A Phase 1B Investigator Initiated Study of Safety and Tolerability of Dexamethasone (D) in Combination With Venetoclax-based Low-Intensity Therapy (LIT) in Treatment-Naïve Acute Myeloid Leukemia (AML): DLIT-AML

Overview

This study is investigating whether adding dexamethasone, an anti-inflammatory medication, to a standard venetoclax-based low-intensity therapy (LIT) is safe and well-tolerated in patients with newly diagnosed Acute Myeloid Leukemia (AML) who are not eligible for intensive chemotherapy. Study Goals Primary Goal: To assess the safety and tolerability of dexamethasone in combination with venetoclax-based LIT. Secondary Goal: To evaluate how this treatment affects patients' quality of life using surveys. Exploratory Goal: To measure the treatment response, including remission rates and signs of minimal residual disease. What Happens in the Study? Patients will receive treatment over six cycles. Dexamethasone is given in different doses during the first six cycles along with venetoclax and another standard chemotherapy drug.

Interventions

• Drug Dexamethasone plus Venetoclax-based Low-Intensity Therapy
  Participants will receive standard low-intensity therapy (LIT) regimens for newly diagnosed AML, which may include venetoclax combined with either azacitidine, decitabine, or low-dose cytarabine, per treating physician's discretion. In addition, participants will receive dexamethasone administered orally at 10 mg twice daily on days 1-3 of cycles 1 and 2, and 20 mg orally on day 1 of cycles 3 through 6. This intervention is being studied to evaluate whether the addition of dexamethasone improves

Primary outcome measures

• Safety and tolerability of adding dexamethasone to venetoclax-based low-intensity therapy in treatment-naïve AML patients [Time frame: From start of treatment through completion of 6 cycles (each cycle is 28 days; approximately 6 months total)]

Eligibility criteria

Inclusion criteria

Age ≥ 18 years

ECOG performance status ≤2

Newly diagnosed AML morphologically confirmed in a bone marrow biopsy and aspiration done within 2 months of study enrollment, following the WHO 2022 morphologic classification for myeloid malignancies9

No prior AML treatment (treatment-naïve)

Ineligibility or unwillingness to undergo high-dose chemotherapy induction. Patient candidacy for high dose intensive chemotherapy or ineligibility due to older age or unfit medical status will be determined by the primary treating physician.

Adequate renal function including creatinine clearance > 30 ml/min based on the Cockcroft-Gault equation

Normal liver function with direct bilirubin ≤ 2xULN, ALT and AST ≤ 3xULN, unless deemed to be related to underlying leukemia

Women of child-bearing potential and men (except if previous vasectomy) must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Ability to understand and the willingness to sign a written informed consent.

Patients with known previous exposure to HMA or LDAC for treatment of a pre-leukemic condition including myelodysplastic syndromes or myeloproliferative neoplasms are eligible.

Exclusion

Acute promyelocytic leukemia diagnosis

Bone marrow transplant expected after first or second cycle of venetoclax-based LIT.

White Blood Cell (WBC) count >25K. If WBC is >25K in an otherwise eligible patient, the use of cytoreduction is allowed and patients can be included when WBC <25K. Hydroxyurea (at any dose) and/or one dose of cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy

The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions: 1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia, or 2) cytoreduction as point 3.2.3.

Uncontrollable infectious disease within 7 days of study enrollment defined as infection confirmed on laboratory tests or imaging and associated with systemic inflammatory response syndrome (SIRS), circulatory compromise or respiratory failure, where steroid treatment may be detrimental according to investigator. Clinically stable febrile neutropenia attributable to AML is not an exclusion criteria.

Patients with any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.

Baseline high-dose steroid treatment at dose preceding AML diagnosis for any cause, including concomitant autoimmune disease. The maximum acceptable daily steroid dose is the equivalent of 5 mg of prednisone.

Adrenal insufficiency

Active peptic ulcer disease (PUD), defined as actively having severe pain requiring intervention or bleeding. A simple history of PUD is not an exclusion criterion. If a patient with history of PUD is enrolled, proton pump inhibitor prophylaxis will be used.

Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known uncontrolled HIV infection. Patients with a history of treated HBV or HCV which has been previously treated, or those with controlled HIV on treatment are eligible.

Patients receiving any other investigational agents

Pregnant or nursing patients

Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications

Patients with uncontrolled diabetes, defined as hemoglobin A1C (HgbA1C) levels >9 and significant baseline hyperglycemia. Patients with controlled diabetes are eligible provided they continue with their treatments and HgbA1C is monitored every 3 months. HgbA1C levels are required only in diabetic patients riteria:

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Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Vermont Medical Center — Burlington

Identifiers

NCT: NCT07014462 · STUDY00003614/UVMC2503

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