senti-202: off-the-shelf logic gated car nk cell therapy in adults with cd33 and/or flt3 blood cancers including aml/mds

Conditions: AML/MDS; CD33 Expressing Hematological Malignancies; FLT3 Expressing Hematological Malignancies

Summary: this is an open-label study of the safety, biodynamics, and anti-cancer activity of senti-202 (an off-the-shelf logic gated car nk cell therapy) in patients with cd33 and/or flt3 expressing blood cancers, including aml and mds.

this is a dose-finding study of senti-202, comprised of an initial dose finding using a modified "3+3" study design to determine the maximum tolerated dose (mtd) and/or recommended phase two dose (rp2d) of senti-202 when administered after lymphodepleting chemotherapy (part 1) followed by disease-specific expansion cohorts at the rp2d (part 2).

Eligibility criteria:
inclusion criteria: * subjects with cd33 and/or flt3 expressing malignancies, including: * relapsed refractory acute myeloid leukemia (aml) with morphologic relapse as defined by ≥5% bone marrow blasts who have received at least 1 prior line, but no more than 3 prior lines of standard anti-aml therapy. subjects with flt3-mutated or idh ½-mutated disease must have received at least one prior targeted therapy. * relapsed refractory myelodysplastic syndrome (mds) with increased blasts who have received at least 1 prior line, but no more than 2 prior lines of anti-mds therapy * other hematological malignancies who have received at least 1 prior line of standard of care for the respective disease * documentation of cd33 expression (or flt3 expression if available) by individual institutional standard of care * ecog performance score of 0-1 * adequate organ function including platelet count \>20x109/l (platelet transfusion is permitted) * adequate recovery from toxicities from previous cancer treatments, as described in the study protocol * willing and able to provide written informed consent exclusion criteria: * white blood cell (wbc) count of ≥20×109/l or circulating blasts ≥10×109/l or rapidly progressive/hyperproliferative disease * acute promyelocytic leukemia with t(15;17) (q22;q12) or abnormal promyelocytic leukemia/retinoic acid receptor alpha (apml-rara) * mds with fibrosis (mds-f) or known prior history of constitutional conditions/syndromes with chemo-responsive aml * evidence of leukemic meningitis or known active central nervous system disease * presence of extra-medullary disease or myeloid sarcoma alone with no morphologic hematologic relapse * prior use of certain anti-cancer therapies and/or use within a certain number of days prior to senti-202 study treatment, as described in the study protocol * hematopoietic cell transplantation (hct) less than 100 days prior to the first dose of senti-202 * prior nk cell or car t cell therapy at any time * prior donor lymphocyte infusion (dli), except if after hct for mrd+ disease * medical conditions or medications prohibited by the study protocol * pregnant or breastfeeding female

Keywords: senti-202 car nk natural killer cell cd33 flt3 allogeneic logic gate relapsed/refractory aml relapsed/refractory mds inhibitory car activating car not logic gate il15 interleukin 15 cell therapy off-the-shelf leukemic stem cells blastic plasmacytoid dendritic cell neoplasm (bpdcn) multiple myeloma (mm) mixed phenotype acute leukemia (mpal) endomucin