ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS

Phase 1Not Yet RecruitingNCT07617363

Washington University School of Medicine27 enrolled

Overview

This is a single-center, open-label, phase I study with dose escalation and dose expansion testing the combination of ATRN-119 and decitabine in patients with TP53-mutated acute myeloid leukemia (AML) or higher-risk myelodysplastic syndrome (HR-MDS). The dose escalation phase will enroll patients with previously untreated, relapsed, or refractory AML or HR-MDS, regardless of TP53 alteration status, with the primary objective of determining safety and tolerability of ATRN-119 plus decitabine. The dose expansion phase will only enroll patients with previously untreated AML or HR-MDS with a TP53 alteration, with the primary objective of identifying the recommended phase 2 dose (RP2D).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myeloid Leukemia High-risk Myelodysplastic Syndrome

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of AML or higher-risk MDS (HR-MDS) according to the World Health Organization (WHO) 5th Edition or International Consensus Classification (ICC) 2022 criteria. * HR-MDS is defined as: * IPSS-R (score \> 3.5) or IPSS-M (score \> 0.5) OR ii.≥ 10% bone marrow blasts * Dose Escalation ONLY - One of the following: * Previously untreated AML with ELN 2022 adverse-risk genetic features based on local testing, in patients who are ineligible for intensive induction chemotherapy (cytarabine plus an anthracycline) due to age, comorbidities, or performance status. * Previously untreated HR-MDS * Relapsed or refractory AML or HR-MDS meeting one or more of the following criteria: Failure to achieve CR, CRh, or CRi after ≥ 4 cycles of a hypomethylating agent (HMA); Failure to achieve CR, CRh, or CRi after ≥ 2 cycles of a HMA plus venetoclax; Overt disease progression during HMA-based therapy; First relapse with an initial remission duration \< 12 months; First relapse following failed salvage chemotherapy; Relapse after allogeneic hematopoietic cell transplant; Second or subsequent relapse * Dose Expansion ONLY - Both of the following: * AML or HR-MDS with a TP53 alteration, defined by the presence of any of the following features on local testing: Pathogenic or likely pathogenic TP53 mutation detected by molecular testing (with a minimum 2% VAF); Cytogenetic and/or FISH evidence of 17p deletion involving TP53 (with a minimum 2% cell involvement or the lower limit of detection of the assay); Increased hematopoietic p53 protein expression by immunohistochemistry (defined as \>20% p53-positive cells). Patients enrolled during the dose expansion phase on the basis of increased p53 protein expression who are subsequently found not to harbor a TP53 mutation on molecular testing may continue study treatment. * No prior therapy for a myeloid neoplasm, with the exception of permitted treatments * At least 18 years of age. * ECOG performance status ≤ 2 * Adequate organ function within 28 days prior to the first dose of ATRN-119 as defined below: * Total bilirubin ≤ 2.0 x IULN; patients with known or suspected Gilbert's syndrome may have total bilirubin ≤ 5 mg/dL * AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN * Estimated glomerular filtration rate (eGFR) \> 30 mL/min/1.73 m2 or creatinine clearance ≥ 30 mL/min/1.73 m2 by Cockcroft-Gault formula or creatinine ≤ 2.0 x IULN * The effects of ATRN-119 and decitabine on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after the last dose of ATRN-119 or decitabine on study (whichever is later) for people of childbearing potential and 3 months for people able to father a child. * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants. Exclusion Criteria: * Dose Expansion ONLY - Prior therapy for AML, HR-MDS, antecedent MDS, or antecedent myeloproliferative neoplasm (MPN) with the exception of erythropoiesis-stimulating agents, hematopoietic growth factors (e.g., G-CSF, thrombopoietin receptor agonists), hydroxyurea, luspatercept, imetelstat, all-trans retinoic acid (ATRA), and leukapheresis. * Active CNS involvement by AML requiring therapeutic intervention. * Active graft-versus-host disease (GVHD) requiring systemic immunosuppressive therapy except for low-dose steroids (prednisone ≤ 10 mg per day or other steroid equivalent) * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial. * Currently receiving any other investigational agents. * Concomitant systemic treatment with strong inhibitors or inducers of CYP3A4. Patients may be eligible after a washout period of 5 half-lives or 28 days (whichever is shorter). * A history of allergic reactions attributed to or known hypersensitivity to compounds of similar chemical or biologic composition to ATRN-119, decitabine, or other agents used in the study. * Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, clinically significant autoimmune disease requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, or clinically significant or uncontrolled cardiac arrhythmia. Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better. * Conditions that may impair oral drug administration or absorption, including inability to swallow oral medications, malabsorption syndromes, or other clinically significant gastrointestinal disorders. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of Cycle 1 Day 1. * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing is not required in the absence of known history of infection. * Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load by PCR on suppressive therapy are eligible. HBV testing is not required in the absence of known history of infection. * History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing is not required in the absence of known history of infection.

Outcomes

Primary Outcomes

Number and grade of treatment-emergent adverse events (TEAEs) as assessed via CTCAE v6.0

Time frame: From start of treatment until 30 days after last dose of ATRN-119 (approximately 23 months)

Incidence of dose-limiting toxicities (DLTs) during Cycle 1 as assessed via CTCAE v6.0

The DLT evaluation period is 28 days from initiation of study treatment (Cycle 1), except in cases of persistent neutropenia meeting hematologic DLT criteria, for which the observation window will extend to 42 days from treatment initiation. DLTs are defined in the protocol.

Time frame: From Cycle 1 Day 1 to end of Cycle 1 Day 28/Cycle 1 Day 42 (total time 28-42 days)

Secondary Outcomes

Rate of Complete Remission (CR)

European LeukemiaNet (ELN) 2022 Response Criteria assesses AML and the International Working Group (IWG) 2023 Response Criteria assesses Higher-Risk MDS (HR-MDS). CR AML: Bone marrow blasts \< 5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥ 1.0 x 10\^9/L (1,000/μL); platelet count ≥ 100 x 10\^9/L (100,000/μL). CR HR-MDS: Bone marrow: \< 5% myeloblasts; dysplasia may persist and peripheral blood: hemoglobin ≥ 10 g/dL, platelets ≥ 100 x 10\^9/L, neutrophils ≥ 1.0 x 10\^9/L, blasts 0%

Time frame: Through completion of treatment (estimated total time 22 months)

Rate of Complete Remission with partial hematologic recovery (CRh)

European LeukemiaNet (ELN) 2022 Response Criteria assesses AML and the International Working Group (IWG) 2023 Response Criteria assesses Higher-Risk MDS (HR-MDS). CRh is defined according to the ELN 2022 Response Criteria: ANC ≥ 0.5 x 10\^9/L (500 μL) and platelet count ≥ 50 x 10\^9/L (50,000/μL), otherwise all other CR criteria met CRh is defined according to the IWG 2023 Response Criteria: Bone marrow: \< 5% myeloblasts; dysplasia may persist; Peripheral blood: not meeting criteria for CR or CRL; no hemoglobin threshold required, platelets ≥ 50 x 10\^9/L, neutrophils ≥ 0.5 x 10\^9/L, blasts 0%

Time frame: Through completion of treatment (estimated total time 22 months)

Rate of Partial Remission (PR)

European LeukemiaNet (ELN) 2022 Response Criteria assesses AML and the International Working Group (IWG) 2023 Response Criteria assesses Higher-Risk MDS (HR-MDS). PR is defined according to the ELN 2022 Response Criteria: All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50% PR is defined according to the IWG 2023 Response Criteria: All CR criteria except: Bone marrow blasts decreased by ≥ 50% over pretreatment but still ≥ 5% and Cellularity and morphology not relevant

Time frame: Through completion of treatment (estimated total time 22 months)

Duration of Response (DoR)

DoR will be measured from the first documented response until disease progression or death from any cause, as defined in the protocol or disease-specific criteria (ELN 2022 for AML and IWG 2023 for HR-MDS). DOR will be summarized among responders only. Individuals who do not exhibit any disease progression or death during the follow-up period are censored at the last date of the response assessment.

Time frame: From first documented response until disease progression or death (up to 46 months)

Event-free Survival (EFS)

EFS will be measured from Cycle 1 Day 1 to treatment failure, relapse after response, progression, or death from any cause, consistent with protocol definitions and disease-specific response criteria (ELN 2022 for AML and IWG 2023 for HR-MDS). EFS will be summarized in the efficacy-evaluable population. Participants without an event will be censored at the last disease assessment date at which they were known to be event-free.

Time frame: From Cycle 1 Day 1 to treatment failure, relapse after response, progression, or death (up to 46 months)

Overall Survival (OS)

OS will be measured from Cycle 1 Day 1 to death from any cause. Participants alive at last follow-up will be censored on the date last known alive. OS will be summarized in all treated participants.

Time frame: From Cycle 1 Day 1 to death from any cause (up to 46 months)

AML Patients only: Rate of Complete Remission with incomplete count recovery (CRi)

Response is assessed according to the ELN 2022 Response Criteria for AML. CRi is defined as all CR criteria except for residual neutropenia \< 1.0 x 10\^9/L (500/μL) or thrombocytopenia \< 100 x 10\^9/L (50,000/μL); CRi should only include patients not meeting the definition of CRh.

Time frame: Through completion of treatment (estimated total time 22 months)

AML Patients only: Rate of morphologic leukemia-free state (MLFS)

Response is assessed according to the ELN 2022 Response Criteria for AML. MLFS is defined as bone marrow blasts \< 5%; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery required.

Time frame: Through completion of treatment (estimated total time 22 months)

AML Patients only: Rate of composite Complete Remission (cCR)

Response is assessed according to the ELN 2022 Response Criteria for AML. cCR is defined as complete remission (CR) + complete remission with partial hematologic recovery (CRh) + complete remission with incomplete hematologic recovery (CRi)

Time frame: Through completion of treatment (estimated total time 22 months)

AML Patients only: Overall Response Rate (ORR)

Response is assessed according to the ELN 2022 Response Criteria for AML. ORR is defined as complete remission (CR) + complete remission with partial hematologic recovery (CRh) + complete remission with incomplete hematologic recovery (CRi) + partial remission (PR) + morphologic leukemia-free state (MLFS)

Time frame: Through completion of treatment (estimated total time 22 months)

HR-MDS patients only: Rate of Complete Remission (CR) equivalent

CR is assessed according to the IWG 2023 Response Criteria for HR-MDS. CR: Bone marrow: \< 5% myeloblasts; dysplasia may persist; Peripheral blood: hemoglobin ≥ 10 g/dL, platelets ≥ 100 x 10\^9/L, neutrophils ≥ 1.0 x 10\^9/L, blasts 0%

Time frame: Through completion of treatment (estimated total time 22 months)

HR-MDS patients only: Rate of Complete Remission with limited count recovery (CRL)

CRL is assessed according to the IWG 2023 Response Criteria for HR-MDS. CRL (CRuni and CRbi): Bone marrow: \< 5% myeloblasts; dysplasia may persist; Peripheral blood: blasts 0%; Complete remission unilineage (CRuni): peripheral blood not meeting CR but only one of the following: hemoglobin ≥ 10 g/dL, platelets ≥ 100 x 10\^9/L, neutrophils ≥ 1.0 x 10\^9/L Complete remission bilineage (CRbi): peripheral blood not meeting CR but only two of the following: hemoglobin ≥ 10 g/dL, platelets ≥ 100 x 10\^9/L, neutrophils ≥ 1.0 x 10\^9/L

Time frame: Through completion of treatment (estimated total time 22 months)

HR-MDS patients only: Rate of Hematological Improvement (HI)

HI is assessed according to the IWG 2018 Response Criteria for HR-MDS. HI: Not meeting criteria for complete remission (CR) (or CR equivalent) or complete remission unilineage (CRuni) or complete remission with limited count recovery (CRL); HIerythroid (HI-E); HIplatelets (HI-P); HIneutrophils (HI-N).

Time frame: Through completion of treatment (estimated total time 22 months)

HR-MDS patients only: Rate of composite Complete Remission (cCR)

cCR is assessed according to the IWG 2023 Response Criteria for HR-MDS. cCR is defined as complete remission (CR) + complete remission (CR) equivalent + complete remission with limited count recover (CRL) + complete remission with partial hematologic recovery (CRh)

Time frame: Through completion of treatment (estimated total time 22 months)

HR-MDS patients only: Overall Response Rate (ORR)

Response is assessed via the IWG 2023 Response Criteria for HR-MDS. ORR is defined as complete remission (CR) + complete remission (CR) equivalent + complete remission with limited count recover (CRL) + complete remission with partial hematologic recovery (CRh) + partial remission (PR) + hematological improvement (HI)

Time frame: Through completion of treatment (estimated total time 22 months)

ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts