FDA Grants Orphan Drug Designation to SENTI-202 for R/R AML and Hematologic Malignancies

R/R Hematologic Malignancies | Image credit:

© Om.Nom.Nom - stock.adobe.com

The FDA has granted orphan drug designation to the first-in-class, off-the-shelf CAR natural killer (NK)–cell therapy SENTI-202 for the treatment of patients with relapsed/refractory hematologic malignancies, including acute myeloid leukemia (AML).¹

SENTI-202 is a synthetic, biology-engineered therapeutic designed to selectively target and eliminate CD33- and/or FLT3-expressing malignant cells, such as those in AML and myelodysplastic syndrome (MDS), without harming healthy bone marrow cells. The agent is currently being evaluated in a phase 1 clinical trial (NCT06325748), which is assessing its safety, tolerability, and preliminary antitumor activity in patients with relapsed or refractory hematologic cancers.

“SENTI-202 continues to demonstrate encouraging promise as a potential treatment option for relapsed/refractory AML, an indication with significant unmet need and a dismal median survival rate of 5.3 months,” Timothy Lu, MD, PhD, co-founder and chief executive officer of Senti Biosciences, stated in a news release. “Receiving orphan drug designation for SENTI-202 provides further validation to our novel approach to overcoming AML heterogeneity and protecting healthy cells and underscores the need for new and effective treatment options. Building upon our recently reported positive preliminary results, this important milestone bolsters our commitment to advancing the development of this important program forward.”

Phase 1 Trial Breakdown

This phase 1 trial is an open-label, multicenter study designed to evaluate the safety, biodynamics, and preliminary antitumor activity of this off-the-shelf, logic-gated CAR NK-cell therapy in patients with relapsed/refractory hematologic malignancies expressing CD33 and/or FLT3, including AML and MDS.2

The study is divided into two parts. Part 1 consists of a dose-escalation phase utilizing a modified 3+3 design to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of SENTI-202 when administered following lymphodepleting chemotherapy. Part 2 will comprise disease-specific expansion cohorts to further evaluate SENTI-202 at the RP2D in target populations.

Eligible patients must be 18 to 74 years of age with relapsed or refractory AML with morphologic relapse (≥5% bone marrow blasts) following 1 to 3 prior lines of standard therapy. For those with FLT3- or IDH1/2-mutated disease, at least one prior targeted therapy is required. Patients with relapsed/refractory MDS with increased blasts must have received 1 to 2 prior lines of therapy. The trial also permits enrollment of patients with other relapsed/refractory hematologic malignancies who have received at least one prior standard-of-care regimen.

Additional eligibility criteria include documented CD33 expression (or FLT3 expression, if available), an ECOG performance status of 0 or 1, and adequate organ function. Participants must have recovered from prior treatment-related toxicities and be willing to provide written informed consent.

Patients with a white blood cell (WBC) count at least 20 × 10⁹/L or a circulating blasts level of at least 10 × 10⁹/L are excluded, as are those with rapidly progressive or hyperproliferative disease. The study also excludes patients with acute promyelocytic leukemia (APL) characterized by t(15;17)(q22;q12) or APML-RARA translocations. Individuals with MDS with fibrosis or a known history of constitutional syndromes associated with chemotherapy-responsive AML are ineligible.

Active central nervous system (CNS) involvement, including leukemic meningitis or other CNS disease, constitutes an exclusion criterion. Additionally, patients with isolated extramedullary disease or myeloid sarcoma in the absence of morphologic hematologic relapse are not eligible.

Restrictions related to prior treatments include recent administration of certain anticancer therapies within protocol-defined windows; receipt of hematopoietic cell transplantation (HSCT) within 100 days of planned SENTI-202 infusion; and prior treatment with natural NK-cell therapy or CAR T-cell therapy at any time. Patients who previously received donor lymphocyte infusion (DLI) are excluded unless the DLI was administered post-HSCT for minimal residual disease–positive disease.

After lymphodepletion with fludarabine and cytarabine, patients are receiving SENTI-202 as either a 3-dose regimen on days 0, 7, and 14; or a 5-dose regimen on days 0, 3, 7, 10, and 14.

Safety is the study’s primary end point. Secondary end points included anticancer activity, pharmacokinetics, and immune response.

References

1. Senti Bio granted U.S. FDA orphan drug designation for use of first-in-class off-the-shelf logic gated selective CD33 or FLT3 not EMCN CAR NK cell therapy, SENTI-202, to treat acute myeloid leukemia. Senti Biosciences, Inc. June 18, 2025. Accessed June 18, 2025. https://investors.sentibio.com/news-releases/news-release-details/senti-bio-granted-us-fda-orphan-drug-designation-use-first-class
2. SENTI-202: Off-the-shelf logic gated CAR NK cell therapy in adults with CD33 and/or FLT3 blood cancers including AML/MDS. ClinicalTrials.gov. Updated March 30, 2025. Accessed June 18, 2025. https://clinicaltrials.gov/study/NCT06325748