LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies
- Conditions
- Burkitt LymphomaNon Hodgkin LymphomaFollicular LymphomaMarginal Zone LymphomaDiffuse Large B Cell LymphomaMantle Cell Lymphoma
- Interventions
- Drug: LV20.19 CAR T cells
- Registration Number
- NCT05990465
- Lead Sponsor
- Medical College of Wisconsin
- Brief Summary
This is a phase I, interventional, single arm, open label, treatment study designed to evaluate the safety and efficacy of LV20.19 CAR -T cells with pirtobrutinib bridging and maintenance in adult patients with B cell malignancies that have failed prior therapies.
- Detailed Description
This is the first study to evaluate the safety and impact of the combination of pirtobrutinib and LV20.19 CAR-T cells.
Pirtobrutinib is a first-in-class non-covalent Bruton's tyrosine kinase (BTK) inhibitor. The safe dose of this agent has been identified the BRUIN study as 200 mg daily administered as an oral agent. As a single agent, the toxicity profile has been favorable and does not overlap with other covalent BTK inhibitors with minimal cardiotoxicity and bleeding complications.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 12
Not provided
A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
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Positive beta-human chorionic gonadotropin (HCG) in female of child-bearing potential or plan to become pregnant during the study or within 1 month of the last dose of study treatment and women who are current lactating or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
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Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
- HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before randomization. Patients who are hepatitis B PCR positive will be excluded.
- 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.
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Known active cytomegalovirus (CMV) infection (Unknown or negative status are eligible).
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History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon requiring steroid therapy defined as >20 mg of prednisone or equivalent daily.
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Presence of ≥ grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
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Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of the drug (whichever is shorter) washout prior to apheresis.
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Refusal to participate in the long-term follow-up protocol.
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Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.
- Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was >4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
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Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are <100 days post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
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Prior allogeneic CAR T-cell therapy <100 days from prior CAR T-cell treatment.
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Previous recipients of autologous CAR-T cell therapy directed at either cluster of differentiation 19 (CD19) or CD20 are excluded if they are <100 days post prior CAR-T cell treatment (does not include re-enrollment) or have >5% residual circulating CAR-T as measured by flow cytometry using a CD19 CAR detection reagent (Miltenyi Biotec).
a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
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Anti-CD20 antibody treatment within 4 weeks of cell infusion.
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Anti-CD19 antibody treatment within 4 weeks of cell infusion.
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Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.
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No other oral chemotherapeutic agents or antibody directed treatment after starting pirtobrutinib other than steroids or radiation to a single site in a palliative fashion.
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Patients post solid organ transplant who develop high grade lymphomas or leukemias.
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Concurrent active malignancy other than basal or squamous cell carcinomas of the skin (underlying low-grade lymphoma chronic lymphocytic leukemia/Follicular lymphoma (FL) / Marginal zone lymphoma (MZL) is allowable in patients with transformed large cell lymphoma/Richter's.
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Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
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History of stroke or intracranial hemorrhage within 6 months of randomization.
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Significant cardiovascular disease defined as myocardial infarction within 6 months of randomization, congestive heart failure with ejection fraction <30%, active unstable angina, QT prolongation (QTcF)>470 msec on ECG.
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Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
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Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
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Patients who had surgery within 4 weeks prior to randomization.
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Patients who have received vaccination with live vaccine within 28 days prior to randomization.
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Patients with known hypersensitivity to any of the excipients of pirtobrutinib.
Special Criteria Regarding Fertility and Contraception
Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy test performed at screening.
Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.
Acceptable birth control includes a combination of two of the following methods:
• Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
• Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Vasectomized partner
• Sexual abstinence: considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyles of the patient.
• Female sterilization
• Fallopian tube implants (if confirmed by hysterosalpingogram) Oocyte donation is prohibited during the duration of participation on this protocol and for 1 month after the last dose of study drug.
Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months which is non-therapy induced or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Pirtobrutinib and CAR T Cells LV20.19 CAR T cells Pirtobrutinib is an oral agent. LV20.19 CAR T cells will be administered either fresh or thawed after cryopreservation by IV injection. Pirtobrutinib and CAR T Cells Pirtobrutinib Pirtobrutinib is an oral agent. LV20.19 CAR T cells will be administered either fresh or thawed after cryopreservation by IV injection.
- Primary Outcome Measures
Name Time Method Number of Adverse Events After CAR 20/19-T Cell Infusion Up until 28 days after infusion This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 5) occurring during the first 28 days following infusion.
Number of Adverse Events After Pirtobrutinib Administration in Part B Day 28 until up to one year Pirtobrutinib will be started again at 200 mg/day orally on day 28-120 for up to one year as maintenance post cell infusion. This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 5).
Number of Adverse Events After Pirtobrutinib Administration in Part A 14 days prior to apheresis until the start of lymphodepletion Pirtobrutinib will be administered at 200 mg/day orally starting at least 14 days prior to apheresis as bridging until the start of lymphodepletion. This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 5).
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
Froedtert & the Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States