Phase 2 Evaluation of Cusatuzumab and Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy
- Trial ID
- 2024-513283-26-00
- Protocol
- CULM20236
- Sponsor
- OncoVerity Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of cusatuzumab in combination with azacitidine in patients with newly diagnosed **Acute Myeloid Leukemia** (AML) who are not eligible for intensive chemotherapy. This is clinically relevant as it aims to provide an alternative treatment option for patients who cannot undergo standard intensive chemotherapy, potentially improving outcomes in this patient population.
Secondary objectives include:
- Determining various response types such as complete response (CR), CR with incomplete recovery (CRi), CR with partial hematological recovery (CRh), CR without minimal residual disease (CRMRD-), morphologic leukemia-free state (MLFS), partial response (PR), stable disease, relapse after CR, CRi, CRh, and progressive disease.
- Assessing time to response and duration of response.
- Determining transfusion independence.
- Assessing the safety profile of cusatuzumab in combination with azacitidine.
- Evaluating the pharmacokinetics of cusatuzumab alone and in combination with azacitidine.
- Assessing the immunogenicity of cusatuzumab alone and in combination with azacitidine.
Participants
The clinical trial involves a total of **64 participants** diagnosed with **Acute Myeloid Leukemia** (AML) who have not previously received treatment and are ineligible for intensive chemotherapy. The study population includes both male and female subjects aged **18 years and older**, with a focus on those **75 years and older** or younger individuals with specific comorbidities that preclude intensive chemotherapy. Participants were selected based on their diagnosis of AML according to WHO 2016 criteria and their inability to undergo intensive chemotherapy due to factors such as severe cardiac or pulmonary comorbidities, moderate hepatic impairment, or reduced creatinine clearance. The trial also includes individuals with an **ECOG Performance Status** score of 0, 1, or 2. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific reproductive health guidelines during and after the study. The trial population is considered vulnerable, reflecting the serious nature of the disease and the specific health challenges faced by the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **cusatuzumab** in combination with **azacitidine** in patients with newly diagnosed **acute myeloid leukemia** (AML) who are not candidates for intensive chemotherapy. This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to last until May 2025, with recruitment having commenced in March 2020. Participants will be involved in the study for a maximum treatment period of 8 months, with the possibility of early termination if they experience severe adverse events or if the investigator deems it necessary for their safety.
The study involves a series of visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, comorbidities, and laboratory values. Participants must be at least 18 years old and meet specific health criteria to be included. Following the screening, participants will undergo regular follow-up visits to monitor their response to treatment and any adverse effects. These visits will include assessments of complete response rates, overall response rates, and safety profiles. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted to assess the primary and secondary endpoints, including the complete response rate per ELN 2017 criteria and overall response rate.
Participants will receive **cusatuzumab** as a concentrate for solution for infusion and **azacitidine** as a powder for suspension or solution for injection, administered via intravenous or subcutaneous routes. The study aims to determine the complete response rate and other secondary endpoints such as the rate of CRh, CRi, and overall response rate. The trial will also evaluate the safety profile, pharmacokinetics, and immunogenicity of the treatment regimen. Conditions that may lead to early termination include severe adverse events or any situation where the investigator believes continued participation is not in the participant's best interest.
Treatment
The clinical trial involves the administration of **Cusatuzumab**, a **concentrate for solution for infusion**. This experimental medication is a humanized defucosylated anti-CD70 monoclonal IgG1 antibody, also known by the synonym ARGX-110. Cusatuzumab is administered via **intravenous use**. The dosing regimen specifies a maximum daily dose of 20 mg/kg, with a total maximum dose of 320 mg/kg over a treatment period of 8 weeks. The medication is not formulated for pediatric use and is designated as an orphan drug under the identifier EU/3/20/2265. The sponsor product code for Cusatuzumab is OV-1001, and it is developed by Oncoverity Inc.
In addition to the experimental treatment, the study includes the administration of **Azacitidine**, which is provided in two pharmaceutical forms: **powder for suspension for injection** and **powder for solution for injection**. Azacitidine is a chemical-origin medication used as a comparator treatment in this trial. It is administered either via **subcutaneous use** or **intravenous use**, depending on the formulation. The dosing schedule for Azacitidine involves a maximum daily dose of 75 mg/m², with a total maximum dose of 4200 mg/m² over an 8-week treatment period. Azacitidine is not a pediatric formulation and does not have orphan drug status in this study.
