CART19 Cells Effects in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma, Relapsed Clinical Trial

— UHKT-CAR19-01  

Official title:

Safety and Efficacy of Anti-CD19 Chimeric Antigen Receptor-modified Autologous T Cells (CART19) in Patients With Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma. A Dose Escalation, Open-label, Phase I Study.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05054257
• Other study ID #: UHKT-CAR19-01
• Secondary ID: 2018-004789-32
• Status: Recruiting
• Phase: Phase 1
• Start date: June 2, 2021
• Est. completion date: June 1, 2025

Study information

• Verified date: September 2023
• Source: Institute of Hematology and Blood Transfusion, Czech Republic
• Contact: Jan Vydra
• Phone: +420221977182
• Email: jan.vydra[@]uhk.cz
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase I Dose Escalation Study of CART19 Cells for Adult Patients With Relapsed / Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma.

Description:

This is an open-label, single arm study on up to 24 adult subjects with refractory or relapsed CD19+ Non-Hodgkin's Lymphoma or B-ALL. Following lymphodepleting conditioning regimen, the patients will receive a single dose of autologous CAR19 T lymphocytes provided by the sponsor´s manufacturing facility. CART19 dose will be escalated in consecutive patients using accelerated titration design in order to establish recommended CART19 dose for further study, which will be either Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD), whichever is reached first.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: June 1, 2025
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patient with refractory or relapsing CD19 positive B-ALL or B-NHL defined as:

1. B-ALL refractory to treatment or in the second or subsequent relapse (hematological OR molecular), OR

2. B-NHL refractory to treatment or in first relapse ineligible for autologous stem cell transplantation (ASCT) or in second to fourth relapse, OR

3. B-ALL or B-NHL relapsing after autologous or allogeneic hematopoietic cell transplantation (HCT).

2. CD19 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.

3. Age =18 years and = 80 yearss.

4. Patient able to understand and sign informed consent.

5. Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit 1.

General Exclusion Criteria:

1. Known hypersensitivity to any component of the Investigational Medicinal Product (IMP).

2. Autologous or allogeneic HCT in 3 months prior to IMP administration.

3. Severe, uncontrolled active infection.

4. Life expectancy < 6 weeks.

5. Parenchymal central nervous system involvement.

6. Respiratory insufficiency (need for oxygen therapy).

7. Significant liver impairment: bilirubin > 50 µmol/L, AST or ALT > 4times normal upper limit.

8. Acute kidney injury with serum creatinine > 180 µmol/L, oliguria or need for acute dialysis.

9. Heart failure with EF < 30% by echocardiography.

10. Presence of active grade 3-4 acute GvHD.

11. Serious uncontrolled neurological comorbidity.

12. Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.

13. Women: pregnancy or breast-feeding.

14. Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:

• female patients of childbearing potential not willing to use a highly effective method of contraception during the study,

• male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.

Exclusion criteria to Procurement of IMP manufacture starting material

1. Severe uncontrolled active infection.

2. Positive test results for HIV1/2, Hepatitis B/C and lues.

3. Concurrent or recent prior therapies before apheresis:

• Autologous or allogeneic hematopoietic cell transplantation within 12 weeks.

• Clofarabine, Fludarabine, Alemtuzumab within 8 weeks.

• Donor lymphocyte infusions within 4 weeks.

• Pegylated asparaginase within 4 weeks.

• Maintenance chemotherapy within 2 weeks.

• Long-acting Granulocyte Colony Stimulating Factor (G-CSF) within 2 weeks.

• Vincristine within 2 weeks.

• Intrathecal methotrexate within 1 week.

• Granulocyte Colony Stimulating Factor (G-CSF) within 5 days.

• Therapeutic dose of corticosteroids within 3 days.

• Short-acting cytostatics within 3 days

Exclusion criteria to IMP administration

1. Severe, uncontrolled active infections.

2. Life expectancy < 6 weeks.

3. Parenchymal central nervous system involvement

4. Respiratory insufficiency (need for oxygen therapy).

5. Significant liver impairment: bilirubin > 50 µmol/L, Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 4times normal upper limit.

