Bortezomib in Combination with CPX-351 for the Treatment of Newly-Diagnosed TP53- Mutated Acute Myeloid Leukemia

Inclusion Criteria

• Documented diagnosis of TP53m AML based on European LeukemiaNet (ELN) classification 2022 with TP53 gene mutation documented by next-generation sequencing (NGS) OR p53 overexpression by immunohistochemistry (IHC). AML with TP53 mutations that are considered pathological or likely pathological will qualify as eligible for this trial. TP53 mutations considered benign or likely benign will not be sufficient eligible for this trial. The classification of TP53 mutations as pathological, likely pathological, likely benign, or benign will be made by the University of Minnesota expert molecular pathologists as part of routine clinical assessments. The molecular pathologists use the following databases to determine TP53 mutation classification: The TP53 Database and the OncoKB database from the Memorial Sloan Kettering Cancer Center
• Have not received any systemic chemotherapy for the treatment of AML. Use of hydroxyurea to control excess peripheral blasts is permissible. White blood cells (WBC) must be < 25,000 to initiate bortezomib, participant must reach this threshold by day 7 of CPX-351 administration
• Adult (age ≥ 18 years at time of consent)
• Karnofsky performance status (KPS) ≥ 70
• An estimated glomerular filtration rate ≥ 30 mL/min/1.73 m^2
• Aspartate aminotransferase (AST) within 3 x institutional normal range
• Alanine aminotransferase (ALT) within 3 x institutional normal range
• Alkaline phosphatase within 3 x institutional normal range
• Total bilirubin within 3 x institutional normal range and bilirubin within 1.5 > upper limit or normal (ULN) unless participant has known Gilbert’s syndrome or leukemic infiltrates of liver
• New York Heart Association (NYHA) class I or II
• Left ventricular ejection fraction > 50% by echocardiogram, MUGA or cardiac MRI
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 7 months after the last dose of study drug. Non-childbearing is defined as > 1 year post-menopausal or surgically sterilized * Examples of highly effective birth control methods include but are not limited to the following: ** Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm) ** Oral contraceptive pills ** Depot or injectable birth control ** Intrauterine device (IUD) ** Transdermal contraceptive patch ** Vaginal contraceptive ring ** Contraceptive implants * Note: Rhythm method or abstinence alone is not considered an adequate method of contraception
• Provides voluntary written consent before the performance of any study related activities not part of standard of care

Exclusion Criteria

• Received systemic chemotherapy for the treatment of AML
• Bi-phenotypic acute leukemia or mixed lineage leukemia, acute promyelocytic leukemia
• Uncontrolled HIV, hepatitis B or hepatitis C * HIV patients must remain on appropriate antiviral regimen and be followed by their treating physician for HIV while on active treatment * Patients with hepatitis B or hepatitis C must follow appropriate antiviral regimen to completion on active treatment
• Has any of the following cardiac abnormalities: * Symptomatic congestive heart failure * Myocardial infarction less than or equal to 6 months prior to enrollment * Unstable angina pectoris * Serious uncontrolled cardiac arrhythmia
• Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Potential participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis
• Pregnant or breastfeeding, or planning pregnancy within 3 months after the treatment completion. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment
• Active uncontrolled systemic infection. Participants receiving treatment for infection are permissible
• Persons with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of cycle 1 day 1. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Known allergy to any of the study components
• Participants for whom administration of CPX-351 would exceed their lifetime cumulative daunorubicin exposure limit of 550 mg/m^2 (or 400 mg/m^2 in patients with prior chest radiation), or equivalent anthracycline dose
• Psychiatric illness/social situations that, in the judgement of the enrolling investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study