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

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/m ² and cyclophosphamide 500mg/m ² 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 1x10 ⁶ 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.

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