6. Acute kidney injury with serum creatinine > 180 µg/L, oliguria or need for acute dialysis.

7. Heart failure with Ejection Fraction (EF) < 30% by echocardiography.

8. Presence of active grade 3 - 4 acute GvHD

9. Serious uncontrolled neurological comorbidity.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin's Lymphoma Refractory
• Non-Hodgkin's Lymphoma, Relapsed
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia

Intervention

Drug:
• Autologous CAR19 T lymphocytes
First-in-human trial examining the safety and efficacy of CART19 in r/r B-ALL and B-NHL

Locations

Country	Name	City	State
Czechia	Institute of Hematology and Blood Transfusion, Czech Republic	Prague

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Hematology and Blood Transfusion, Czech Republic

Country where clinical trial is conducted

Czechia, 

References & Publications (42)

Comerota AJ, Throm RC, Miller KA, Henry T, Chronos N, Laird J, Sequeira R, Kent CK, Bacchetta M, Goldman C, Salenius JP, Schmieder FA, Pilsudski R. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg. 2002 May;35(5):930-6. doi: 10.1067/mva.2002.123677. — View Citation

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014 Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226. — View Citation

Dotti G. T lymphocytes are not immune. Mol Ther. 2013 Jun;21(6):1114-5. doi: 10.1038/mt.2013.102. No abstract available. — View Citation

Fedoroff NV. Presidential address. Transposable elements, epigenetics, and genome evolution. Science. 2012 Nov 9;338(6108):758-67. doi: 10.1126/science.338.6108.758. No abstract available. — View Citation

Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O'Connor RS, Hwang WT, Pequignot E, Ambrose DE, Zhang C, Wilcox N, Bedoya F, Dorfmeier C, Chen F, Tian L, Parakandi H, Gupta M, Young RM, Johnson FB, Kulikovskaya I, Liu L, Xu J, Kassim SH, Davis MM, Levine BL, Frey NV, Siegel DL, Huang AC, Wherry EJ, Bitter H, Brogdon JL, Porter DL, June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018 May;24(5):563-571. doi: 10.1038/s41591-018-0010-1. Epub 2018 Apr 30. Erratum In: Nat Med. 2021 Mar;27(3):561. — View Citation

Gonin P, Gaillard C. Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development. Gene Ther. 2004 Oct;11 Suppl 1:S98-S108. doi: 10.1038/sj.gt.3302378. — View Citation

Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003 Jan 16;348(3):255-6. doi: 10.1056/NEJM200301163480314. No abstract available. — View Citation

Hackett PB, Largaespada DA, Switzer KC, Cooper LJ. Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Transl Res. 2013 Apr;161(4):265-83. doi: 10.1016/j.trsl.2012.12.005. Epub 2013 Jan 10. — View Citation

Hamada M, Nishio N, Okuno Y, Suzuki S, Kawashima N, Muramatsu H, Tsubota S, Wilson MH, Morita D, Kataoka S, Ichikawa D, Murakami N, Taniguchi R, Suzuki K, Kojima D, Sekiya Y, Nishikawa E, Narita A, Hama A, Kojima S, Nakazawa Y, Takahashi Y. Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR. EBioMedicine. 2018 Aug;34:18-26. doi: 10.1016/j.ebiom.2018.07.008. Epub 2018 Aug 3. — View Citation

Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017 Sep;9(9):1183-1197. doi: 10.15252/emmm.201607485. — View Citation

Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, Lopez JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017 Nov 23;130(21):2295-2306. doi: 10.1182/blood-2017-06-793141. Epub 2017 Sep 18. — View Citation

Heinrich T, Rengstl B, Muik A, Petkova M, Schmid F, Wistinghausen R, Warner K, Crispatzu G, Hansmann ML, Herling M, von Laer D, Newrzela S. Mature T-cell lymphomagenesis induced by retroviral insertional activation of Janus kinase 1. Mol Ther. 2013 Jun;21(6):1160-8. doi: 10.1038/mt.2013.67. Epub 2013 Apr 23. — View Citation

Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, Jena B, Dawson MJ, Kumaresan PR, Su S, Maiti S, Dai J, Moriarity B, Forget MA, Senyukov V, Orozco A, Liu T, McCarty J, Jackson RN, Moyes JS, Rondon G, Qazilbash M, Ciurea S, Alousi A, Nieto Y, Rezvani K, Marin D, Popat U, Hosing C, Shpall EJ, Kantarjian H, Keating M, Wierda W, Do KA, Largaespada DA, Lee DA, Hackett PB, Champlin RE, Cooper LJ. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016 Sep 1;126(9):3363-76. doi: 10.1172/JCI86721. Epub 2016 Aug 2. — View Citation

Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106-15. doi: 10.1158/1078-0432.CCR-06-1183. — View Citation

Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8. — View Citation

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20;33(6):540-9. doi: 10.1200/JCO.2014.56.2025. Epub 2014 Aug 25. — View Citation

Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama JW. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013 Apr;21(4):904-12. doi: 10.1038/mt.2013.17. Epub 2013 Feb 19. — View Citation

Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. — View Citation

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222. Erratum In: N Engl J Med. 2016 Mar 10;374(10):998. — View Citation

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866. — View Citation

Milone MC, Bhoj VG. The Pharmacology of T Cell Therapies. Mol Ther Methods Clin Dev. 2018 Jan 31;8:210-221. doi: 10.1016/j.omtm.2018.01.010. eCollection 2018 Mar 16. — View Citation

Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009 Aug;17(8):1453-64. doi: 10.1038/mt.2009.83. Epub 2009 Apr 21. Erratum In: Mol Ther. 2015 Jul;23(7):1278. — View Citation

Mueller KT, Waldron E, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, Boyer MW, August KJ, Hamilton J, Awasthi R, Stein AM, Sickert D, Chakraborty A, Levine BL, June CH, Tomassian L, Shah SS, Leung M, Taran T, Wood PA, Maude SL. Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res. 2018 Dec 15;24(24):6175-6184. doi: 10.1158/1078-0432.CCR-18-0758. Epub 2018 Sep 6. — View Citation

Norelli M, Casucci M, Bonini C, Bondanza A. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects. Biochim Biophys Acta. 2016 Jan;1865(1):90-100. doi: 10.1016/j.bbcan.2015.12.001. Epub 2015 Dec 31. — View Citation

Otahal P, Prukova D, Kral V, Fabry M, Vockova P, Lateckova L, Trneny M, Klener P. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. Oncoimmunology. 2015 Dec 3;5(4):e1115940. doi: 10.1080/2162402X.2015.1115940. eCollection 2016 Apr. — View Citation

Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007 Apr;15(4):825-33. doi: 10.1038/sj.mt.6300104. Epub 2007 Feb 13. — View Citation

Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. doi: 10.1126/scitranslmed.aac5415. — View Citation

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. doi: 10.1056/NEJMoa1103849. Epub 2011 Aug 10. Erratum In: N Engl J Med. 2016 Mar 10;374(10):998. — View Citation

Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008 Jul 1;118(1):58-65. doi: 10.1161/CIRCULATIONAHA.107.727347. Epub 2008 Jun 16. — View Citation

Ptackova P, Musil J, Stach M, Lesny P, Nemeckova S, Kral V, Fabry M, Otahal P. A new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21. Cytotherapy. 2018 Apr;20(4):507-520. doi: 10.1016/j.jcyt.2017.10.001. Epub 2018 Feb 21. — View Citation

Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, Campos LS, Yusa K, Banerjee R, Li MA, de la Rosa J, Strong A, Lu D, Ellis P, Conte N, Yang FT, Liu P, Bradley A. PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science. 2010 Nov 19;330(6007):1104-7. doi: 10.1126/science.1193004. Epub 2010 Oct 14. — View Citation

