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825 Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Expanding Targets and Cellular Sources for Immunotherapies
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Acute Myeloid Malignancies, AML, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, Clinically Relevant, Diseases, Therapies, Myeloid Malignancies
Monday, December 13, 2021: 5:00 PM

David A. Sallman, MD1, Hany Elmariah, MD, MS2, Kendra Sweet, MD3, Chetasi Talati, MD1*, Asmita Mishra, MD4*, Cheryl A Cox5*, Roshanak Semnani6*, Rutul R Shah7*, Helen Sabzevari, PhD7,8*, Marion Chakiath6*, Justin Uthuppan, BS2*, Amy Lankford, PhD9*, Chen Wang10*, Eric Padron, MD11, Andrew T. Kuykendall, MD12, Rami S. Komrokji, MD11, Jeffrey E. Lancet, MD13, Marco L. Davila, MD, PhD14 and Nelli Bejanyan, MD15

1Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
2Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
3Department of Hematology and Oncology, Moffitt Cancer Center, Tampa, FL
4Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
5Cell Therapy Facility, Moffitt Cancer Center, Tampa, FL
6Precigen, Germantown, MD
7Precigen, Inc, Germantown, MD
8National Cancer Institute, National Institutes of Health, Bethesda, MD
9Precigen, Inc., Germantown, MD
10Department of Internal Medicine, University of South Florida, Tampa, FL
11Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
12Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
13Department of Malignant Hematology, H. Lee Moffitt Cancer Ctr. & Rsrch. Institute, Tampa, FL
14Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa
15Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL

Introduction: Therapeutic options for relapsed/refractory (r/r) acute myeloid leukemia (AML) and hypomethylating agent (HMA) failure higher risk myelodysplastic syndrome (MDS) are limited with a median overall survival of < 6 months. Although chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B-cell malignancies, significant challenges exist in myeloid CAR development. PRGN-3006 UltraCAR-T are engineered using non-viral gene delivery to simultaneously express CD33 CAR, membrane bound IL-15 (mbIL15) and kill switch to be effective against AML with improved safety profile. UltraCAR-T cells are manufactured at medical center’s cGMP facility using autologous T cells in < 48 hours without ex vivo expansion.

Methods: A Phase 1/1b first-in-human dose escalation/dose expansion clinical trial (NCT03927261) of PRGN-3006 in adult pts with r/r AML, HMA failure higher risk MDS or chronic myelomonocytic leukemia (CMML) with ≥ 5% blasts. Pts who have relapsed post allogeneic stem cell transplant (SCT) are allowed if > 3 months out from transplant without evidence of active graft versus host disease (GvHD) and off immunosuppression for 6 weeks. Ps receive PRGN-3006 infusion without (Cohort 1) or with lymphodepletion (fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 days -5 to -3; Cohort 2). Dose escalation of Cohorts 1 and 2 occur in parallel with initial clearance of Cohort 1 at each dose level (DL; Table 1).

Results: As of July 25, 2021, data cut-off, 15 r/r AML pts have been treated in Cohort 1 (n=9) and Cohort 2 (n=6) with a median age of 60 years (33-77). Pts were heavily pre-treated with a median of 3 prior regimens (1-7), with 93% and 80% of pts being r/r to a HMA + venetoclax or intensive chemotherapy, respectively. Additionally, 40% of pts (n=6) had relapsed after SCT. 93% of pts were int/adv by ELN 2017 criteria (60% adverse). PRGN-3006 infusion at doses up to 1x106 cells/kg was well tolerated. There have been no deaths, DLTs, bone marrow aplasia, neurotoxicity or unexpected on-target/off-target toxicities related to PRGN-3006, and no use of the kill switch to date. One incidence of grade 2 GvHD was observed in a post-SCT patient (Cohort 2) on day 31, which resolved completely with corticosteroid therapy, and notably this patient responded to therapy. Cytokine release syndrome (CRS) occurred in 47% of pts (n=7; G1 in 5 pts) with only 1 transient grade 3 event (DL 1, Cohort 1) that resolved in < 24 hours with tocilizumab and dexamethasone. Median onset to maximum CRS was 11 days (range 4-15 days). Peak CRP and ferritin levels occurred at a median of days 8 and 9, respectively. No significant increase in plasma levels of inflammatory cytokines, including IL-6 and TNFa, was observed post treatment. The plasma levels of IL-15 did not increase with treatment confirming mbIL15 is not shed.

In Cohort 1, dose escalation through DL3 has been completed. Dose-dependent expansion of PRGN-3006 was observed in all patients with mean peak copy numbers following DL1, DL2 and DL3 in peripheral blood at approximately 600, 9,700 and 28,000 copies/µg DNA, respectively, with persistence up to 7 months post-infusion in a pt with stable disease/blast reduction. No objective responses in cohort 1 have been observed to date.

In Cohort 2, dose escalation through DL2 has been completed. Expansion of PRGN-3006 was higher in Cohort 2 compared to Cohort 1 with mean peak copy numbers following DL1 and DL2 in peripheral blood at approximately 11,000 and 120,000 copies/µg DNA, respectively, and persistence 3+ months post-infusion. The objective response rate (ORR) for Cohort 2 was 50% (3/6). At DL1, 1 of 3 pts obtained CRi and was bridged to SCT and remains in a measurable residual disease negative CR 6 months post-SCT. At DL2, 2 post-SCT relapse patients also obtained response: 1 CRh with complete cytogenetic remission and NGS clearance with a remission length of 2 months; and 1 PR that lasted 3 months in a patient with isolated extramedullary leukemia (Figure 1). All 3 responders remain alive at data cut-off (5-10 months).

Conclusion: PRGN-3006 UltraCAR-T cells targeting CD33 have been well tolerated with low grade CRS. In the setting of mbIL15, there has been a dose-dependent robust expansion and durable persistence of PRGN-3006 with encouraging responses (50%) in patients treated following lymphodepletion. Enrollment is ongoing to DL4, and updated safety, efficacy, PK/PD and cytokine data to be presented.

Disclosures: Sallman: AbbVie: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talati: AbbVie: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau. Mishra: Novartis: Research Funding. Semnani: Precigen: Current Employment. Shah: Precigen: Current Employment, Current equity holder in publicly-traded company. Sabzevari: Precigen: Current Employment, Current equity holder in publicly-traded company; Compass Therapeutics: Current equity holder in publicly-traded company; Kinnate BioPharma: Membership on an entity's Board of Directors or advisory committees. Chakiath: Precigen: Current Employment. Lankford: Precigen: Current Employment, Current equity holder in publicly-traded company. Padron: Stemline: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; BMS: Research Funding; Taiho: Honoraria. Kuykendall: PharmaEssentia: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria. Komrokji: Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau. Lancet: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Astellas: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy. Davila: Precigen: Research Funding; Atara Biotherapeutics: Patents & Royalties, Research Funding; CRISPR: Patents & Royalties, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Bejanyan: Medexus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Avrobio (Spouse disclosure): Current equity holder in publicly-traded company; Magenta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen (Spouse disclosure): Consultancy, Membership on an entity's Board of Directors or advisory committees; Crispr Therapeutics (Spouse disclosure): Current equity holder in publicly-traded company; Teladoc Health (Spouse disclosure): Current equity holder in publicly-traded company; Organon (Spouse disclosure): Current equity holder in publicly-traded company; Kadmon (Spouse disclosure): Consultancy; Merck (Spouse disclosure): Current equity holder in publicly-traded company; American Well Corp (Spouse disclosure): Current equity holder in publicly-traded company; Thermo Fisher (Spouse disclosure): Current equity holder in publicly-traded company; Unitedhealth Group (Spouse disclosure): Current equity holder in publicly-traded company.

*signifies non-member of ASH