A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts
Authors: Mackensen Andreas , Hanssens Linda , Stelljes Matthias , Bethge Wolfgang A , Feuchtinger Tobias , Künkele Annette , Aigner Michael , Yakushina Alisa , Karitzky Sandra , Holtkamp Silke , Assenmacher Mario , Jurk Marion , Rauser Georg , Schneider Dina , Rossig Claudia 
Published: November 2021

Abstract
Introduction
This phase I first-in-human clinical study assesses the safety and preliminary efficacy of a CD19-directed, CAR (4-1BBz) gene-modified, autologous T-cell immunotherapy (MB-CART19.1) intended for use in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL). The study also evaluates the feasibility of a hybrid manufacturing model, combining central and academic manufacturing capabilities with central QP oversight.
Methods
MB-CART19.1 is evaluated in a Phase I (EudraCT 2017-002848-32) multi-center, open label, dose escalation trial enrolling 33 to 48 patients in three disease cohorts, defined by disease biology and age. Pediatric (1-17 years) and adult patients are eligible if diagnosed with relapsed/refractory (r/r) CD19-expressing B-cell ALL or B-cell high-grade and low-grade (adults) NHL, including chronic lymphocytic leukemia (CLL). Enrollment is still ongoing. The starting material, a fresh patient leukapheresis product, is enriched for CD4/CD8 T-cells, transduced with a lentiviral vector (LV) and expanded using the CliniMACS Prodigy System allowing a high degree of control and consistency of the manufacturing process in both a central and decentralized facilities. MB-CART19.1 is presented as fresh cellular dispersion for single infusion and undergoes central release. Subjects undergo lymphodepletion with fludarabine (25 mg/m 2 daily for 3 days) and cyclophosphamide (1000 mg/m 2 on day -3). Dose escalation includes 3 dose levels (DL) 5x10 5 (DL I), 1x10 6 (DL II), 3x10 6 (DL III) CAR T cells/kg BW, respectively, and a safety dose level 0. The primary objective is to determine the recommended dose of MB-CART19.1. Secondary objectives are preliminary efficacy parameters evaluation of as well as CART persistence.
Results
Disease cohort I: pediatric ALL and aggressive NHL, 1-17 years. Up to the data lock point for interim analysis (DLP, 02 June 2021), 9 pediatric ALL patients were treated, 6 at DL I and 3 at DL II. All 9 patients completed the 28 days safety follow-up. At DL I, 5 of 6 patients experienced CRS (4 grade I-II, 1 grade III,) starting 5 to 7 days after IMP infusion. Two CRS cases were managed with tocilizumab and resolved within 1-2 weeks. 1 patient developed signs of neurotoxicity (grade IV seizure) concurrently with grade II CRS, which was effectively managed and fully resolved within 48 hours. The event was evaluated as DLT and led to the extension of the dose group from 3 to 6 patients. No further neurotoxicities occurred. Four of 6 patients treated at DL I finished the active part of the trial (12 months after administration of IMP) in CR-MRD and entered the long term follow-up. Two patients had CD19-negative relapses 4 and 10 months post MB-CART19.1 infusion. At DL II, 1 patient completed the 6 months follow up in ongoing CR, and 2 patients relapsed.
Disease cohort II adult ALL: Up to the DLP, 4 adult ALL patients were treated at DL I. 1 patient died due to progression of disease on day 20 after the IMP infusion. All 4 adult patients experienced a grade I or II CRS all cases were reversible within 1-2 weeks , 1 patient received tocilizumab One patient developed neurologic symptoms (grade III visual impairment and grade III muscle weakness right-sided) with onset 41 and 72 days after administration of MB-CART19.1, respectively. 2 of the 3 patients who completed the safety follow-up finished the active part of the trial and entered the long-term follow-up, both in molecular CR up to Month 6.
Disease cohort III adult NHL/CLL: 4 patients were enrolled with the starting dose of 1x10 6 CAR+ cells/kg (DL II). 1 patient experienced grade III CRS and was treated with tocilizumab. 3 patients completed the 28 days safety follow up. One patient with CLL achieved a CR, which is maintained at 6 months. Another CLL patient was in PR at the assessment visit Day 28. Data from the 2 other patients, 1 with MCL and 1 with DLBCL were in PR at month 3. Later data is not yet available.

Conclusions
18 of 19 patients completed the follow-up safety period of 28 days defined as observation period for dose limiting toxicity (DLT). One DLT was observed as well as 3 grade III CRS events and 1 grade III neurological event. Early efficacy results are very encouraging. Longer follow-up will establish whether treatment results in durable responses. The hybrid manufacturing model provides flexibility and a timely delivery of the fresh drug product to the patients

Disclosures
Hanssens: Miltenyi Biomedicine GmbH: Current Employment. Stelljes: MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Yakushina: Miltenyi Biomedicine GmbH: Current Employment. Holtkamp: Miltenyi Biomedicine GmbH: Current Employment. Assenmacher: Miltenyi Biotec: Current Employment. Jurk: Miltenyi Biotec: Current Employment. Rauser: Miltenyi Biomedicine GmbH: Current Employment. Schneider: Employee of Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Rossig: AdBoards by Amgen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS and Celgene: Honoraria.