Riviere I, Sadelain M. Chimeric Antigen Receptors: A Cell and Gene Therapy Perspective. Mol Ther. 2017 May 3;25(5):1117-1124. doi: 10.1016/j.ymthe.2017.03.034. Epub 2017 Apr 26. — View Citation

Saha S, Woodard LE, Charron EM, Welch RC, Rooney CM, Wilson MH. Evaluating the potential for undesired genomic effects of the piggyBac transposon system in human cells. Nucleic Acids Res. 2015 Feb 18;43(3):1770-82. doi: 10.1093/nar/gkv017. Epub 2015 Jan 20. — View Citation

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jager U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak O, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1. — View Citation

Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47. doi: 10.1093/jnci/89.15.1138. — View Citation

Singh H, Figliola MJ, Dawson MJ, Olivares S, Zhang L, Yang G, Maiti S, Manuri P, Senyukov V, Jena B, Kebriaei P, Champlin RE, Huls H, Cooper LJ. Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLoS One. 2013 May 31;8(5):e64138. doi: 10.1371/journal.pone.0064138. Print 2013. — View Citation

Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008 Sep 15;112(6):2261-71. doi: 10.1182/blood-2007-12-128843. Epub 2008 May 28. — View Citation

Tipanee J, VandenDriessche T, Chuah MK. Transposons: Moving Forward from Preclinical Studies to Clinical Trials. Hum Gene Ther. 2017 Nov;28(11):1087-1104. doi: 10.1089/hum.2017.128. Epub 2017 Aug 22. — View Citation

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Jun 1;126(6):2123-38. doi: 10.1172/JCI85309. Epub 2016 Apr 25. — View Citation

Wang W, Lin C, Lu D, Ning Z, Cox T, Melvin D, Wang X, Bradley A, Liu P. Chromosomal transposition of PiggyBac in mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9290-5. doi: 10.1073/pnas.0801017105. Epub 2008 Jun 25. — View Citation

Yusa K, Zhou L, Li MA, Bradley A, Craig NL. A hyperactive piggyBac transposase for mammalian applications. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1531-6. doi: 10.1073/pnas.1008322108. Epub 2011 Jan 4. — View Citation

Zhao S, Jiang E, Chen S, Gu Y, Shangguan AJ, Lv T, Luo L, Yu Z. PiggyBac transposon vectors: the tools of the human gene encoding. Transl Lung Cancer Res. 2016 Feb;5(1):120-5. doi: 10.3978/j.issn.2218-6751.2016.01.05. — View Citation

* Note: There are 42 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CART19 cells in peripheral blood, bone marrow and cerebrospinal fluid	Assessment of quantity and phenotype of CART19 cells in peripheral blood, bone marrow and cerebrospinal fluid using using flow-cytometry	Up to 24 months
Primary	Incidence of adverse events	Cumulative incidence of IMP-related adverse events (AEs) graded by ASTCT consensus grading criteria for Cytokine Release Syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) and by Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 for other AEs. Toxicities will be followed from the start of Blood Collection or Apheresis until the end of the study.	Up to 2 years post treatment
Primary	Assessment of Dose-Limiting Toxicities (DLTs)	Incidence of Dose-limiting toxicities (DLTs) during the first 28 days after IMP administration	Up to 28 days after IMP administration
Secondary	Complete remission ( CR) rate	Assessment of the efficacy of IMP cells administration in patients with refractory or relapsed CD19+ NHL and B-ALL evaluated by Complete Remission rate	CR rate at 100 days and 6 months after IMP administration
Secondary	Overall Survival	Assessment of the efficacy of IMP cells administration in patients with refractory or relapsed CD19+ NHL and B-ALL evaluated by Overall Survival	OS at 1 year after IMP administration
Secondary	Quality of life using the European Organization for the Research and Treatment of Cancer 30 item questionnaire (EORTC QLQ-C30).	EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small. A change of 10 - 20 points is considered a moderate change.	At 6 months and 1 year following IMP administration