse oximetry ≥ 90 percent on room air 10. Female
                 patients of childbearing potential and non-sterile male patients (with partners of
                 childbearing potential) must agree to use highly effective methods of contraception
                 from registration on the study to 30 days after the last dose of ibrutinib and 12
                 months after Tisagenlecleucel infusion and until Tisagenlecleucel is no longer present
                 by qPCR on two consecutive tests (whichever is later):
    
                   -  Total abstinence from sexual intercourse when this is in line with the preferred
                      and usual life style of the patient. Periodic abstinence (e.g., calendar,
                      ovulation, symptothermal, post-ovulation methods) and withdrawal are not
                      acceptable methods of contraception
    
                   -  Female sterilisation (have had surgical bilateral oophorectomy with or without
                      hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks
                      prior to registration. In case of oophorectomy alone, only when the reproductive
                      status of the woman has been confirmed by follow-up hormone level assessment
    
                   -  Male sterilisation (at least 6 months prior to screening). For female patients on
                      the study, the vasectomised male partner should be the sole partner for that
                      patient
    
                   -  Use of oral, (estrogen and progesterone), injected or implanted hormonal methods
                      of contraception or placement of an intrauterine device (IUD) or intrauterine
                      system (IUS), or other forms of hormonal contraception that have comparable
                      efficacy (failure rate <1%), for example hormone vaginal ring or transdermal
                      hormone contraception. In case of use of oral contraception women should have
                      been stable on the same pill for a minimum of 3 months before enrolment into this
                      study.
    
            Women are considered post-menopausal and not of child bearing potential if they have had 12
            months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
            appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy
            (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks
            ago. In the case of oophorectomy alone, only when the reproductive status of the woman has
            been confirmed by follow-up hormone level assessment is she considered not of child bearing
            potential.
    
            11. Female patients of childbearing potential must have a negative serum (beta-human
            chorionic gonadotropin (β-hCG) or urine pregnancy test within 7 days of registration 12.
            Sexually active male patients must use a condom during intercourse and must agree to
            refrain from sperm donation, from registration on the study until 30 days after the last
            dose of ibrutinib or 12 months after Tisagenlecleucel infusion and until Tisagenlecleucel
            is no longer present by qPCR on two consecutive tests
    
            Exclusion Criteria:
    
              -  Patients who meet any of the following criteria will be excluded from study entry:
    
                   1. Prior allogeneic transplantation
    
                   2. Autologous transplantation within 6 weeks prior to registration
    
                   3. Active and uncontrolled autoimmune cytopenias
    
                   4. Active central nervous system involvement with MCL
    
                   5. Previous treatment with adoptive T-cell therapy
    
                   6. Receipt of a non BTK-inhibitor investigational medical product within the last 30
                      days prior to planned leukapheresis
    
                   7. Receipt of a non-anti CD20- monoclonal antibody with anti-neoplastic intent
                      within 30 days prior to planned leukapheresis
    
                   8. Receipt of steroids >20mg prednisolone or equivalent in the fortnight prior to
                      planned leukapheresis
    
                   9. Requirement for ongoing therapy with:
    
                        -  Potent CYP3A inhibitors (e.g. indinavir, ketoconazole, clarithromycin)
    
                        -  Potent CYP3A inducers (e.g. rifampin, phenytoin, carbamazepine)
    
                        -  Vitamin K antagonists (e.g. warfarin or equivalent)
    
                        -  Antiretroviral medications
    
                  10. Consumption within 3 days prior to registration:
    
                        -  Grapefruit or grapefruit products
    
                        -  Seville oranges
    
                        -  Star fruit
    
                  11. Significant cardiovascular disease such as uncontrolled or symptomatic
                      arrhythmias, congestive heart failure or myocardial infarction within 6 months of
                      screening or class III to IV cardiac disease as defined by the New York Heart
                      Association Functional Classification
    
                  12. Active neurological disorders of clinical relevance (e.g. epilepsy, severe brain
                      injury, dementia, Parkinson's disease or autoimmune/inflammatory disorders (e.g.
                      Guillain-Barre syndrome, motor neurone disease, chronic inflammatory
                      demyelinating polyneuropathy)
    
                  13. Other significant life-threatening illness or medical condition which, in the
                      investigator's opinion, could compromise the subject's safety, interfere with
                      absorption or metabolism of study drug, or put the study outcomes at undue risk
    
                  14. History of other active malignancy, with the exception of:
    
                        -  Adequately treated in situ carcinoma of the cervix or breast
    
                        -  Adequately treated basal cell carcinoma of skin or localised squamous cell
                           carcinoma of the skin
    
                        -  Previous malignancy confined and surgically resected (or treated with other
                           modalities) with curative intent and without evidence of recurrence for at
                           least 2 years prior to registration
    
                  15. History of human immunodeficiency (HIV) or active hepatitis C virus or active
                      hepatitis B virus. NOTE: Serology must be repeated at the pre-conditioning stage
                      prior to infusion with Tisagenlecleucel.
    
