AOH1996 Alone or in Combination With Venetoclax With or Without Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia

Phase 1

Not yet recruiting

• Conditions: Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia
• Interventions: Procedure: Biospecimen Collection; Drug: Azacitidine; Procedure: Bone Marrow Aspiration; Drug: PCNA Inhibitor AOH1996; Drug: Venetoclax

• Registration Number: NCT06763341
• Lead Sponsor: City of Hope Medical Center

Brief Summary

This phase I trial tests safety, side effects, and best dose of AOH1996 alone or in combination with venetoclax with or without azacitidine for the treatment of patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or AML that has not responded to previous treatment (refractory). AOH1996 is in a class of medications called PCNA inhibitors. It inhibits cancer growth and induces deoxyribonucleic acid (DNA) damage. This may help keep cancer cells from growing and damage cancer cell DNA. 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. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. Giving AOH1996 alone or in combination with venetoclax with or without azacitidine may be safe, tolerable and/or effective in treating patients with AML.

Detailed Description

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of PCNA inhibitor AOH1996 (AOH1996) alone or in combination with the BCL2 inhibitor/BH3-mimetic venetoclax or venetoclax plus the hypomethylating agent azacitidine in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).

II. Determine the maximum tolerated planned dose (MTPD) and recommended phase 2 dose (RP2D) of AOH1996 as monotherapy or when combined with venetoclax ± azacitidine.

SECONDARY OBJECTIVES:

I. Evaluate the anti-leukemic activity, as assessed by overall response rate (\[ORR\]: complete response \[CR\]+CR with incomplete hematologic recovery rate \[CRi\]+CR with partial hematologic recovery \[CRh\]+partial response \[PR\]) within the first 28 days (cycle 1).

II. Evaluate the anti-leukemic activity, as assessed by complete remission (CR+CRi+CRh), overall response (ORR: CR+CRi+CRh+PR) and minimal residual disease (MRD)- rate and duration over the study period.

III. Estimate overall survival (OS), progression-free survival (PFS) and duration of response (DOR) rate at 6 months and 1 year.

IV. Describe the plasma pharmacokinetics (PK) of AOH1996 alone or when given in combination with venetoclax or venetoclax plus azacitidine.

V. Describe the plasma PK of venetoclax when given in combination with AOH or AOH plus azacitidine.

EXPLORATORY OBJECTIVES:

I. Determine biomarkers that may be predictive of AOH1996 activity alone or in combination with venetoclax +/- azacitidine.

II. Study the impact of AOH1996 alone or in combination with venetoclax +/- azacitidine on altered mitochondrial metabolism and dynamics.

III. Determine pharmacodynamics parameters (alteration of OPA1) of AOH1996 alone or in combination with venetoclax +/- azacitidine.

IV. Explore the potential relationship between changes in BH3 protein expression profiles (pre- and post-treatment) and response.

OUTLINE: This is a dose-escalation study of AOH1996 followed by a dose-expansion study. Patients are assigned to 1 of 3 cohorts.

COHORT I: Patients receive AOH1996 orally (PO) twice daily (BID) on days 1 - 28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.

COHORT II: Patients receive AOH1996 PO BID on days 1 - 28 and venetoclax PO once daily (QD) on days 1 - 21 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.

COHORT III: Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine intravenously (IV) over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 30 days and up to one year.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-02
• Study First Submitted QC: 2025-01-02
• Last Update Submitted: 2025-01-02
• Study First Posted: 2025-01-08
• Last Update Posted: 2025-01-08
• Study Start: 2025-08-16
• Primary Completion: 2027-01-16
• Study Completion: 2027-01-16

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Life expectancy > 3 months

• Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease who have failed treatment with, or are ineligible for, available therapies known to be effective for treatment of their AML

  • Patients with extramedullary disease may be included if they also have marrow involvement
  • Patients with acute promyelocytic leukemia (APL) will not be eligible

• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy

• Ability to swallow pills

• White blood cell (WBC) ≤ 25 x 10^9/L prior to initiation of study therapy. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required (within 14 days prior to day 1 of protocol therapy)

• Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (within 14 days prior to day 1 of protocol therapy)

• Aspartate aminotransferase (AST) =< 3.0 x ULN (within 14 days prior to day 1 of protocol therapy)

• Alanine aminotransferase (ALT) =< 3.0 x ULN (within 14 days prior to day 1 of protocol therapy)

• Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 14 days prior to day 1 of protocol therapy)

• International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

• Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

• Corrected QT interval (QTc)F ≤ 480 ms based on Fridericia's formula

  • Note: To be performed within 28 days prior to day 1 of protocol therapy

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 14 days prior to day 1 of protocol therapy)

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential* to use an effective method of birth control (nonhormonal) or abstain from heterosexual activity for the course of the study through at least 4 months (females) and 7 months (males) after the last dose of protocol therapy

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria

• Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol therapy. Patients who have stopped calcineurin inhibitors (CNI) must be off CNIs for at least 2 weeks prior to day 1 of protocol therapy

• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days prior to day 1 of protocol therapy with the following exception of hydroxyurea which is allowed prior to treatment and through cycle 1 for control of rapidly progressing leukemia

• Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior to day 1 of protocol therapy

• Strong inhibitors or inducers of CYP2C9 within 7 days prior to day 1 of protocol therapy

• Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 3 days prior to initiation of and during study treatment

• Systemic steroid therapy > 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 14 days. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted

• Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment

• Patients with blast phase chronic myeloid leukemia (CML)

• Patients with translocation (t)(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)

• Active central nervous system (CNS) disease

• Active graft versus (vs) host disease (GVHD)

• Unstable cardiac disease as defined by one of the following:

  • Cardiac events such as myocardial infarction (MI) within the past 6 months
  • Uncontrolled atrial fibrillation or hypertension

• No measurable disease in the bone marrow

• Gastrointestinal disorder that interferes with oral drug absorption such as malabsorption syndrome

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

• Uncontrolled active infection

• Clinically significant uncontrolled illness

• Diagnosis of Gilbert's disease

• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort I (AOH1996)	Biospecimen Collection	Patients receive AOH1996 PO BID on days 1 - 28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort I (AOH1996)	Bone Marrow Aspiration	Patients receive AOH1996 PO BID on days 1 - 28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort I (AOH1996)	PCNA Inhibitor AOH1996	Patients receive AOH1996 PO BID on days 1 - 28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort II (AOH1996, venetoclax)	Biospecimen Collection	Patients receive AOH1996 PO BID on days 1 - 28 and venetoclax PO QD on days 1 - 21 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort II (AOH1996, venetoclax)	Bone Marrow Aspiration	Patients receive AOH1996 PO BID on days 1 - 28 and venetoclax PO QD on days 1 - 21 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort II (AOH1996, venetoclax)	PCNA Inhibitor AOH1996	Patients receive AOH1996 PO BID on days 1 - 28 and venetoclax PO QD on days 1 - 21 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort II (AOH1996, venetoclax)	Venetoclax	Patients receive AOH1996 PO BID on days 1 - 28 and venetoclax PO QD on days 1 - 21 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort III (AOH1996, venetoclax, azacitidine)	Azacitidine	Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine IV over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort III (AOH1996, venetoclax, azacitidine)	Biospecimen Collection	Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine IV over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort III (AOH1996, venetoclax, azacitidine)	Bone Marrow Aspiration	Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine IV over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort III (AOH1996, venetoclax, azacitidine)	PCNA Inhibitor AOH1996	Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine IV over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.
Cohort III (AOH1996, venetoclax, azacitidine)	Venetoclax	Patients receive AOH1996 PO BID on days 1 - 28, venetoclax PO QD on days 1 - 21 and azacitidine IV over 10 to 40 minutes on days 1 - 7 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi by the end of cycle 4 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.

Primary Outcome Measures

Name	Time	Method
Incidence of dose limiting toxicity (DLT)	During cycle 1 (Cycle length = 28 days)	Will evaluate for DLTs in patients that receive at least 75% of the planned dose(s) for each agent as per dose level assignment. In-evaluable subjects will be replaced. Will grade toxicity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Incidence of adverse events	Up to 2 years	Will evaluate toxicity in patients that receive any agent as part of the combination therapy. Will grade toxicity according to the NCI CTCAE v5.0. Will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

Secondary Outcome Measures

Name	Time	Method
First response	From start of treatment to attainment of first documented CR/CRi/CRh/morphologic leukemia-free state/partial response, assessed up to 1 year	Will evaluate time to first response.
Response	Up to 1 year	Will evaluate in all eligible patients with a baseline assessment who start therapy (i.e., receiving at least one dose of a study drug). These patients will be considered in the primary analysis of response rate as the denominator, with number of responders in the numerator. Patients will have their response classified according European LeukemiaNet criteria of Dohner and others (2022). Response rates will also be explored based on number/type of prior therapy(ies).
Minimal residual disease (MRD) status	Up to 1 year	Will be determined by conventional care flow cytometry assay performed locally using a 0.01% blast threshold for positivity. Will report MRD over the study period using both descriptive statistics and graphical methods.
Complete response (CR)	From start of treatment to attainment of CR/CR with incomplete hematologic recovery rate (CRi)/CR with partial hematologic recovery (CRh), assessed up to 1 year	Will evaluate time to CR. Rates and 95% Clopper-Pearson binomial confidence interval will be calculated for the complete remission rate (CR/CRi/CRh). Response rates will also be explored based on number/type of prior therapy(ies).
Duration of response (DOR)	Time interval from the date of first documented response (CR+CRi+CRh) to the date of documented disease relapse or death whichever occurs first, assessed up to 2 years	Will evaluate DOR. Will be estimated using the product-limit method of Kaplan and Meier.
Overall survival (OS)	Time interval from start of study treatment to the date of death from any cause, assessed up to 2 years	Will evaluate OS. OS will be censored at last follow-up if patients are known to be alive. Will be estimated using the product-limit method of Kaplan and Meier.
Progression-free survival (PFS)	Time interval from start of study treatment to the date of first documented disease relapse/progression or death from any cause, whichever occurs first, assessed up to 2 years	Will evaluate PFS. PFS will be censored at last follow-up if patients are alive and relapse/progression-free. Will be estimated using the product-limit method of Kaplan and Meier.
AOH1996 in plasma	0-2 hours pre-dose and 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 24 hours post-dose on days 1 and 8 of cycle 1 (Cycle length= 28 days)	Will evaluate levels of AOH1996 in plasma.
Venetoclax in plasma	0-2 hours pre-dose and 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 24 hours post-dose on days 1 and 8 of cycle 1 (Cycle length= 28 days)	Will evaluate levels of venetoclax in plasma.

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States