Clinical Trial 22557

• Overview

  Study Title:

  A Phase 2, Open-Label, Randomized Study of Pirtobrutinib and Brexucabtagene Autoleucel in Patients with Relapsed or Refractory Mantle Cell Lymphoma

  Objective:

  Primary Objectives: Evaluate the efficacy of pirtobrutinib and brexu-cel. We hypothesize that use of pirtobrutinib will improve intent-to-treat progression free survival (PFS) after brexu-cel in R/R MCL. Compare the efficacy, in brexu-cel infused patients, between concurrent pirtobrutinib to no concurrent pirto with brexu-cel. We hypothesize that concurrent pirtobrutinib will improve PFS after brexu-cel in R/R MCL. Safety and tolerability of pirtobrutinib when used in conjunction with brexu-cel CAR T-cell therapy in patients with MCL. Secondary Objectives: Evaluate CAR-T cell-specific toxicities when combining pirtobrutinib with brexu-cel. We hypothesize that the addition of pirtobrutinib will reduce the likelihood of severe CAR T toxicities after brexu-cel. Evaluate the effect of pirtobrutinib on systemic inflammation and CAR T-cell expansion. We hypothesize that pirtobrutinib will reduce tumor-driven systemic inflammation and will reduce tumor burden without affecting CAR T-cell expansion.

• Treatments

  Therapies:

  Cell Therapy; Therapy (NOS)

  Medications:

  CD19 CAR T Cells (); Pirtobrutinib ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patients with a histologically confirmed diagnosis of mantle cell lymphoma (MCL) will be eligible.
  • Adult males or females who are 18 years of age or older at time of signing informed consent.
  • Must have ability to comprehend and the willingness to sign written informed consent for study participation.
  • Eligible to receive CAR T-cell therapy (Brexucabtagene autoleucel) for MCL by the standard of care label, which states: "TECARTUS or Brexucabtagene autoleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of: Adult patients with relapsed or refractory mantle cell lymphoma (MCL)".
  • ECOG performance status 0 to 2.
  • Patients are required to have the following washout periods prior to leukapheresis. In addition, prior treatment-related AEs must have recovered to Grade 1 or less with the exception of alopecia and Grade 2 peripheral neuropathy. Targeted agents (i.e. BTK inhibitors), investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter. Antibody-drug conjugates (ADC): 10 weeks. Radiation therapy: Broad field radiation (30% or more of the bone marrow or whole brain radiotherapy): 14 days. Palliative limited field radiation: 7 days. Note: In the case of known central nervous system (CNS) involvement by systemic lymphoma: Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval. Bendamustine or other purine analogues: 3 months. Corticosteroids: 5 days.
  • The effects of Pirtobrutinib on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation as outlined in the protocol.
  • Patients must meet the laboratory parameters defined by the protocol at screening.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Patients who have previously received treatment with pirtobrutinib for >2 months prior to study enrollment are ineligible. Patients who are relapsed or refractory and then received less than 2 months of pirtobrutinib as holding therapy while awaiting CAR T-cell therapy evaluation, and who did not demonstrate disease progression while on pirtobrutinib holding therapy, are eligible.
  • Patients who have previously discontinued pirtobrutinib due to disease progression, intolerance, or toxicity.
  • Patients who are currently receiving or who have received any investigational study agent 4 weeks or less prior to screening visit are ineligible.
  • Prior treatment with chimeric antigen receptor (CAR) T-cell therapy.
  • Participants with clinically significant or uncontrolled cardiac disease, including unstable angina or acute coronary syndrome within the past 2 months prior to randomization, history of myocardial infarction within 3 months prior to randomization, documented LVEF by any method of 40% or less in the 12 months prior to randomization, or Grade 3 or higher NYHA functional classification system of heart failure.
  • Uncontrolled or symptomatic arrhythmias, including prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericias Formula (QTcF): QTcF = QT/(RR0.33). Correction of suspected drug induced QTcF prolongation can be attempted at the investigators discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation. Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker.
  • Evidence of active uncontrolled/untreated infection (viral, bacterial, fungal, opportunistic) of any origin.
  • Participants with active immunologic or inflammatory/autoimmune disease affecting the CNS, and unrelated to their disease under study or previous treatment.
  • Patients with active CNS involvement of Mantle Cell Lymphoma. A history of CNS Mantle Cell Lymphoma is allowed, as long as it has cleared, and the patient is able to comply with study procedures. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible with documented Sponsor approval.
  • Known positive Human immunodeficiency virus (HIV) status. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment.
  • Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before randomization. Patients who are HBV DNA PCR positive will be excluded. Patients who are HBV DNA PCR negative with positive anti-HBc require prophylaxis against Hepatitis B reactivation (see Section 6.4 "General Guidance for Hepatic Monitoring").
  • Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded.
  • Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
  • Major surgery within 4 weeks prior to enrollment.
  • History of a previously diagnosed hereditary bleeding disorder.
  • Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
  • Other exclusion criteria may apply.

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