Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
clinical trials, Research, Acute Myeloid Malignancies, AML, Biological therapies, adult, elderly, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, Adverse Events, Myeloid Malignancies, Technology and Procedures, gene editing, Study Population, Human, Minimal Residual Disease , molecular testing
Methods Key inclusion criteria included rrAML patients with ECOG ≤ 1, CD123 expression in ≥ 20% of blasts, and no suitable approved treatment option available or MRD positive AML patients. Initial dosing was applied using an adaptive Bayesian optimal interval design for drug-combination trials, escalating either cell dose or TM concentration based on posterior probability calculation of AEs. Dose escalation for the two additional dose levels was guided by a classical 3+3 design. Patients received standard Flu/Cy lymphodepletion (LD) for 3 days and TM was administered as continuous infusion, whereas UniCAR-T cells were given as one-time infusion on cycle 1 day 1. After completion of the initial 20-day induction cycle, responding patients were allowed to receive up to 3 consolidation cycles of 12 days continuous TM infusion with 7-14 days treatment free intervals in between cycles.
Results As of this time 19 patients have received the induction cycle, 8 patients have also received at least one consolidation cycle (1-3, total 13 cycles). Patients were heavily pretreated with a median of 4 (2-7) prior treatment lines. Twelve of these patients had received a prior allogeneic (Allo) stem cell transplantation (SCT). Most of the patients (60%) were in adverse risk category according to ELN classification. In the initial escalation phase, 19 patients were treated in 16 dose cohorts. We observed a single DLT at DL 8 (reversible drop in fibrinogen levels, reported earlier) but no DLTs occurred in 11 patients treated in the yet highest dose cohort of 4 mg/day TM and 500 million UniCAR-T. Treatment was generally well tolerated irrespective of age and prior treatments. CRS was observed in 12 patients, mostly grade 1 or 2. Three grade 3 CRS and 1 grade 2 ICANS were reported, all resolving within 24 hrs from interruption of TM administration. Treatment-related AEs were most frequent in cycle 1, none were reported in cycles 3 and 4. No treatment-induced lasting myelosuppression was observed, and no patient required SCT support for WBC reconstitution.
ORR in the first 19 patients was 53% (8/15) for the rrAML population and 75% (3/4) for the MRD population. Since the last presentation, extended administration of TM (20-day induction followed by three 12-day consolidation cycles 1-2 weeks apart) initiated by protocol amendment resulted in durable, ongoing responses approaching 5 months, longer than any prior. A 64-year-old MRD+ patient (#19) with 4 prior lines of therapy experienced a 3-log reduction in MRD levels (NPM1 mutation by qPCR) in both bone marrow and blood (Figure 1) and became transplant eligible. Re-administration of TM resulted in a significant re-expansion of UniCAR-T (Figure 2) without further cell dosing or LD. Another patient (#20) with overt hematological relapse after AlloSCT achieved a CR, ongoing at 5 months.
Full safety and efficacy results of the additional 2 dose cohorts with prolonged TM consolidation will be presented at the meeting.
Conclusions AVC-101 continues to be safe and tolerable. Repeated dosing of TM in consolidation cycles resulted in robust re-expansion of UniCAR-T with deeper remissions of extended durability. The switchable mechanism provides proven rapid reversal of safety events, enabling higher dose levels.
Disclosures: Wermke: Immatics: Consultancy; Lilly: Consultancy, Honoraria; MSD: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Cellex GmbH: Consultancy; Novartis: Consultancy, Honoraria; GeMoab: Consultancy, Other: Travel, accommodations, expenses; AstraZeneca: Consultancy, Other: Travel, accommodations, expenses; ISA Pharmaceuticals: Consultancy; Amgen: Consultancy, Other: Travel, accommodations, expenses; Roche: Consultancy, Honoraria, Other: Travel, accommodations, expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, accommodations, expenses. Kraus: Jazz Pharmaceuticals: Honoraria, Other: Support for meeting attendance; BMS: Honoraria, Other: Support for meeting attendance; Gilead: Other: Support for meeting attendance; LinkCare: Honoraria; AstraZeneca: Speakers Bureau; Janssen: Honoraria; Pfizer: Honoraria. Sala: Novartis: Honoraria; Takeda: Consultancy; Medac: Other; Kite Gilead: Consultancy, Honoraria, Other: Support for meeting attendance; BMS: Consultancy, Honoraria, Other; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Support for meeting attendance. Fiedler: AbbVie: Consultancy, Honoraria, Other: Support in medical writing; Morphosis: Consultancy; Apis: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Support for meeting attendance; Servier: Consultancy, Other: Support for meeting attendance; Pfizer: Consultancy; Stemline: Consultancy; Clinigen: Consultancy; Amgen: Consultancy, Other: Support for meeting attendance, Patents & Royalties. Goebeler: Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb (BMS): Honoraria; Amgen: Consultancy; AstraZeneca: Honoraria; Novartis: Honoraria; Gemoab: Consultancy; Roche: Honoraria. Koedam: AvenCell: Current Employment, Current equity holder in private company. Franke: AvenCell Europe GmbH: Current Employment. Vänskä: AvenCell Europe GmbH: Current Employment; ICON plc: Ended employment in the past 24 months. Ehninger: AvenCell Europe GmbH: Current Employment; AvenCell Therapeutics, Inc.: Current equity holder in private company, Current holder of stock options in a privately-held company. Cartellieri: AvenCell Europe GmbH: Current Employment; AvenCell Therapeutics, Inc.: Current holder of stock options in a privately-held company. Ehninger: AvenCell Europe GmbH: Current equity holder in private company, Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: Support for meeting attendance; CelleCell Professionals GmbHx: Current Employment, Current equity holder in private company. Maniar: AvenCell Therapeutics, Inc.: Current Employment.
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