AML/MDS, CD33 Expressing Hematological Malignancies, FLT3 Expressing Hematological Malignancies
Conditions
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
Brief 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.
Detailed description
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).
Interventions
BIOLOGICALSENTI-202
SENTI-202 is an investigational off-the-shelf CAR NK cell therapy designed to selectively target and eliminate CD33 and/or FLT3 expressing hematological malignancies while sparing healthy cells using a NOT logic gate. SENTI-202 is administered in either a 3 dose regimen (Schedule 1: Days 0, 7, 14) or a 5 dose regimen (Schedule 2: Days 0, 3, 7, 10, 14) of a 28-day treatment cycle following a lymphodepletion conditioning regimen of fludarabine and cytarabine (flu/Ara-C). Subjects will receive a minimum of 1 and maximum of 3 treatment cycles to achieve optimal response with the optionality of an additional consolidation cycle thereafter. Additional dosing schedules may be explored depending on study data.
Sponsors
Senti Biosciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability for dose determination of SENTI-202 | At the end of each treatment cycle (each cycle is 28 days) and through study completion, up to 2 years | Incidence, type, frequency, and severity of adverse events and dose limiting toxicities will be assessed to determine the maximum tolerated dose and/or recommended phase 2 dose and dosing regimen |
| For subjects enrolled in the Dose Expansion Cohort(s): Anti-cancer activity of SENTI-202 | Through study completion, up to 2 years | The response rate to SENTI-202 will be measured using clinical measures of benefit as defined by standard consensus criteria for the respective disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For subjects enrolled in the Dose Finding Cohorts: Anti-cancer activity of SENTI-202 | Through study completion, up to 2 years | The response rate to SENTI-202 will be measured using clinical measures of benefit as defined by standard consensus criteria for the respective disease |
| Pharmacokinetic (PK) and pharmacodynamic (PDn) profile of SENTI-202 | Through study completion, up to 2 years | Levels of circulating SENTI-202 and peripheral cytokine levels will be measured to assess the PK/PDn profile of SENTI-202 |
| Host immune response to SENTI-202 | Through study completion, up to 2 years | Anti-SENTI-202 immune response and RCR will be measured in blood samples |
Countries
Australia, United States
Contacts
STUDY_DIRECTORRochelle Emery, MD
Senti Biosciences, Medical Director
Outcome results
None listed