Burkitt Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Non Hodgkin Lymphoma
Conditions
Keywords
CAR-T, Chimeric antigen receptor T-cell therapy, CAR Therapy, Pirtobrutinib, B Cells, BTK inhibitor, Bruton's tyrosine kinase
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.
Interventions
DRUGPirtobrutinib
Pirtobrutinib will be administered at 200 mg/day orally starting at least 14 days prior to apheresis as bridging until the start of lymphodepletion and restarted between day 28-120 for up to one year as maintenance post cell infusion.
DRUGLV20.19 CAR T cells
Subjects will receive a dose of 2.5x10\^6 CAR-T cells/kg as a previously identified safe in a Phase 1 protocol at the Medical College of Wisconsin.
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 81 Years
Healthy volunteers
No
Inclusion criteria
To facilitate rapid start of pirtobrutinib, there will be separate inclusion/exclusion for pirtobrutinib and LV20.19 CAR T-cells in addition to the general inclusion as outlined below. General inclusion criteria for trial: 1. Patients must be aged ≥18 years and \<81 years with relapsed or refractory B-cell non-Hodgkin Lymphoma (NHL). 2. Diagnosis of relapsed or refractory B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), Mantle Cell Lymphoma, Burkitt Lymphoma and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive (EBV)+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation). 3. Disease specific criteria as follows: 1. DLBCL and associated subtypes (listed above) i. Must have received Rituximab or another cluster of differentiation 20 (CD20) antibody with combination anthracycline based chemotherapy regimen and have ONE of the following: <!-- --> 1. Primary refractory lymphoma or early relapse ≤6 months after one line of therapy. 2. For relapse \>6.00 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant. ii. Relapse post-autologous transplant. iii. Relapse post-allogeneic transplant. iv. Relapse post-CAR T-cell therapy (maximum 2 patients allowed with this designation). b. Mantle Cell Lymphoma i. Must have received Rituximab or another CD 20 antibody with one chemotherapy regimen appropriate for this disease (bendamustine or cytarabine, or anthracycline based treatment) and have ONE of the following: 1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of anti-CD20 antibody. 2. Progressive disease after ≥second line BTK inhibitor. 3. Relapse post-autologous transplant. 4. Relapse post-allogeneic transplant. c. Marginal Zone Lymphoma and Follicular Lymphoma i. Must have received Rituximab or another CD20 antibody with chemotherapy regimen appropriate for the disease and have ONE of the following: <!-- --> 1. Relapsed disease after two lines of therapy including administration of anti-CD20 antibody. 2. Relapse post-autologous transplant. 3. Relapse post-allogeneic transplant. d. Burkitt's Lymphoma i. Must have received Rituximab or another CD20 antibody in combination with anthracycline based chemotherapy regimen and have ONE of the following: <!-- --> 1. Primary refractory lymphoma. 2. Relapse within 6 months. 3. For relapse \>6 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant. i. Relapse post-autologous transplant. ii. Relapse post-allogeneic transplant. 4. Able to provide written informed consent. 5. Negative urine or serum pregnancy test in females of childbearing potential at screening. 6. Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for duration of treatment and for 1 month following the last dose if study treatment. 7. Karnofsky performance score ≥70. 8. Expected survival \>12 weeks. 9. Patient has demonstrated compliance with prior therapies. 10. Able to take oral medications. 11. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x upper limit of normal (ULN). 12. Patients are required to have the following washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related adverse events (AEs) must have recovered to Grade ≤ 1 with the exception of alopecia and Grade 2 peripheral neuropathy. 1. Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter. 2. immunoconjugated antibody treatment within 10 weeks prior to randomization. 3. broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment. 4. palliative limited field radiation must be completed 7 days prior to study enrollment. Inclusion Criteria to START Pirtobrutinib Bridging: 1. Absolute neutrophil count (ANC) ≥1000 with no G-CSF within 7 days or pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement. 2. Platelets≥50,000 with no transfusion within 7 days unless patient has biopsy proven bone marrow involvement. 3. Hemoglobin ≥8g/dL (≥80 g/L) \[blood transfusions are allowable to reach this goal\]. 4. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine transaminase (ALT) \<3 x upper limit of normal (ULN) or \< 5 x ULN with documented liver involvement; serum bilirubin \<1.5 x ULN or \<3 x ULN with documented liver involvement , or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease. 5. Adequate renal function, defined as creatinine clearance≥50 ml/min. 1. No IV hydration within 24 hours of eligibility. 2. No dialysis dependent renal failure. Inclusion criteria for Pirtobrutinib Maintenance (part B) 1. Recovery of neutrophils count after CAR T-cell infusion with ANC ≥1000/dL without G-CSF within the last 7 days. 2. Recovery of platelet count after CAR T-cell infusion with platelet count ≥50,000/dL. 3. Adequate hepatic function, defined as back to baseline or AST and ALT \<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase \<3 x ULN, or considered not clinically significant as per the clinical PI's discretion (e.g., Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease. 4. Adequate renal function, defined as creatinine clearance≥40 ml/min. 5. Evidence of response or stable disease (complete response/partial response/stable disease) at day 28 after CAR T-cell therapy. Inclusion Criteria for Apheresis and LV20.19 CAR T-cells: 1. Active Measurable disease must be documented within 4 weeks of lymphodepletion start defined as nodal lesions greater than 15 mm in the long axis or extranodal lesions \>10 mm in long and short axis OR bone marrow involvement that is biopsy proven for B-cell NHL. 2. Absolute cluster of differentiation (CD) 3 count≥50 mm\^3. 3. MRI brain and Lumbar Puncture with cerebrospinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement ONLY in patients with history of CNS involvement or clinical suspicion at the time of enrollment. 4. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥45% (by echocardiogram (ECHO) or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%. 5. No contraindication to central line access. 6. ANC≥1000 with no pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement. 7. Platelets≥50,000 with no transfusion within 72 hours unless patient has biopsy proven bone marrow involvement. 8. Adequate hepatic function, defined as AST and ALT \<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase \<3 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease. 9. Adequate renal function, defined as creatinine clearance≥50 ml/min. a. No IV hydration within 24 hours of eligibility. b. No dialysis dependent renal failure.
Exclusion criteria
A potential subject who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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). |
| 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). |
Countries
United States
Contacts
CONTACTMedical College of Wisconsin Cancer Center Clinical Trials Office
PRINCIPAL_INVESTIGATORNirav Shah, MD
Medical College of Wisconsin
Outcome results
None listed