Phase I/II Clinical Trial of Proteasome Inhibitor in Combination With CPX-351 for the Treatment of Newly-Diagnosed TP53-mutated Acute Myeloid Leukemia (AML)

Phase 1

Not yet recruiting

• Conditions: Acute Myeloid Leukemia; TP53
• Interventions: Drug: Bortezomib; Drug: CPX-351

• Registration Number: NCT07008638
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

This is a Phase I/II study evaluating safety and efficacy of proteasome inhibitor (bortezomib) in combination with CPX-351 (liposomal daunorubicin and cytarabine) for the treatment of newly-diagnosed TP53-mutated acute myeloid leukemia (TP53m AML).

The primary endpoint of the study is to define safety/tolerability (phase I) and preliminary efficacy profile (phase II) of the treatment. The secondary endpoints of interest are complete remission (CR) rate, detectable minimal residual disease (MRD) status, overall response rate (ORR), rate of allogeneic hematopoietic cell transplantation (allo-HCT), treatment-related mortality (TRM), overall survival (OS), achievement of complete remission anytime in 1 year, and disease-free survival (DFS) at 1 year and 2 years. All the patient outcomes assessments will be performed as part of standard-of-care AML management.

The hypothesis is the combination of bortezomib and CPX-351 will have an acceptable safety profile in this patient population based on the data from previous studies. The treatment will attenuate Nuclear Factor kB pathway activation in these cells and eradicate TP53m leukemia stem cells (LSC) leading to increased response rate and survival in these patients.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-29
• Study First Submitted QC: 2025-06-05
• Last Update Submitted: 2025-06-05
• Study First Posted: 2025-06-06
• Last Update Posted: 2025-06-06
• Study Start: 2025-07-01
• Primary Completion: 2027-12-30
• Study Completion: 2028-01-27

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

• Adult (age ≥ 18 years at time of consent)
• Have not received any systemic chemotherapy for the treatment of AML. Use of hydroxyurea and leukapheresis to control excess peripheral blasts is permissible. WBC < 25,000 to initiate bortezomib, must reach this threshold by day 7 of CPX-351.
• Karnofsky performance status (KPS) ≥ 70
• Adequate renal, hepatic and cardiac function defined as
• Renal: An estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2
• Hepatic: AST and ALT ≤3 x ULN, ALP ≤2.5 x ULN, and total bilirubin ≤1.5 x ULN. (exception for Gilbert's syndrome or leukemic infiltration of liver)
• Cardiac: New York Heart Association (NYHA) Class I or II, left ventricular ejection fraction > 50% by echocardiogram, MUGA or cardiac MRI
• Sexually active couples of childbearing potential must agree to use effective contraception or abstinence during treatment and for at least 7 months after the final dose of study drug
• 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
• Active central nervous system malignancy or symptoms of CNS involvement
• Symptomatic extramedullary disease
• Known history of uncontrolled HIV or active hepatitis B or active hepatitis C infection
• 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
• Participants for whom administration of CPX-351 would exceed their lifetime cumulative daunorubicin exposure limit of 550 mg/m2 (or 400 mg/m2 in patients with prior chest radiation) or equivalent anthracycline dose.
• Pregnant or breastfeeding, or planning pregnancy within 3 months after the treatment completion

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Dose Level -1	Bortezomib	Bortezomib 0.7mg/m2 in combination with CPX-351
Phase 1: Dose Level -1	CPX-351	Bortezomib 0.7mg/m2 in combination with CPX-351
Phase 1: Dose Level 2	Bortezomib	Bortezomib 1mg/m2 in combination with CPX-351
Phase 1: Dose Level 2	CPX-351	Bortezomib 1mg/m2 in combination with CPX-351
Phase 1: Dose Level 3	Bortezomib	Bortezomib 1.3 mg/m2 in combination with CPX-351
Phase 1: Dose Level 3	CPX-351	Bortezomib 1.3 mg/m2 in combination with CPX-351
Phase 1: Dose Level 4	Bortezomib	Bortezomib 1.5 mg/m2 in combination with CPX-351
Phase 1: Dose Level 4	CPX-351	Bortezomib 1.5 mg/m2 in combination with CPX-351
Phase 2	Bortezomib	Maximum tolerated dose of Bortezomib in combination with CPX-351
Phase 2	CPX-351	Maximum tolerated dose of Bortezomib in combination with CPX-351

Primary Outcome Measures

Name	Time	Method
Percentage of Participants with Complete Response	2 years	To evaluate the CR rate of bortezomib + CPX-351 for the treatment of TP53m AML.
Determine Maximum Tolerated Dose	1 year

Secondary Outcome Measures

Name	Time	Method
Determine Overall Response Rate	2 years	Evaluate ORR (CR+CRi) after treatment
Average rate of allo-HCT among participants	2 years	Evaluate the rate of allo-HCT within 2 years among patients who received treatment
Overall Survival	2 year	estimate 1-year and 2-year OS, defined as the time from cohort assignment to death from any cause
Average time to relapse	2 year	• To estimate time to relapse, defined as the time from cohort assignment to disease recurrence