Evaluating the Safety and Efficacy of DuoCAR20.19.22-D95 in Adult Patients With Relapsed or Refractory B-cell Malignancies

NCT06879340 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: STUDY00161006
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

This multicenter phase 1 trial with "3 + 3" dose escalation design seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of chimeric antigen receptors targeting the B cell surface antigens CD19/20/22 following administration of a chemotherapy lymphodepletion regimen in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin's lymphoma (NHL). The overall goals of this study are to estimate maximum tolerated dose (MTD) level, establish the overall safety profile and evaluate initial efficacy of administering duo-CAR-T cell treatment in this patient population.

Conditions

B-Cell Non-Hodgkin Lymphoma; B-cell Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (5)

• Maximum Tolerated Dose (MTD)

  The MTD is defined as the dose level immediately below that in which ≥ 2/6 participants experience a dose limiting toxicity (DLT).

  Approximately 30 days

• Recommended Phase 2 Dose (RP2D)

  Determine using MTD and DLTs.

  Approximately 30 days

• Safety: Incidence of Serious Adverse Events/Adverse Events

  Toxicities of DuoCAR20.19.22-D95 in combination with preceding lymphodepleting chemotherapy regimen As measured with CTCAE v 5.0,

  Approximately 30 days

• Treatment-related Mortality (TRM)

  defined by the absence of progressive disease at the time of death.

  Approximately 1 year

• Presence of replication competent lentivirus (RCL) in peripheral blood samples

  Measured with qPCR

  Approximately 15 years

Secondary Outcomes (8)

• Efficacy of DuoCAR 20.19.22-D95

  up to 24 months

• Safety related to DuoCAR20.19.22-D95

  Approximately 15 years

• Pharmacology (Expansion kinetics)

  28 days

• Manufacturing Feasibility of Miltenyi CliniMACS Prodigy (By number of participants)

  2 weeks

• Blood DuoCAR20.19.22-D95 concentrations (PCR)

  approximately 2 years

Study Arms (1)

Phase 1 (Dose Escalation)

EXPERIMENTAL

Lymphodepletion: Fludarabine: Days -6 to -3 (4 days total) Cyclophosphamide: Days -6 and -5 (2 days total) Investigational Treatment: DuoCAR20.19.22-D95 will be infused on day # 0 Patients will receive lymphodepletion chemotherapy and receive the CAR T cell infusion on day 0 (or up to day +14 in extenuating clinical conditions). Patients will be hospitalized inpatient period of at least 7 days from the day of the CAR T infusion.

Drug: DuoCAR20.19.22-D95; Drug: Fludarabine (Conditional therapy); Drug: Cyclophosphamide (Conditional therapy)

Interventions

DuoCAR20.19.22-D95 DRUG

Patient derived autologous T cells, lentiviral transduced to generate, using the Miltenyi CliniMACS Prodigy® closed transduction system, a Duo-CAR-T cells targeting cell surface antigens CD19/20/22.

Phase 1 (Dose Escalation)

Fludarabine (Conditional therapy) DRUG

Lymphodepletion chemotherapy

Phase 1 (Dose Escalation)

