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

Leukemia, Myeloid, Acute Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06384261
• Other study ID #: OV-AML-1231
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 2024
• Est. completion date: June 2027

Study information

• Verified date: April 2024
• Source: OncoVerity, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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?

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: June 2027
• Est. primary completion date: January 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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, and/or 1 dose of 1 to 2 g/m2 cytarabine 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 (by the Modification of Diet in Renal Disease [MDRD] formula). Participants who are <75 years of age may have an eGFR =15 mL/min.

• Women of childbearing potential (WOCBP), defined as fertile women between menarche and post menopause unless permanently sterile, must have a negative highly sensitive serum ß-human chorionic gonadotropin (ß-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 or myelodysplastic syndrome (MDS) (except those outlined in inclusion criterion #4)
• Participant has received a hypomethylating agent (HMA) 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
• 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

Related Conditions & MeSH terms

• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Cusatuzumab
CD70 monoclonal antibody
• Venetoclax
BCL-2 inhibitor
• Azacitidine
Hypomethylating agent

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
OncoVerity, Inc.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	In all randomized participants	From date of randomization until the date of death from any cause, assessed up to 5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to first CR	Defined per ELN 2022 criteria	From date of randomization to first occurrence of CR, assessed up to 3 years
Secondary	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
Secondary	Proportion of participants proceeding to hematopoietic stem cell transplantation (HSCT)		From date of randomization to date of HSCT, assessed up to 5 years
Secondary	OS in participants undergoing HSCT		From date of randomization to death from any cause, assessed up to 5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb)		From date of randomization to end of treatment, assessed up to 5 years
Secondary	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
Secondary	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