phase 1/2 study of cd19 chimeric antigen receptor t-cell (cd19 car-t; pl001) for relapsed or refractory b-cell lymphoma

Conditions: Diffuse Large B Cell Lymphoma; Primary Mediastinal Large B Cell Lymphoma; Large B-cell Lymphoma; Follicular Lymphoma Grade 3A; Follicular Lymphoma Grade 3B

Summary: this is a multiple center, non-randomized, open-label, phase 1/2 study. the primary objective of phase 1 is to evaluate the safety of pl001 and find the recommended phase 2 dose (rp2d). the objective of phase 2 is to evaluate the safety and efficacy of cd19 car-t(known as pl001).

cluster of differentiation (cd) 19 chimeric antigen receptor t-cell (car-t) has been a very promising treatment option for multiple types of b-cell lymphoma. kymriah® (tisagenlecleucel, novartis) and yescarta® (axicabtagene ciloleucel, gilead) were licensed by the united states food and drug administration (us fda) and european medicines agency (ema) in 2017 to treat relapsed or refractory b-cell acute lymphoblastic leukemia (b-all), diffuse large b-cell lymphoma (dlbcl), and high-grade b-cell lymphoma (hgbcl). a third anti-cd19 car-t product, tecartus (brexucabtagene autoleucel, gilead) was approved by the us fda for relapsed and refractory mantle cell lymphoma (mcl) in july 2020. in february 2021, another product, breyanzi® (lisocabtagene maraleucel, juno therapeutics, inc.), was approved by the us fda for relapsed or refractory large b-cell lymphoma after two or more lines of systemic therapy, including dlbcl not otherwise specified (including dlbcl arising from indolent lymphoma), high-grade b-cell lymphoma, primary mediastinal large b cell lymphoma (pmlbcl), and gr. 3b fl. currently, in taiwan, no cd19 car-t therapies are available commercially.this phase 1/phase 2 study will test pl001, a cd19 car-t therapy manufactured by pell bio-med technology co., ltd., as a monotherapy for relapsed or refractory b-cell lymphoma. the phase 1 of the study will be conducted to establish a dose range that is well tolerated by the majority of patients and to provide a safety profile of pl001 in the target patient population. the results of the phase 1 of the study will recommend the dose selection for the phase 2 of the study. phase 2 of the study will assess the efficacy and safety of pl001 in patients with relapsed or refractory b cell lymphoma.