Cyclophosphamide (Conditional therapy) DRUG

Lymphodepletion chemotherapy

Phase 1 (Dose Escalation)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability of participant to understand this study, and participant willingness to sign a written informed consent
• Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to the start of preparatory regimen
• Patients must have histologically confirmed aggressive B-Cell NHL or ALL as stated below:
• A. Patients with relapsed or refractory B-Cell ALL i. Demonstration of one or more antigens of interest (CD19, CD20, CD22) in most recent disease evaluation prior to study entry and within 30 days of study entry.
• ii. Patients with relapsed/refractory disease in blood, marrow, and extramedullary sites including CSF will be eligible when there is immunophenotypic evidence of CD19 and/or CD20 and/or CD22 expression
• iii. Primary refractory disease at study entry defined as: A morphologic complete response has never been achieved prior to study entry.
• iv. Early first relapse at study entry defined as: Disease recurrence by morphologic assessment after duration of first remission at ≤ 18 months
• v. Relapsed Refractory disease (first or later relapse) at study entry defined as: Morphologic complete response was not achieved after initiation of a second-line (or later) systemic therapy
• vi. Second or greater relapse at study entry defined as: Any disease recurrence following a second or later complete response (with treatment history including two or more lines of systemic therapy)
• vii. Additional considerations beyond above criteria:
• Patients with relapsed or refractory disease after allogeneic stem cell transplantation must be \>100 days from HSCT to be eligible for study participation. Furthermore, post-HSCT immunosuppressive medications must be discontinued for at least 4 weeks prior to study entry
• Prior CAR-T therapy is permissible if ≥ 3 months from therapy completion
• Morphological disease in the bone marrow Note: Morphologic disease is defined as blasts being at least 5% in the bone marrow.
• B. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008 after 2 or more lines of prior therapy:
• i. DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary cutaneous DLBCL, leg type; OR ii. Primary mediastinal (thymic) large B cell lymphoma iii. Follicular lymphoma 3b and transformation of follicular lymphoma to DLBCL will also be included iv. High-grade B cell lymphoma v. Chemotherapy-refractory disease, defined as one or more of the following:

You may not qualify if:

• Patients with CLL, Richter's transformation, and Burkitt lymphoma
• Active CNS involvement by malignancy - CNS3 disease, i.e., patients with WBC count in CSF ≥5 and having blasts in the CSF in patients with ALL or detection of NHL on CSF by flow cytometry or active CNS involvement on imaging)
• Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
• Investigational medicinal product within the last 30 days prior to screening Note: Investigational therapies must not be used at any time while on study until the first progression following DuoCAR20.19.22-D95 CAR T infusion.
• The following medications are excluded:
• Steroids: Therapeutic doses of steroids must be stopped \> 72 hours prior to leukapheresis and \> 72 hours prior to DuoCAR20.19.22-D95 infusion. However, the following physiological replacement doses of steroids are allowed: \<12 mg/m2/day hydrocortisone or equivalent
• Immunosuppression: Any other immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and ≥ 2 weeks prior to DuoCAR20.19.22-D95 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators).
• Antiproliferative therapies other than lymphodepleting chemotherapy within 2 weeks prior to infusion
• Short acting drugs used to treat leukemia or lymphoma (e.g., tyrosine kinase inhibitors, and hydroxyurea) must be stopped \> 72 hour prior to leukapheresis and \> 72 hours prior to DuoCAR20.19.22-D95 infusion
• Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to DuoCAR20.19.22-D95 infusion.
• Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respective antibody, whichever is longer. Note: Rituximab is excluded within 4 weeks prior to infusion.
• CNS disease prophylaxis or treatment must be stopped \> 1 week prior to DuoCAR20.19.22-D95 infusion (e.g., intrathecal methotrexate)
• Prior radiation therapy within 2 weeks of infusion
• Active replication of or prior infection with hepatitis B or active hepatitis C (HCV RNA positive)
• HIV positive patients (excluding false positive HIV test resulting from the viral vector used in prior CAR T)

Sponsors & Collaborators

• University of Kansas Medical Center: lead

Study Sites (1)

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

RECRUITING

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• Dioverti V, Boghdadly ZE, Shahid Z, Waghmare A, Abidi MZ, Pergam S, Boeckh M, Dadwal S, Kamboj M, Seo S, Chemaly RF, Papanicolaou GA. Revised Guidelines for Coronavirus Disease 19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients (August 2022). Transplant Cell Ther. 2022 Dec;28(12):810-821. doi: 10.1016/j.jtct.2022.09.002. Epub 2022 Sep 11.

  PMID: 36103987 BACKGROUND

• 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.

  PMID: 30592986 BACKGROUND

• Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. doi: 10.1200/JCO.2005.12.516. Epub 2005 Mar 14.

