Myelodysplastic Syndrome Clinical Trial

Iadademstat in Combination With Azacitidine and Venetoclax in Treating Newly Diagnosed Acute Myeloid Leukemia

Summary

This phase I trial tests the safety, side effects, and best dose of iadademstat when given together with azacitidine and venetoclax in treating patients with newly diagnosed acute myeloid leukemia (AML). Iadademstat inhibits the LSD1 protein and may lead to inhibition of cell growth in LSD1-overexpressing cancer cells. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving iadademstat with azacitidine and venetoclax may be safe, tolerable and/or effective in treating patients with newly diagnosed AML who cannot undergo intensive chemotherapy.

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Full Description

PRIMARY OBJECTIVE:

I. Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of iadademstat (IADA) when administered as part of the investigational combination (i.e., iadademstat + azacitidine + venetoclax [IADA+AZA+VEN]).

SECONDARY OBJECTIVES:

I. Assess the preliminary efficacy of the investigational regimen based on disease remission.

II. Assess the preliminary efficacy of the investigational regimen based on clinical response.

III. Assess the safety of the investigational regimen.

EXPLORATORY OBJECTIVES:

I. Assess survival in the absence of treatment failure, hematologic relapse, or progressive disease.

II. Assess overall survival. III. Assess duration of response, based on morphological assessments. IV. Identify mechanisms of transcriptional reprogramming and cell death. V. Identify predictive biomarkers of response to LSD1 inhibition. VI. Assess participant quality of life using Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE).

OUTLINE: This is a dose-escalation study of iadademstat in combination with azacitidine and venetoclax.

Patients receive iadademstat orally (PO) once daily (QD) on days 1-5 of cycle 0 and then days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 or 1-28 and azacitidine subcutaneously (SC) QD days 1-7. Patients with complete remission (CR), CR with partial hematologic recovery (CRh), CR with incomplete blood count recovery, (CRi), or morphologic leukemia-free state (MLFS) after cycle 1 continue to receive IADA PO QD on days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 or 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening as clinically indicated on study. Patients under bone marrow biopsy throughout the trial. Additionally, patients undergo blood sample collection during screening and on the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Patients at least 18 years of age will be considered for inclusion without bias against gender identity, race, or ethnicity
Ability to comprehend the investigational nature of the study and provide written informed consent

Patients with previously untreated, morphologically documented AML based on World Health Organization (WHO) 2008 definitions who are ineligible for standard of care (SOC) intensive chemotherapy induction and also meet the following criteria:

Documented intermediate- or adverse-risk AML based on European Leukemia Network (ELN) 2022 criteria
Note: Cases of AML/myelodysplastic syndrome (MDS) overlap with 10-19% bone marrow (BM) or peripheral blood (PB) blasts will be considered
Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1 fusions will be excluded
Eastern Cooperative Oncology Group (ECOG) performance ≤ 2 (Patients aged ≥ 75 years, at the time of consent)

Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients aged ≥ 75 years, at the time of consent)

High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert's syndrome may be considered for enrollment despite high indirect (and total) bilirubin
Creatinine clearance (CrCl) of ≥ 60 mL/min (estimated using the Cockcroft Gault formula or measured by 24 hours urine collection) (Patients aged ≥ 75 years, at the time of consent)

Patients aged ≥ 18 to 74 years (ECOG performance status [PS] ≤ 3 is accepted) at consent must meet ≥ 1 of the following criteria defining a co morbidity:

ECOG PS of 2 or 3 (Note: Patients ≥ 18 to 74 years of age with PS of 0-1 must meet criteria of one of the following comorbidities.)
Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina
Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%
CrCl ≥ 30 mL/min to < 45 ml/min

Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN;

High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert's syndrome may be considered for enrollment despite high indirect (and total) bilirubin
Other comorbidities that the physician judges to be incompatible with intensive chemotherapy (IC). In these cases, the comorbidity must be reviewed and approved by the principal investigator (PI) before study enrollment
Ability to swallow oral medications
No ongoing anticoagulation or antiplatelet therapy within 14 days of start of treatment with IADA (i.e., cycle 0 day 1 [C0D1])
No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
No history of stroke or intracranial hemorrhage within 180 days of start of IADA
No major bleeding event, as defined by the International Society of Thrombosis and Hemostasis (ISTH), within 12 weeks of start of IADA

Uncorrected international normalized ratio (INR) or activated partial thromboplastin time (aPTT) of < 1.5 x ULN.

If INR or aPTT > 1.5 x ULN has been corrected (prior to enrollment), then history of disseminated intravascular coagulation (DIC) must be absent

White blood cell (WBC) < 20 x 10^9/L prior to study start. Cytoreduction prior to study treatment is allowed with

Hydroxyurea for up to 14 days and until 24 hours prior to start of IADA; or
Leukapheresis for up to 14 days prior to start of IADA

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x institutional ULN

Lower hepatic function may be considered if liver enzyme abnormalities are determined by the treating MD and principal investigator (PI) to be due to leukemic infiltration

Willing and able to

Adhere to study schedule of activities and life style restrictions while on treatment;
Provide bone marrow (BM) aspirate and core biopsy samples; and
Accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequelae, including transfusions
Negative pregnancy test within 72 hours of start of IADA for persons of childbearing potential (PCBP)
Willingness to comply with study requirements for contraception, as follows: PCBP and sperm-producing participants who are sexually active with a PCBP must use study approved contraception from start of investigational product (first dose of IADA) until 6 months after the last dose of IADA. Pregnancy is exclusionary because the agents used in this study have the potential for teratogenic or abortifacient effects

Exclusion Criteria:

Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or any excipients in the formulations
Body weight < 50 kg
Investigational therapy within 5 half-lives or, if unknown, within 28 days prior to start of IADA
Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patients with proliferative disease must meet the criteria listed in inclusion criteria
Radiotherapy less than 14 days prior to start of IADA
Recent and significant medical interventions, such as major surgery within 28 days prior to the start of IADA, or stem cell transplant within 100 days prior to the start of IADA. Patients with active treatment for graft-versus-host disease (GVHD) are excluded
Another active malignancy within 5 years prior to the start of IADA, or at the investigator's discretion
Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to the start of IADA
Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment is not finalized at least 3 weeks prior to the start of IADA
Active central nervous system involvement with AML
Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to start of IADA and must be amenable to alternate treatment if current treatment will interact with investigational regimen
Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV, respectively) status, except in cases of undetectable HBV/HCV viral load for at least 3 months prior to the start of IADA. (Hepatitis B or C testing is not required for eligibility assessment.)
Individuals serology positive for human immunodeficiency virus (HIV) and under active treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents). Otherwise, enrollment may be considered in cases of HIV that is controlled with another treatment type or in cases that that acceptable modification of the patient's HIV treatment exists
Use a P-gp inhibitor within 23 days prior to treatment with venetoclax
Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives whichever is longer, prior to start of treatment with venetoclax
Unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided throughout the study and until at least 60 days after last dose of IADA
Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before C1D1 is allowed
Patients with poorly controlled diabetes. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) ≥ 8%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met
Patients with mean of triplicate corrected QT interval (Fridericia's correction formula [QTcF]) > 450 ms at Screening based on central reading
Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), or psychiatric illness or social situation that could limit compliance with study requirements, at the discretion of the investigator

Study is for people with:

Myelodysplastic Syndrome

Phase:

Phase 1

Estimated Enrollment:

24

Study ID:

NCT06357182

Recruitment Status:

Not yet recruiting

Sponsor:

OHSU Knight Cancer Institute

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There is 1 Location for this study

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OHSU Knight Cancer Institute
Portland Oregon, 97239, United States More Info
Curtis A. Lachowiez
Contact
503-494-5058
[email protected]
Curtis A. Lachowiez
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Myelodysplastic Syndrome

Phase:

Phase 1

Estimated Enrollment:

24

Study ID:

NCT06357182

Recruitment Status:

Not yet recruiting

Sponsor:


OHSU Knight Cancer Institute

How clear is this clinincal trial information?

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