                  16. Clinically significant active infection confirmed by clinical evidence, imaging
                      or positive laboratory tests (e.g. blood cultures, viral DNA/RNA by PCR)
    
                  17. Receipt of live, attenuated vaccines within 4 weeks of registration
    
                  18. Major surgery within 4 weeks prior to registration
    
                  19. Pregnant or nursing (lactating) women. Note: Women of child-bearing potential
                      must have a negative serum pregnancy test performed within 24 hours before
                      leukapheresis, lymphodepletion (if performed) and prior to Tisagenlecleucel
                      infusion.
    
                  20. Known hypersensitivity to the excipients of Tisagenlecleucel or to any product to
                      be given to the patient as per the study protocol (e.g. tocilizumab and
                      lymphodepleting agents)
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Estimate complete response (CR) rate at month 4 following the infusion of Tisagenlecleucel using the Lugano criteria
    Time Frame:4 months after Tisagenlecleucel infusion using the Lugano criteria
    Safety Issue:
    Description:Using the Lugano criteria

    Secondary Outcome Measures

    Measure:Evaluate safety of combination therapy with Tisagenlecleucel and ibrutinib through monitoring of the incidence, nature and severity of adverse events (graded according to NCI CTCAE v5.0), SAEs, dose interruptions and dose reductions of ibrutinib
    Time Frame:From date of registration until the date of first progression or until the date of death from any cause, whichever occurs first, assessed up to the date of the patient's last annual assessment, on average for five years
    Safety Issue:
    Description:Through monitoring of the incidence, nature and severity of adverse events (graded according to NCI CTCAE v5.0), Serious Adverse Events, dose interruptions and dose reductions of ibrutinib
    Measure:Estimate objective response (OR) rate at day 28, month 4, 6, 9 and 12 following the infusion of Tisagenlecleucel using Lugano criteria
    Time Frame:day 28, month 4, 6, 9 and 12 following the infusion of Tisagenlecleucel
    Safety Issue:
    Description:Using Lugano criteria
    Measure:To estimate objective response (OR) rate at day 28, month 4, 6, 9 and 12 following the infusion of Tisagenlecleucel by TP53 status
    Time Frame:day 28, month 4, 6, 9 and 12 following the infusion of Tisagenlecleucel by TP53 status
    Safety Issue:
    Description:Assessment of TP53 status
    Measure:To estimate Minimal Residual Disease (MRD) negative response rates by aggregate measure of peripheral blood/or bone marrow flow cytometry, PCR and ctDNA
    Time Frame:At day 28, months 4, 6, 9 and 12 following the infusion of Tisagenlecleucel
    Safety Issue:
    Description:Measured through aggregate measure of peripheral blood/or bone marrow flow cytometry, PCR and ctDNA
    Measure:To estimate progression-free survival
    Time Frame:From date of registration until the date of first progression or until the date of death from any cause, whichever occurs first, assessed up to the date of the patient's last annual assessment, on average for five years
    Safety Issue:
    Description:According to Lugano criteria
    Measure:To estimate duration of response
    Time Frame:From date of registration until the date of first progression or until the date of death from any cause, whichever occurs first, assessed up to the date of the patient's last annual assessment, on average for five years
    Safety Issue:
    Description:Using Lugano criteria
    Measure:To estimate overall survival
    Time Frame:From date of registration until the date of first progression or until the date of death from any cause, whichever occurs first, assessed up to the date of the patient's last annual assessment, on average for five years
    Safety Issue:
    Description:By monitoring for patient death due to any cause

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Peter MacCallum Cancer Centre, Australia

    Trial Keywords

    • ibrutinib
    • Tisagenlecleucel
    • Chimeric Antigen Receptor - Tcell (CAR-T)
    • B-cell non-Hodgkin lymphoma
    • TP53 mutation
    • bruton's tyrosine kinase (BTK) inhibitor

    Last Updated

    January 15, 2020