  PMID: 15767647 BACKGROUND

• Hedger MP, Meinhardt A. Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. J Reprod Immunol. 2000 Oct-Nov;48(2):69-80. doi: 10.1016/s0165-0378(00)00071-1.

  PMID: 11011073 BACKGROUND

• Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz K, Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients. Blood. 2001 Sep 15;98(6):1847-51. doi: 10.1182/blood.v98.6.1847.

  PMID: 11535520 BACKGROUND

• Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.

  PMID: 17242396 BACKGROUND

• Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP, Schwartz LH, Zucca E, Fisher RI, Trotman J, Hoekstra OS, Hicks RJ, O'Doherty MJ, Hustinx R, Biggi A, Cheson BD. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014 Sep 20;32(27):3048-58. doi: 10.1200/JCO.2013.53.5229.

  PMID: 25113771 BACKGROUND

• Pulsipher MA, Han X, Maude SL, Laetsch TW, Qayed M, Rives S, Boyer MW, Hiramatsu H, Yanik GA, Driscoll T, Myers GD, Bader P, Baruchel A, Buechner J, Stefanski HE, Kalfoglou C, Nguyen K, Waldron ER, Thudium Mueller K, Maier HJ, Kari G, Grupp SA. Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia. Blood Cancer Discov. 2022 Jan;3(1):66-81. doi: 10.1158/2643-3230.BCD-21-0095. Epub 2021 Dec 1.

  PMID: 35019853 BACKGROUND

• Rossoff J, Baggott C, Prabhu S, Pacenta H, Phillips CL, Stefanski H, Talano JA, Moskop A, Margossian SP, Verneris MR, Myers GD, Karras N, Brown PA, Qayed M, Hermiston M, Satwani P, Krupski C, Keating AK, Wilcox R, Rabik CA, Fabrizio VA, Kunicki M, Chinnabhandar V, Goksenin AY, Curran KJ, Mackall CL, Laetsch TW, Schultz LM. Out-of-specification tisagenlecleucel does not compromise safety or efficacy in pediatric acute lymphoblastic leukemia. Blood. 2021 Nov 25;138(21):2138-2142. doi: 10.1182/blood.2021012392. No abstract available.

  PMID: 34499715 BACKGROUND

• Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, Buechner J, De Moerloose B, Davis KL, Nemecek E, Driscoll T, Mechinaud F, Boissel N, Rives S, Bader P, Peters C, Sabnis HS, Grupp SA, Yanik GA, Hiramatsu H, Stefanski HE, Rasouliyan L, Yi L, Shah S, Zhang J, Harris AC. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. 2019 Dec;20(12):1710-1718. doi: 10.1016/S1470-2045(19)30493-0. Epub 2019 Oct 9.

  PMID: 31606419 BACKGROUND

• Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, Bleakley M, Brown C, Mgebroff S, Kelly-Spratt KS, Hoglund V, Lindgren C, Oron AP, Li D, Riddell SR, Park JR, Jensen MC. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017 Jun 22;129(25):3322-3331. doi: 10.1182/blood-2017-02-769208. Epub 2017 Apr 13.

  PMID: 28408462 BACKGROUND

• Schneider D, Xiong Y, Wu D, Hu P, Alabanza L, Steimle B, Mahmud H, Anthony-Gonda K, Krueger W, Zhu Z, Dimitrov DS, Orentas RJ, Dropulic B. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci Transl Med. 2021 Mar 24;13(586):eabc6401. doi: 10.1126/scitranslmed.abc6401.

  PMID: 33762438 BACKGROUND

• Dekker L, Calkoen FG, Jiang Y, Blok H, Veldkamp SR, De Koning C, Spoon M, Admiraal R, Hoogerbrugge P, Vormoor B, Vormoor HJ, Visscher H, Bierings M, Van Der Vlugt M, Van Tinteren H, Nijstad AL, Huitema ADR, Van Der Elst KCM, Pieters R, Lindemans CA, Nierkens S. Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Blood Adv. 2022 Apr 12;6(7):1969-1976. doi: 10.1182/bloodadvances.2021006700.

