Acute Myeloid Leukemia
Conditions
Brief summary
This is a randomized, open-label, Phase I clinical study with expansion. It will assess the safety and efficacy of high-dose ascorbate administered concomitantly with azacitidine and venetoclax in newly diagnosed AML.
Detailed description
The purpose of this research study is to see if adding high dose ascorbate (vitamin c) intravenous infusion (IV) to the standard treatment regimen for AML (azacitidine/venetoclax or decitabine/venetoclax) is safe, and also to see if the addition of high dose ascorbate enhances the anti-AML impact of the azacitidine given with standard care.
Interventions
DRUGAzacitidine
A chemotherapy drug known as a hypomethylating agent
DRUGVenetoclax
Targeted cancer therapy used to treat certain blood cancers. It specifically targets a protein called BCL-2 to trigger the self-destruction of cancer cells.
Administering vitamin C intravenously to achieve very high concentrations in the bloodstream. In contrast to low doses, which act as antioxidants, these pharmacological doses can function as a pro-oxidant, killing cancer cells while leaving healthy cells unharmed.
DRUGDecitabine
Azacitidine may be substituted with decitabine 20 mg/m2 daily, on days 1-5, at PI discretion in the event of toxicity/drug supply shortage.
Sponsors
Kittika Poonsombudlert
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Adults aged ≥ 18 who are deemed unfit for intensive chemotherapy by meeting at least one of the following criteria: * age ≥ 75 * Eastern Cooperative Oncology Group (ECOG) performance of 2-3 * Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina) * Severe pulmonary disorder (e.g., DLCO ≤ 65% or FEV1 ≤ 65%) * Calculated Creatinine clearance 25 - 45 mL/min using the Cockcroft-Gault formula * Hepatic disorder with total bilirubin \> 1.5 times the upper limit of normal * Any other comorbidity that the investigators determine to be incompatible with intensive chemotherapy * Newly diagnosed (non-APL) acute myeloid leukemia except those with cytogenetic/molecular abnormalities in the
Exclusion criteria
* Participants must have adequate organ function, defined as: * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN) * International normalized ratio (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) \< 1.5 x ULN (patient could be eligible if they respond appropriately to correction with FFP or cryoprecipitate) * Patients with a history of antecedent myelodysplasia (MDS) are eligible if they have not had prior chemotherapy/hypomethylating agent (e.g., azacitidine or decitabine). Prior exposure to other investigational agents could be considered at PI's discretion * Patients who have developed therapy-related AML after prior radiation or chemotherapy for other malignancy(ies) are eligible if they have not been exposed to hypomethylating agent (e.g., azacitidine or decitabine) and/or venetoclax * Patients presenting with marked leukocytosis (WBC \> 25 k/mm3) should receive cytoreduction with hydroxyurea or cytarabine dose ≤ 1 g/m2 to mitigate the risk of tumor lysis syndrome before initiation of therapy with venetoclax * For female participants of childbearing potential, a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening * Ability to understand and the willingness to sign a written informed consent document. * Both male and female participants of childbearing potential agree to use an adequate method of contraception from screening through 6 months after the last dose of study treatment. * Patients with evidence of Central Nervous System (CNS) disease involvement or who are at high risk of developing CNS disease at baseline/screening (defined as: presenting WBC \> 200k/mm3, or monocytic differentiation or active CSN symptoms concerning CNS involvement per the treating physician) are eligible for this trial and may continue to receive or initiate intrathecal chemotherapy as treatment or prophylaxis, respectively, per institutional practice
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Dose-limiting toxicities (DLTs) according to CTCAE version 5.0 | Days 1 through 28 | As this is the first time high-dose ascorbate has been administered in combination with standard of care aza/ven, the safety of the combination will be assessed in the first 6 patients randomized to Arm B. An initial DLT assessment will be made when 3 participants have been randomized to the Investigational Arm B and are evaluable for DLTs. If at most 1 out of 3 participants experience a DLT, an additional cohort of 3 participants will be evaluated for DLTs. If at most 1 out of 6 participants experience a DLT, the combination will be deemed safe. Should greater than or equal to 2 (≥2) out of 3 or 6 participants experience a DLT, the combination will be deemed unsafe, and accrual will be terminated. |
| Expansion: Composite complete remission rate defined as the proportion of patients with a complete remission (CR or CRi) | Three years from initiation of study | The primary objective of the expansion is to estimate the composite complete remission rate defined as the proportion of patients with a complete remission (CR or CRi) by the end of study treatment for each arm separately. |
Countries
United States
Contacts
CONTACTKittika Poonsombudlert, MD
PRINCIPAL_INVESTIGATORKittika Poonsombudlert, MD
University of Iowa
Outcome results
None listed