A Study Comparing Venetoclax and Azacitidine Plus Cusatuzumab to Venetoclax and Azacitidine in Newly Diagnosed AML Ineligible for Intensive Therapy

Multicenter, Open-label, Randomized, Phase 2 Study of Venetoclax and Azacitidine Plus Cusatuzumab Versus Venetoclax and Azacitidine Alone in Newly Diagnosed AML Patients Who Are Not Candidates for Intensive Therapy

The goal of this clinical trial is to learn if participants treated with the experimental drug cusatuzumab added to venetoclax and azacitidine works to treat acute myeloid leukemia (AML) compared to venetoclax and azacitidine. Venetoclax and azacitidine are drugs commonly used to treat AML in patients that are unable to receive chemotherapy to treat AML. The main question the clinical trial aims to answer is does cusatuzumab added to venetoclax and azacitidine prolong the length of time participants live compared to venetoclax and azacitidine?

Study Overview

• Status: Active, not recruiting
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: Azacitidine; Drug: Cusatuzumab; Drug: Venetoclax

Detailed Description

This is a randomized, open-label, multicenter, Phase 2 trial to evaluate the efficacy, safety, and pharmacodynamics of cusatuzumab in combination with venetoclax and azacitidine (VAC) compared to venetoclax and azacitidine (VA) in persons with newly diagnosed AML who are deemed ineligible for intensive chemotherapy. The trial will be conducted in 2 Parts. Part A will seek to randomize approximately 120 participants 2:1 to receive VAC or VA. Randomized participants will be stratified based on AML risk features (adverse, intermediate, and favorable risk). Part B will seek to include approximately 20 participants to receive an alternative dose of cusatuzumab in combination with VA in a non-randomized fashion.

Parts A and B will utilize the same eligibility criteria, study assessments, and treatment guidelines and procedures unless otherwise specified. Potential participants will be considered ineligible for intensive chemotherapy and, therefore, eligible for the study, if they meet the trial eligibility criteria and provide informed consent. Participants will undergo a diagnostic bone marrow biopsy and aspirate collected for pathology review, cytogenetics, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) analysis and other studies for confirmation of a diagnosis of AML and to define whether participants have adverse, intermediate, or favorable AML risk features.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Center-Alberta Health Services - University of Calgary
    • Edmonton, Alberta, Canada, T6G 2B7
      • Stollery Children's Hospital-Walter C Mackenzie Health Sciences Centre - University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre
  • Ontario
    • London, Ontario, Canada, N6A5W9
      • University of Western Ontario
    • Ottawa, Ontario, Canada, K1H8L6
      • The Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M5F 2M9
      • Princess Margaret Cancer Centre
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N4H4
      • Saskatchewan Cancer Agency - Saskatoon Cancer Centre
• Germany
  • Düsseldorf, Germany, 40479
    • Marien Hospital Duesseldorf
  • Frankfurt, Germany, 60560
    • Universitaetsklinik Frankfurt
  • Kiel, Germany, 24105
    • Universitaetsklinik um Schleswig-Holstein, UKSH-Campus Kiel
• Spain
  • Barcelona, Spain
    • Vall d'Hebron Institute of Oncology
  • Barcelona, Spain
    • Hospital De La Santa
  • Barcelona, Spain
    • Instituto Catalán de Oncología - Hospital Duran i Reynals
  • Pamplona, Spain
    • Universidad de Navarra - Clinica Universidad de Navarra
  • Salamanca, Spain
    • Hospital Universitario de Salamanca
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Bern
  • Fribourg, Switzerland, Switzerland
    • HFR Fribourg - Hôpital Cantonal
  • Sankt Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health - Anschutz Cancer Pavilion - Anschutz Medical Campus
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Comprehensive Cancer Center - Miami
    • Orlando, Florida, United States, 32804
      • AdventHealth Medical Group Blood & Marrow Transplant at Orlando
    • Tampa, Florida, United States, 33612
      • University of South Florida = Moffitt Cancer Center and Research Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa Hospitals & Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • Norton Healthcare, Inc.
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Lake Success, New York, United States, 11042
      • Hofstra/Northwell Health
    • New York, New York, United States, 10065
      • Cornell University
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest North Carolina
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Taussig Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch Seattle Cancer Care Alliance
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisonsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women ≥18 years old
• Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for the study and is willing to participate in the study
• Diagnosis of AML according to ICC 2022 (with the exclusion of MDS/AML with 10-19% blasts)
• Previously untreated AML except may have received emergency leukapheresis, hydroxyurea before study entry to control hyperleukocytosis

• Deemed unfit for intensive chemotherapy by meeting at least 1 of the following criteria:

  1. Participant is ≥75 years of age with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 OR

  2. Participant is ≥18 to 74 years of age and has any of the following comorbidities:

     1. ECOG performance status of 2 or 3
     2. Cardiac status including any one of the following: congestive heart failure requiring treatment or ejection fraction ≤50% or chronic stable angina
     3. Known history of diffusion capacity of lung for carbon monoxide (DLCO) ≤65% of forced expiratory volume in the first second (FEV1) ≤65%
     4. Creatinine clearance (CrCl) ≥15 mL/min to <45 mL/min
     5. Hepatic disorder with total bilirubin >1.5 to 3x the upper limit of normal (ULN)
     6. Any other comorbidity that the investigators determine to be incompatible with conventional intensive chemotherapy

• Adequate liver and renal function defined as:

  1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3xULN; for participants with leukemic infiltration of the liver (documented by biopsy or imaging), AST and ALT <5xULN is permitted
  2. Total bilirubin ≤1.5xULN, unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin. Participants who are <75 years of age may have a bilirubin up to 3xULN.
  3. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (by the Modification of Diet in Renal Disease [MDRD] formula). Participants who are <75 years of age may have an eGFR ≥15 mL/min/1.73 m2.
• Women of childbearing potential (WOCBP), defined as fertile women between menarche and post menopause unless permanently sterile, must have a negative highly sensitive serum β-human chorionic gonadotropin (β-hCG) or urine pregnancy test at screening

• Must be willing to use contraception as consistent with institutional guidelines regarding the use of contraceptive methods for participants participating in clinical studies

  1. WOCBP must agree to adhere to the following birth control measures while receiving study treatment continuing to 3 months after the last dose of study drug:

     1. Must be practicing a highly effective method of birth control (failure rate of <1% per year when used consistently and correctly) as determined by institutional standards
     2. Must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
     3. Must not be breastfeeding and not planning to become pregnant

  2. Male participants who are sexually active with WOCBP, and male partners of study participants who are WOCBP, and who are not surgically or otherwise sterile must agree to adhere to the following birth control measures while receiving study treatment and for 3 months after the last dose of study drug:

     1. Must agree to use a barrier method of birth control (e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam, gel, film, cream, or suppository)
     2. Must not donate sperm
     3. Must no plan to father a child

• Participants with HIV infection are eligible for the trial if the following criteria are met:

  1. CD4+ T-cell count ≥200 cells/μL
  2. No prior history of AIDS-defining opportunistic infection within the past 12 months
  3. Receiving treatment with antiretroviral therapy
  4. Undetectable viral load within 6 months of screening

Exclusion Criteria:

• Any prior treatment for AML (except those outlined in inclusion criterion #4)
• Participant has received a hypomethylating agent (HMA) or venetoclax for MDS or myeloproliferative neoplasm
• Leukemic involvement in the central nervous system
• Participants with acute promyelocytic leukemia (APL)
• ECOG performance status of 4 for participants 18 to 74 years of age and ECOG performance status of 3 or 4 for participants ≥75 years of age
• Use of immune suppressive agents ≤4 weeks before the first administration of cusatuzumab. Participants may be included if free of systemic corticosteroids >5 days before the first administration of cusatuzumab with the exception of corticosteroids at physiologic replacement doses.
• Received a live, attenuated vaccine within 4 weeks prior to initiation of study drug

• Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Exceptions to this exclusion criterion include the following:

  1. Nonmelanoma skin cancer treated within the last 24 months that is considered completely cured
  2. Adequately treated breast lobular carcinoma in situ and breast ductal carcinoma in situ
  3. Adequately treated cervical carcinoma in situ and breast ductal carcinoma in situ
  4. History of localized breast cancer and receiving anti-hormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen depravation therapy
  5. A malignancy that is considered cured with minimal risk of recurrence
• Any active systemic infection
• History of prior HSCT (allogeneic or autologous transplants)

• Active hepatitis B or C infection or other clinically active liver diseases ad defined below:

  1. Seropositivity for hepatitis B is defined by a positive test for hepatitis B surface antigen (HBsAg)

  2. Participants with resolved infection (i.e., participants who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.

     • Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
  3. Active hepatitis C infection as defined by being positive for a nucleic acid test for hepatitis C virus (HCV) RNA
• Congestive hear failure severity that is New York Heart Association Class III or IV
• Unstable angina
• Known allergies, hypersensitivity, or intolerance to cusatuzumab, venetoclax, or azacitidine or their excipients (e.g., mannitol, an excipient of azacitidine)
• Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function
• Any condition for which, in the investigator's opinion, participation would not be in the best interest of the participant (e.g., compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments
• Major surgery (e.g., requiring general anesthesia) ≤4 weeks prior to initiation of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Cusatuzumab in combination with venetoclax and azacitidine; Cusatuzumab 20 mg/kg administered intravenously on days 3 and 17 in combination with venetoclax administered orally up to 400 mg once daily and azacitidine 75 mg/m^2 administered subcutaneously or intravenously once daily for 7 days of a 28 day cycle	Drug: Azacitidine; Hypomethylating agent; Drug: Cusatuzumab; CD70 monoclonal antibody; Other Names: OV-1001; Drug: Venetoclax; BCL-2 inhibitor
Active Comparator: Part A: Venetoclax in combination with azacitidine; Venetoclax administered orally up to 400 mg once daily and azacitidine 75 mg/m^2 administered subcutaneously or intravenously once daily for 7 days of a 28 day cycle	Drug: Azacitidine; Hypomethylating agent; Drug: Venetoclax; BCL-2 inhibitor
Experimental: Part B: Cusatuzumab in combination with venetoclax and azacitidine; Cusatuzumab 10 mg/kg administered intravenously on days 3 and 17 for cycle 1 and cycle 2 and 20 mg/kg intravenously on days 3 and 17 for cycle 3 and beyond in combination with venetoclax administered orally up to 400 mg once daily and azacitidine 75 mg/m^2 administered subcutaneously or intravenously once daily for 7 days of a 28 day cycle	Drug: Azacitidine; Hypomethylating agent; Drug: Cusatuzumab; CD70 monoclonal antibody; Other Names: OV-1001; Drug: Venetoclax; BCL-2 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	In all randomized participants	From date of randomization until the date of death from any cause, assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission rate (CR)	Proportion of participants achieving CR per the European LeukemiaNet (ELN) 2022 criteria	From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
Event-free survival (EFS)	Defined per ELN 2022 criteria	From date of randomization to date of treatment failure, hematologic relapse from CR/CRh/CRi or death from any cause, assessed up to 5 years
Composite CR rate (CRc)	Sum of CR+CRh+CRi rate. CRh is defined as CR with partial hematologic recovery. CRi is defined as CR with incomplete hematologic recovery. Defined per ELN 2022 criteria.	From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
Rate of CRh and CRi	Defined per ELN 2022 criteria	From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
Duration of CR	Defined per ELN 2022 criteria	From date of first CR to hematological relapse or death from any cause, assessed up to 5 years
Time to first CR	Defined per ELN 2022 criteria	From date of randomization to first occurrence of CR, assessed up to 3 years
Rate of minimal residual disease (MRD) negativity in patients achieving CR, CRh, or CRi	Defined per ELN 2022 criteria and guidelines for testing	From date of randomization to relapse or criteria for refractory disease are met, assessed up to 5 years
Proportion of participants proceeding to hematopoietic stem cell transplantation (HSCT)		From date of randomization to date of HSCT, assessed up to 5 years
OS in participants undergoing HSCT		From date of randomization to death from any cause, assessed up to 5 years
Incidence of adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation	Per CTCAE criteria	Signing of informed consent to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
Incidence of dose modifications due to AEs	Includes interruptions and/or delays	Randomization to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
Number of participants with abnormal laboratory test results	Findings will be summarized	Signing of informed consent to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb)		From date of randomization to end of treatment, assessed up to 5 years
Overall survival in subgroups of participants according to specified AML risk stratification models		From date of randomization to death from any cause, assessed up to 5 years
Complete Remission rate	In subgroups of participants according to specified AML risk stratification models. CR defined per ELN 2022 criteria.	From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years

Collaborators and Investigators

• Sponsor: OncoVerity, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 22, 2024
• First Posted (Actual): April 25, 2024

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax
• Other Study ID Numbers: OV-AML-1231; 2024-510991-19-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No