  PMID: 35134115 BACKGROUND

• Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 2001 Sep;15(3):445-55. doi: 10.1016/s1074-7613(01)00191-1.

  PMID: 11567634 BACKGROUND

• Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000 Sep 15;165(6):3043-50. doi: 10.4049/jimmunol.165.6.3043.

  PMID: 10975814 BACKGROUND

• Maxwell JR, Weinberg A, Prell RA, Vella AT. Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion. J Immunol. 2000 Jan 1;164(1):107-12. doi: 10.4049/jimmunol.164.1.107.

  PMID: 10605000 BACKGROUND

• Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020 Mar;17(3):147-167. doi: 10.1038/s41571-019-0297-y. Epub 2019 Dec 17.

  PMID: 31848460 BACKGROUND

• Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, Pulsipher MA, Phillips CL, Keating A, Frigault MJ, Salzberg D, Jaglowski S, Sasine JP, Rosenthal J, Ghosh M, Landsburg D, Margossian S, Martin PL, Kamdar MK, Hematti P, Nikiforow S, Turtle C, Perales MA, Steinert P, Horowitz MM, Moskop A, Pacaud L, Yi L, Chawla R, Bleickardt E, Grupp S. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020 Nov 10;4(21):5414-5424. doi: 10.1182/bloodadvances.2020003092.

  PMID: 33147337 BACKGROUND

• Frigault MJ, Maus MV. State of the art in CAR T cell therapy for CD19+ B cell malignancies. J Clin Invest. 2020 Apr 1;130(4):1586-1594. doi: 10.1172/JCI129208.

  PMID: 32235098 BACKGROUND

• Moreno-Cortes E, Franco-Fuquen P, Garcia-Robledo JE, Forero J, Booth N, Castro JE. ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype. Front Oncol. 2023 Aug 18;13:1200914. doi: 10.3389/fonc.2023.1200914. eCollection 2023.

  PMID: 37719008 BACKGROUND

• Fabrizio VA, Boelens JJ, Mauguen A, Baggott C, Prabhu S, Egeler E, Mavroukakis S, Pacenta H, Phillips CL, Rossoff J, Stefanski HE, Talano JA, Moskop A, Margossian SP, Verneris MR, Myers GD, Karras NA, Brown PA, Qayed M, Hermiston M, Satwani P, Krupski C, Keating AK, Wilcox R, Rabik CA, Chinnabhandar V, Kunicki M, Goksenin AY, Mackall CL, Laetsch TW, Schultz LM, Curran KJ. Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv. 2022 Apr 12;6(7):1961-1968. doi: 10.1182/bloodadvances.2021006418.

  PMID: 34788386 BACKGROUND

• Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. doi: 10.1016/j.jtct.2023.03.006. Epub 2023 Mar 9.

  PMID: 36906275 BACKGROUND

• Poe JC, Minard-Colin V, Kountikov EI, Haas KM, Tedder TF. A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice. J Immunol. 2012 Sep 1;189(5):2318-25. doi: 10.4049/jimmunol.1201000. Epub 2012 Jul 23.

  PMID: 22826319 BACKGROUND

• Fruman DA. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr Opin Immunol. 2004 Jun;16(3):314-20. doi: 10.1016/j.coi.2004.03.014.

  PMID: 15134780 BACKGROUND

• Rogel A, Willoughby JE, Buchan SL, Leonard HJ, Thirdborough SM, Al-Shamkhani A. Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1178-E1187. doi: 10.1073/pnas.1611299114. Epub 2017 Jan 30.

  PMID: 28137869 BACKGROUND

• Gravestein LA, Nieland JD, Kruisbeek AM, Borst J. Novel mAbs reveal potent co-stimulatory activity of murine CD27. Int Immunol. 1995 Apr;7(4):551-7. doi: 10.1093/intimm/7.4.551.

  PMID: 7547681 BACKGROUND

• Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, Logothetis C, Sharma P. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14987-92. doi: 10.1073/pnas.0806075105. Epub 2008 Sep 25.

  PMID: 18818309 BACKGROUND

• Haas KM, Sen S, Sanford IG, Miller AS, Poe JC, Tedder TF. CD22 ligand binding regulates normal and malignant B lymphocyte survival in vivo. J Immunol. 2006 Sep 1;177(5):3063-73. doi: 10.4049/jimmunol.177.5.3063.

  PMID: 16920943 BACKGROUND

• Hombach AA, Heiders J, Foppe M, Chmielewski M, Abken H. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4(+) T cells. Oncoimmunology. 2012 Jul 1;1(4):458-466. doi: 10.4161/onci.19855.

  PMID: 22754764 BACKGROUND

• Majzner RG, Mackall CL. Tumor Antigen Escape from CAR T-cell Therapy. Cancer Discov. 2018 Oct;8(10):1219-1226. doi: 10.1158/2159-8290.CD-18-0442. Epub 2018 Aug 22.

  PMID: 30135176 BACKGROUND

• Shah NN, Maatman T, Hari P, Johnson B. Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies. Front Oncol. 2019 Mar 12;9:146. doi: 10.3389/fonc.2019.00146. eCollection 2019.

  PMID: 30915277 BACKGROUND

• Holland EM, Molina JC, Dede K, Moyer D, Zhou T, Yuan CM, Wang HW, Stetler-Stevenson M, Mackall C, Fry TJ, Panch S, Highfill S, Stroncek D, Little L, Lee DW, Shalabi H, Yates B, Shah N. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022 May;10(5):e004483. doi: 10.1136/jitc-2021-004483.

  PMID: 35534047 BACKGROUND

• Cao Y, Xiao Y, Wang N, Wang G, Huang L, Hong Z, Meng L, Zhou X, Wang J, Yang Y, Xu H, Zhang S, Xiao M, Chen L, Zheng M, Li C, Mao X, Gu C, Zhang T, Zhang Y, Zhou J. CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. Transplant Cell Ther. 2021 Nov;27(11):910.e1-910.e11. doi: 10.1016/j.jtct.2021.08.012. Epub 2021 Aug 20.

  PMID: 34425260 BACKGROUND

• Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, Shalabi H, Fountaine TJ, Shern JF, Majzner RG, Stroncek DF, Sabatino M, Feng Y, Dimitrov DS, Zhang L, Nguyen S, Qin H, Dropulic B, Lee DW, Mackall CL. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018 Jan;24(1):20-28. doi: 10.1038/nm.4441. Epub 2017 Nov 20.

  PMID: 29155426 BACKGROUND

• Pan J, Niu Q, Deng B, Liu S, Wu T, Gao Z, Liu Z, Zhang Y, Qu X, Zhang Y, Liu S, Ling Z, Lin Y, Zhao Y, Song Y, Tan X, Zhang Y, Li Z, Yin Z, Chen B, Yu X, Yan J, Zheng Q, Zhou X, Gao J, Chang AH, Feng X, Tong C. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia. 2019 Dec;33(12):2854-2866. doi: 10.1038/s41375-019-0488-7. Epub 2019 May 20.

  PMID: 31110217 BACKGROUND

• Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7. Epub 2018 Dec 2.

  PMID: 30518502 BACKGROUND

• Fayad L, Offner F, Smith MR, Verhoef G, Johnson P, Kaufman JL, Rohatiner A, Advani A, Foran J, Hess G, Coiffier B, Czuczman M, Gine E, Durrant S, Kneissl M, Luu KT, Hua SY, Boni J, Vandendries E, Dang NH. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013 Feb 10;31(5):573-83. doi: 10.1200/JCO.2012.42.7211. Epub 2013 Jan 7.

  PMID: 23295790 BACKGROUND

• Rigaud C, Auperin A, Jourdain A, Haouy S, Couec ML, Aladjidi N, Gandemer V, Lambliotte A, Plat G, Landman-Parker J, Michon J, Leblanc T, Patte C, Minard-Colin V. Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. Pediatr Blood Cancer. 2019 Sep;66(9):e27873. doi: 10.1002/pbc.27873. Epub 2019 Jun 17.

  PMID: 31207026 BACKGROUND

• Hochberg J, El-Mallawany NK, Abla O. Adolescent and young adult non-Hodgkin lymphoma. Br J Haematol. 2016 May;173(4):637-50. doi: 10.1111/bjh.14074. Epub 2016 Apr 12.

  PMID: 27071675 BACKGROUND

• Anoop P, Sankpal S, Stiller C, Tewari S, Lancaster DL, Khabra K, Taj MM. Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. Leuk Lymphoma. 2012 Oct;53(10):1882-8. doi: 10.3109/10428194.2012.677534. Epub 2012 Apr 23.

  PMID: 22448922 BACKGROUND

• Egan G, Goldman S, Alexander S. Mature B-NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies. Br J Haematol. 2019 Jun;185(6):1071-1085. doi: 10.1111/bjh.15734. Epub 2019 Jan 6.

  PMID: 30613948 BACKGROUND

• Cairo M, Auperin A, Perkins SL, Pinkerton R, Harrison L, Goldman S, Patte C. Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group. Br J Haematol. 2018 Sep;182(6):859-869. doi: 10.1111/bjh.15491. Epub 2018 Jul 9.

  PMID: 29984828 BACKGROUND

• Moleti ML, Testi AM, Foa R. Treatment of relapsed/refractory paediatric aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2020 Jun;189(5):826-843. doi: 10.1111/bjh.16461. Epub 2020 Mar 6.

  PMID: 32141616 BACKGROUND

• Rytting ME, Thomas DA, O'Brien SM, Ravandi-Kashani F, Jabbour EJ, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Cortes JE, Borthakur G, Garris R, Cardenas-Turanzas M, Schroeder K, Jorgensen JL, Kornblau SM, Kantarjian HM. Augmented Berlin-Frankfurt-Munster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014 Dec 1;120(23):3660-8. doi: 10.1002/cncr.28930. Epub 2014 Jul 17.

  PMID: 25042398 BACKGROUND

• Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012 May;87(5):472-8. doi: 10.1002/ajh.23149. Epub 2012 Mar 3.

  PMID: 22388572 BACKGROUND

• Essig S, Li Q, Chen Y, Hitzler J, Leisenring W, Greenberg M, Sklar C, Hudson MM, Armstrong GT, Krull KR, Neglia JP, Oeffinger KC, Robison LL, Kuehni CE, Yasui Y, Nathan PC. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2014 Jul;15(8):841-51. doi: 10.1016/S1470-2045(14)70265-7. Epub 2014 Jun 19.

  PMID: 24954778 BACKGROUND

• Hunger SP, Baruchel A, Biondi A, Evans WE, Jeha S, Loh M, Moericke A, Pieters R, Relling MV, Schmiegelow K, Schrappe M, Silverman LB, Stanulla M, Valsecchi MG, Vora A, Pui CH. The thirteenth international childhood acute lymphoblastic leukemia workshop report: La Jolla, CA, USA, December 7-9, 2011. Pediatr Blood Cancer. 2013 Feb;60(2):344-8. doi: 10.1002/pbc.24354. Epub 2012 Sep 28. No abstract available.

  PMID: 23024117 BACKGROUND

• Faderl S, O'Brien S, Pui CH, Stock W, Wetzler M, Hoelzer D, Kantarjian HM. Adult acute lymphoblastic leukemia: concepts and strategies. Cancer. 2010 Mar 1;116(5):1165-76. doi: 10.1002/cncr.24862.

  PMID: 20101737 BACKGROUND

• Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.

  PMID: 25113753 BACKGROUND

• Gill S, Carney D, Ritchie D, Wolf M, Westerman D, Prince HM, Januszewicz H, Seymour JF. The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy. Ann Oncol. 2010 Feb;21(2):331-334. doi: 10.1093/annonc/mdp297. Epub 2009 Jul 22.

  PMID: 19625344 BACKGROUND

• Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, Shimoni A, Nagler A, Toren A, Jacoby E. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019 Oct;54(10):1643-1650. doi: 10.1038/s41409-019-0487-3. Epub 2019 Feb 26.

  PMID: 30809033 BACKGROUND

• Levine JE, Grupp SA, Pulsipher MA, Dietz AC, Rives S, Myers GD, August KJ, Verneris MR, Buechner J, Laetsch TW, Bittencourt H, Baruchel A, Boyer MW, De Moerloose B, Qayed M, Davies SM, Phillips CL, Driscoll TA, Bader P, Schlis K, Wood PA, Mody R, Yi L, Leung M, Eldjerou LK, June CH, Maude SL. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. 2021 Aug;9(8):e002287. doi: 10.1136/jitc-2020-002287.

  PMID: 34353848 BACKGROUND

• Schuster, SJ, Svoboda J, Nasta SD, et al, Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas. Blood, 2015. 126(23): p. 183-183.

  BACKGROUND

• Jourdain A, Auperin A, Minard-Colin V, Aladjidi N, Zsiros J, Coze C, Gandemer V, Bertrand Y, Leverger G, Bergeron C, Michon J, Patte C; SFCE LNH Committee. Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective "Lymphomes Malins B" protocols. A Societe Francaise des Cancers de l'Enfant study. Haematologica. 2015 Jun;100(6):810-7. doi: 10.3324/haematol.2014.121434. Epub 2015 Feb 27.

  PMID: 25724577 BACKGROUND

• Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE, Frigault MJ, Lee J, Posey AD Jr, Scholler J, Scholler N, Bonneau R, June CH. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood. 2014 Aug 14;124(7):1070-80. doi: 10.1182/blood-2013-10-535245. Epub 2014 Jul 1.

  PMID: 24986688 BACKGROUND

• 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.

  PMID: 26333935 BACKGROUND

• Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, Patel PR, Guedan S, Scholler J, Keith B, Snyder NW, Blair IA, Milone MC, June CH. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. 2016 Feb 16;44(2):380-90. doi: 10.1016/j.immuni.2016.01.021.

  PMID: 26885860 BACKGROUND

• Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, Plotkin J, Sadelain M. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell. 2015 Oct 12;28(4):415-428. doi: 10.1016/j.ccell.2015.09.004.

  PMID: 26461090 BACKGROUND

• Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, Kaplan RN, Patterson GH, Fry TJ, Orentas RJ, Mackall CL. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015 Jun;21(6):581-90. doi: 10.1038/nm.3838. Epub 2015 May 4.

  PMID: 25939063 BACKGROUND

• 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.

  PMID: 27111235 BACKGROUND

• Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-528. doi: 10.1016/S0140-6736(14)61403-3. Epub 2014 Oct 13.

  PMID: 25319501 BACKGROUND

• National Institute of Health/National Cancer Institute - Cancer Therapy Evaluation Program (CTEP). Common Terminology Criteria for Adverse Events (CTCAE). URL: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_60 Accessed 01-26-2022

  BACKGROUND

MeSH Terms

Conditions

Lymphoma, B-Cell; Burkitt Lymphoma

Interventions

fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Joseph McGuirk, D.O.

  University of Kansas Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Division Director Hematologic Malignancies and Cellular Therapeutics

Study Record Dates

• First Submitted: March 3, 2025
• First Posted: March 17, 2025
• Study Start: March 31, 2025
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2040
• Last Updated: May 14, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)