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

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ClinicalTrials.gov Identifier: NCT04234061
Recruitment Status : Recruiting
First Posted : January 21, 2020
Last Update Posted : July 1, 2020
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Peter MacCallum Cancer Centre, Australia

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Recurrent Combination Product: ibrutinib and Tisagenlecleucel Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: single arm
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 7, 2020
Estimated Primary Completion Date : September 1, 2027
Estimated Study Completion Date : September 1, 2030


Arm Intervention/treatment
Experimental: Single
ibrutinib and Tisagenlecleucel
Combination Product: ibrutinib and Tisagenlecleucel
Single-arm study investigating combination of ibrutinib and Tisagenlecleucel treatment




Primary Outcome Measures :
  1. 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 ]
    Using the Lugano criteria


Secondary Outcome Measures :
  1. 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 ]
    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

  2. 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 ]
    Using Lugano criteria

  3. 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 ]
    Assessment of TP53 status

  4. 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 ]
    Measured through aggregate measure of peripheral blood/or bone marrow flow cytometry, PCR and ctDNA

  5. 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 ]
    According to Lugano criteria

  6. 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 ]
    Using Lugano criteria

  7. 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 ]
    By monitoring for patient death due to any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04234061


Contacts
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Contact: Michael Dickinson +61 3 9656 1701 michael.dickinson@petermac.org

Locations
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Australia, Victoria
Peter Mac Callum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3002
Contact: Michael Dickinson, Dr    +61 3 9656 1701    michael.dickinson@petermac.org   
Principal Investigator: Michael Dickinson, Dr         
Sponsors and Collaborators
Peter MacCallum Cancer Centre, Australia
Novartis
Investigators
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Principal Investigator: Michael Dickinson Peter MacCallum Cancer Centre, Australia
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Responsible Party: Peter MacCallum Cancer Centre, Australia
ClinicalTrials.gov Identifier: NCT04234061    
Other Study ID Numbers: 19/008
First Posted: January 21, 2020    Key Record Dates
Last Update Posted: July 1, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Peter MacCallum Cancer Centre, Australia:
ibrutinib
Tisagenlecleucel
Chimeric Antigen Receptor - Tcell (CAR-T)
B-cell non-Hodgkin lymphoma
TP53 mutation
bruton's tyrosine kinase (BTK) inhibitor
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin