Clinical trial NCT06384261: A Study Comparing Venetoclax and Azacitidine Plus Cusatuzumab to Venetoclax and Azacitidine in Newly Diagnosed AML Ineligible for Intensive Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Lead sponsor: OncoVerity, Inc.
Sponsor class: INDUSTRY
First posted: 2024-04-25
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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?

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 compared to venetoclax and azacitidine in persons with newly diagnosed AML who are deemed ineligible for intensive chemotherapy.

Potential participants will be considered ineligible for intensive chemotherapy and, therefore, eligible for the study, if they meet the trial eligibility criteria. Potential 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.

The enrolled trial population will be enriched for participants with adverse risk features by enrolling adverse, intermediate, and favorable risk participants at a ratio of 3:1:1, respectively (i.e., 72 adverse risk, 24 intermediate risk, and 24 favorable risk participants will be enrolled). Enrolled participants will then be randomized 2:1 to either the experimental arm or the active comparator arm.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: From date of randomization until the date of death from any cause, assessed up to 5 years
Secondary outcomes:
measure: Complete Remission rate (CR)
timeFrame: From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
measure: Event-free survival (EFS)
timeFrame: 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
measure: Composite CR rate (CRc)
timeFrame: From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
measure: Rate of CRh and CRi
timeFrame: From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
measure: Duration of CR
timeFrame: From date of first CR to hematological relapse or death from any cause, assessed up to 5 years
measure: Time to first CR
timeFrame: From date of randomization to first occurrence of CR, assessed up to 3 years
measure: Rate of minimal residual disease (MRD) negativity in patients achieving CR, CRh, or CRi
timeFrame: From date of randomization to relapse or criteria for refractory disease are met, assessed up to 5 years
measure: Proportion of participants proceeding to hematopoietic stem cell transplantation (HSCT)
timeFrame: From date of randomization to date of HSCT, assessed up to 5 years
measure: OS in participants undergoing HSCT
timeFrame: From date of randomization to death from any cause, assessed up to 5 years
measure: Incidence of adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation
timeFrame: Signing of informed consent to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
measure: Incidence of dose modifications due to AEs
timeFrame: Randomization to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
measure: Number of participants with abnormal laboratory test results
timeFrame: Signing of informed consent to 30 days after the last dose of study treatment or until start of subsequent anti-AML therapy
measure: Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb)
timeFrame: From date of randomization to end of treatment, assessed up to 5 years
measure: Overall survival in subgroups of participants according to specified AML risk stratification models
timeFrame: From date of randomization to death from any cause, assessed up to 5 years
measure: Complete Remission rate
timeFrame: From date of randomization to relapse or criteria for refractory disease are met, assessed up to 3 years
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado Health - Anschutz Cancer Pavilion - Anschutz Medical Campus
state: Colorado
city: Orlando
country: United States
facility: AdventHealth Medical Group Blood &amp; Marrow Transplant at Orlando
state: Florida
city: Iowa City
country: United States
facility: The University of Iowa Hospitals & Clinics
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Norton Healthcare, Inc.
state: Kentucky
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: Hofstra/Northwell Health
state: New York
city: New York
country: United States
facility: Cornell University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest North Carolina
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Seattle
country: United States
facility: Fred Hutch Seattle Cancer Care Alliance
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisonsin
state: Wisconsin
city: Calgary
country: Canada
facility: Tom Baker Cancer Center-Alberta Health Services - University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital-Walter C Mackenzie Health Sciences Centre - University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre
state: British Columbia
city: London
country: Canada
facility: University of Western Ontario
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Saskatoon
country: Canada
facility: Saskatchewan Cancer Agency - Saskatoon Cancer Centre
state: Saskatchewan
city: Dusseldorf
country: Germany
facility: Marien Hospital Duesseldorf
city: Frankfurt
country: Germany
facility: Universitaetsklinik Frankfurt
city: Hannover
country: Germany
facility: Medizinische Hochschule Hanover, Hannover Medical School
city: Kiel
country: Germany
facility: Universitaetsklinik um Schleswig-Holstein, UKSH-Campus Kiel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Fribourg
country: Switzerland
facility: HFR Fribourg - Hopital Cantonal
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
Study officials:
References: