A Phase 1 Study of PBCAR19B in Subjects with CD19-expressing Malignancies
This is a Phase 1, nonrandomized, open-label, single-dose, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR19B in adult study participants with CD-19 expressing malignancies.
Primary: -To evaluate the safety and tolerability of PBCAR19B in subjects with relapsed/refractory Non-Hodgkin Lymphoma (r/r NHL) and find an appropriate dose to optimize safety and efficacy. Secondary: -To evaluate the clinical activity of PBCAR19B in subjects with r/r NHL.
Cell Therapy; Chemotherapy (NOS); Therapy (NOS)
- Inclusion Criteria:
- 18 years of age or older at the time of signing the informed consent.
- Must be willing to practice birth control and refrain from donating sperm or oocytes from the time of enrollment in this study through 3 months after receiving the study treatment.
- Women of childbearing potential (WOCBP) must be tested negative for pregnancy at Screening because of the potentially harmful effects of the preparative chemotherapy to the fetus. WOCBP are defined as any women who are not postmenopausal or who have not had a hysterectomy. Postmenopausal is defined as women over the age of 55 who have not had a menstrual period for at least 1 year.
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
- Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function as defined in protocol. Criteria for NHL:
- Has relapsed/refractory CD19+ B-cell NHL that is histologically confirmed by archived tumor biopsy tissue from the last relapse and corresponding pathology report. Alternatively, if at least 1 tumor involved site is accessible at Screening, the patients’ diagnosis will be confirmed by pretreatment biopsy (excisional when possible). If a patient never had a CR during prior lines of therapy, a sample from the most recent biopsy is acceptable.
- Measurable or detectable disease (positron emission tomography [PET]-positive) with evidence of disease progression after most-recent therapy according to the Lugano classification.
- Primary refractory disease or relapsed/refractory disease after treatment with 2 prior regimens, unless per standard of care treatment guidance (e.g., National Comprehensive Cancer Network) no second line therapy of known benefit exists. Patients including but not limited to those with the following types of lymphoma and have received the associated standard therapies are eligible: (a) Primary mediastinal B-cell lymphoma (PMBCL)/FL including Grade 3B or transformed FL/high-grade B-cell lymphoma/diffuse large B-cell lymphoma (DLBCL) including Richter’s transformation. Patients must have received rituximab or other anti-CD20 antibody and anthracycline-based chemotherapy. All patients should be evaluated for approved anti-CD19 CAR T-cell therapy when applicable. (b) Indolent B-cell lymphoma (Grades 1, 2, and 3A)/transformed CLL (Richter’s)/marginal zone lymphoma. Patients must have failed 2 prior lines of systemic therapy including an alkylator (e.g., bendamustine, cyclophosphamide/vincristine/ prednisone) plus an anti-CD20 antibody. (c) patients with relapsed/refractory Burkitt’s lymphoma must have failed 1 prior therapy. (d) MCL. Patients must have failed 2 prior lines of systemic therapy including chemotherapy (bendamustine/rituximab; R-CHOP; or Nordic-type regimen) with or without autologous stem cell transplant (ASCT) and a Bruton’s tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib). (e) Patients with CLL/SLL must have previously failed/intolerant to at least 2 prior lines of systemic targeted therapy including a BTK inhibitor and venetoclax ± rituximab.
- For patients with CLL/SLL: diagnosis of CD19+ CLL with indication for treatment based on the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines and clinically measurable disease or CD19+ SLL (lymphadenopathy and/or splenomegaly and <5 × 109 cd19+ and cd5+ clonal b cells l in peripheral blood at diagnosis) with measurable disease that is biopsy proven sll.>5>
- Exclusion Criteria:
- Patient has had a malignancy, besides the malignancies of inclusion (B-cell NHL or CLL/SLL), that in the investigator's opinion, has a high risk of relapse in the next 2 years
- Recent clinically significant fungal, bacterial, viral, protozoal, or other infection must be resolved and not requiring therapeutic anti-microbial medications at least 7 days prior to lymphodepletion. Patients with elevated CRP must undergo infectious disease (ID) workup and the recommendations discussed with medical monitor to be considered on an individual basis. The CRP must be trending toward the normal range for the laboratory. Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if the patient is responding to active treatment and with medical monitor approval.
- Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease).
- History of human immunodeficiency virus (HIV) infection.
- Active hepatitis B or hepatitis C confirmed by polymerase chain reaction (PCR). Patients testing positive for inactive hepatitis B will be allowed to enroll if on prophylactic treatment.
- Any known uncontrolled cardiovascular disease at the time of Screening that, in the investigator's opinion, is clinically significant and renders the subject ineligible.
- History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening.
- History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- Presence of a neurological disorder that, in the opinion of the investigator, may impair the ability to evaluate neurotoxicity.
- Abnormal findings during the Screening Period or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient's safety.
- History of a genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome. Prior/concomitant therapy
- Patients who have received ASCT within 45 days of Screening are excluded.
- Patients who have received systemic corticosteroid (greater than physiologic replacement) therapy for at least 7 days prior to initiating lymphodepletion chemotherapy are excluded.
- Patients who have received a live vaccine within 4 weeks before Screening are excluded. Non-live virus vaccines are not excluded.
- Patients undergoing Radiotherapy to target lesions within 4 weeks before Screening are excluded.
- Patients who have an indwelling catheter (i.e., pleural, peritoneal, pericardial as well as biliary and ureteral stents) are excluded. This does not apply to intravenous lines.
- Pregnant or breastfeeding women.
- Patients are excluded unless there has been documented progression of the disease after prior most recent systemic anti-cancer therapeutic agents and resolution of adverse events caused by their administration.
- In the investigator's judgment, the patient is unlikely to complete all protocol required study visits or procedures, including follow-up visits, or is unlikely to comply with the study requirements for participation.
- Any mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study, and/or evidence of an uncooperative attitude. Criteria for NHL:
- Requirement for urgent therapy due to mass effects such as bowel obstruction, spinal cord, or blood vessel compression.
- Any history of CNS disease. If active CNS involvement is suspected, a negative computed tomography (CT)/magnetic resonance imaging (MRI) is required at Screening. Criteria for CLL/SLL
- Any history of CNS disease. If active CNS involvement is suspected, a negative lumbar puncture is required at Screening.
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