Eligibility criteria:
inclusion criteria: screening 1: 1. patient is ≥14 years of age, inclusive, at the time of signing the informed consent. 2. histologically confirmed diagnosis of diffuse large b-cell lymphoma (dlbcl), primary mediastinal large b-cell lymphoma (pmlbcl), large b-cell lymphoma transformed from follicular lymphoma (fl), or grade 3a or 3b fl. 3. on-site documentation of cd19 on the dominant population of cancer cells. 4. disease status should meet any one of the below: 1. patients with previous autologous-hematopoietic stem cell transplantation (auto hsct) have relapsed, progressive, or refractory disease (defined as having not achieved a cr) after transplantation regardless of lines of systemic therapy. 2. patients without previous hsct have relapsed, progressive, or refractory disease (defined as having not achieved a cr) after at least 2 lines of systemic therapy, including anti-cd20 antibody and anthracycline. 5. have no available effective systemic therapy as judged by the investigator. 6. at least one measurable non-cns (central nervous system) lesion based on lugano classification for lymphoma. 7. eastern cooperative oncology group (ecog) performance status of 0 to 2. 8. life expectancy of at least 3 months. 9. patient is male or female. 10. a male patient must agree to use a highly effective contraception as detailed in section 10.4 (appendix 4) during the treatment period and for at least 2 years after the dose of pl001 and refrain from donating sperm during this period. female patients: 11. a female patient is eligible to participate if she is not pregnant (section 10.4; appendix 4), not breastfeeding, and at least one of the following conditions applies: • not a woman of childbearing potential (wocbp) as defined in section 10.4 (appendix 4). or • a wocbp who agrees to follow the contraceptive guidance in section 10.4 (appendix 4) during the treatment period and for at least 2 years after the dose of pl001 and refrain from donating ova during this period. 12. patient/patient's parent/legal guardian is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (icf) and in this protocol. screening 2: 1. eastern cooperative oncology group (ecog) performance status of 0 to 2. 2. car-t is successfully manufactured and ready for use, from cells harvested by non mobilized leukapheresis. 3. wocbp who have a negative serum pregnancy test at screening 2. exclusion criteria: screening 1: 1. chronic lymphocytic leukemia with richter's transformation. 2. primary cns lymphoma. (non-primary cns lymphoma with cns involvement is eligible). 3. primary intra-ocular lymphoma. 4. prior cd19 targeted therapy, such as car-t, bi-specific t-cell engagers (bite), or monoclonal antibody. 5. history of cancers (includes myelodysplastic syndrome) other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease-free without active treatment for at least 3 years. 6. history of allogeneic hsct. 7. history of autologous hsct within 3 months prior to consent. 8. received any investigational product within 4 weeks prior to consent. 9. systemic anticancer therapy within 3 weeks prior to apheresis. 10. long-term use of systemic corticosteroids, defined as daily use \>10 mg of prednisolone or equivalent, within 2 weeks prior to leukapheresis. exception examples: * nasal, ophthalmic, inhaled, intra-articular, and topical steroid preparation. * short term systemic steroid for drug, contrast, or blood transfusion allergic reaction management. * low dose maintenance steroid therapy for other conditions (e.g., asthma). 11. use of long-acting and short-acting myeloid growth factor within 2 weeks, 5 days prior to leukapheresis, respectively. 12. received anti-thymocyte globulin within 4 weeks prior to consent. 13. intrathecal chemotherapy within 1 week prior to leukapheresis. 14. inadequate major organ functions at screening, which were defined as any of below: 1. absolute neutrophil count (anc) \<500/µl 2. absolute lymphocyte count (alc) \<300/µl, excluding leukemic cells. 3. hemoglobin (hb) \<8.0 g/dl 4. platelet count \<75,000/µl without transfusion support within 3 days 5. e. baseline o2 saturation \<92% by pulse oximetry at room air 6. significant cns diseases such as dementia, major stroke, seizure while under antiepileptic drug 7. aspartate aminotransferase (ast) \>5 × upper limit of normal (uln) and alanine aminotransferase (alt) \>5 × uln, or total bilirubin \>2 × uln (except for constitutional jaundice) 8. serum creatinine \> 1.5 × uln and estimated glomerular filtration rate (egfr) \< 60 ml/min/1.73 m², as calculated by the cockcroft-gault formula. 9. significant cardiac disease including but not limited to: left ventricular ejection fraction (lvef) \ 480 msec based on fredericia's formula, clinically significant arrhythmias, history of myocardial infarction or unstable angina within 3 months prior to consent. 15. active hepatitis b virus (hbv) infection defined as detectable hbv dna (patients with positive anti-hepatitis b core antibody \[hbcab\] must consent to regular monitoring of hbv dna, and anti-hbv prophylaxis with oral anti-viral agent (such as entecavir) is mandatory until end-of-study visit \[visit 15\].) 16. active hepatitis c virus (hcv) infection defined as positive anti- hcv antibody plus detectable hcv rna. 17. positive for human immunodeficiency virus (hiv) or human t-cell lymphotropic virus (htlv) infection. 18. uncontrolled acute life-threatening bacterial, viral, or fungal infection (e.g., the need for intravenous therapeutic antibiotics, blood culture positive ≤72 hours prior to apheresis). 21. any medical conditions which might compromise the patient's safety from leukapheresis, lymphodepletion chemotherapy, or car-t therapy and anticipated aes, according to the investigator's evaluation. 22.patients with insufficient leukapheresis cells. screening 2: 1. inadequate major organ functions at screening which were defined as any of below: 1. anc \<500/µl 2. hb \<8.0 g/dl 3. platelet count \<50,000/µl, without transfusion support within 3 days 4. baseline o2 saturation \<92% by pulse oximetry on room air 5. ast \>5 × uln and alt\>5 × uln, or total bilirubin \>2 × uln (except for constitutional jaundice) 6. significant cns diseases such as dementia, major stroke, seizure while under antiepileptic drug 7. serum creatinine \> 1.5 × uln and estimated glomerular filtration rate (egfr) \< 60 ml/min/1.73 m², as calculated by the cockcroft-gault formula. 2. long-term use of systemic corticosteroids, defined as daily use \>10 mg of prednisolone or equivalent. exception examples: * nasal, ophthalmic, inhaled, intra-articular, and topical steroid preparation. * short term systemic steroid for drug, contrast, or blood transfusion allergic reaction management. * low dose maintenance steroid therapy for other conditions (e.g., asthma). 3. use of long-acting and short-acting myeloid growth factor within 12 days, 2 days prior to lymphodepletion therapy, respectively. 4. uncontrolled acute life-threatening bacterial, viral, or fungal infection (e.g. the need for intravenous therapeutic antibiotics, blood culture positive ≤72 hours prior to lymphodepletion). 5. any medical condition which might compromise the patient's safety because of lymphodepletion chemotherapy or car-t therapy and anticipated aes, according to the investigator's opinion.

Keywords: dlbcl pmlbcl fl