Efficacy
The efficacy of the investigational combination of **cusatuzumab** and azacitidine in patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy will be assessed through a series of predefined endpoints. The primary endpoint is the complete response (CR) rate as per the European LeukemiaNet (ELN) 2017 criteria. Secondary endpoints include the rate of complete response with partial hematologic recovery (CRh), the combined rate of CR and CRh, the rate of complete response with incomplete hematologic recovery (CRi), and the overall response rate (ORR), which encompasses CR, CRh, and CRi. Additional secondary endpoints involve the rate of CR without minimal residual disease (MRD), the rate of MRD negativity among participants achieving CR, CRh, CRi, or morphologic leukemia-free state (MLFS), and the time to response, defined as the time from randomization or enrollment to achieving the first response of CR, CRh, or CRi. The duration of response, transfusion independence, safety profile of adverse events (AEs) and serious adverse events (SAEs), pharmacokinetics, and immunogenicity through anti-drug antibody testing are also evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥18 years of age
- Criterion modified per Amendment 1 2.1. AML according to WHO 2016 criteria and fulfilling all of the following criteria that defines those who are "not candidates for intensive chemotherapy": ● ≥75 years of age or ● <75 years of age with of at least one of the following comorbidities: o Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 o Severe cardiac comorbidity defined as congestive heart failure or ejection fraction ≤50% o Severe pulmonary comorbidity defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected, or forced expiratory volume in 1 second (FEV1) ≤65% of expected or dyspnea at rest requiring oxygen o Moderate hepatic impairment defined according to National Cancer Institute (NCI) organ dysfunction classification criteria (total bilirubin ≥1.5 up to 3 times upper limit of normal [ULN]) o Creatinine clearance <45 mL/ min/1.73 m² (by MDRD formula) o Comorbidity that, in the Investigator's opinion, makes the patient unsuitable for intensive chemotherapy and must be documented and approved by the Sponsor before randomization
- Criterion numbering modified per Amendment 1 3.1. De novo or secondary AML;
- Criterion modified per Amendment 1 4.1. Previously untreated AML (except: emergency leukapheresis, hydroxyurea, and /or 1 dose of cytarabine [eg, 1-2g/m^2] during the screening phase to control hyperleukocytosis. Theses treatments mst be discontinued ≥ 24 hours prior to start of study drug). Empiric all trans retinoic acid (ATRA) treatment for presumed acute promyelocytic leukemia (APL) is permited but APL mus be ruled out and ATRA mus be discontinued ≥ 24 hours prior to the start of the study drug;
- Criterion numbering modified per Amendment 1 5.1. Not eligible for an allogeneic hematopoietic stem cell transplantation.
- Criterion numbering modified per Amendment 1 6.1. ECOG Performance Status score of 0, 1 or 2.
- Criterion numbering modified per Amendment 1 7.1. The following clinical laboratory values at screening: ● Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 times ULN; for participants with leukemic infiltration of the liver (documented by biopsy or imaging), AST and ALT <5 times ULN is permitted ● Total bilirubin ≤ 3 times ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin or in case of liver infiltration by AML (documented by biopsy or imaging) serum total bilirubin <5 times ULN ● Creatinine Clearance >30 mL/min (by MDRD formula)
- Criterion numbering modified per Amendment 1 8.1. A woman must be either: ● Not of childbearing potential: postmenopausal (>45 years of age with amenorrhea for at least 12 months); ● Of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in the clinical study while receiving study tratment and for at least 3 months after the last dose of study treatment. A woman of childbearing potential must have a negative highly-sensitive serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening. A woman fo childbearing potential must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study treatment and for 3 months after the last dose of study treatment. Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described above.
- Criterion modified per Amendment 1 9.1. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, 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/suppository for at least 3 months after last study treatment. ● Must agree to not donate sperm during the study treatment and for 3 months after the last dose of study treatment. ● Not plan to father a chld during the study treatment and for 3 months after the last dose os study treatment.
- Criterion modified per Amendment 10.1. Must sign and informed consent form (ICF) indicating that he or she (or their legally acceptable representative) understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Exclusion Criteria
- Criterion modified per Amendment 1 1.1. Acute promyelocytic leukemia
- Leukemic involvement or clinical symptoms of leukemic involvement of the central nervous system.
- Criterion modified per Amendment 1 3.1. Use of immune suppressive agents for the past 4 weeks before the first administration of cusatuzumab on Cycle 1 Day 3. For regular use of systemic corticosteroids, participants may only be included if free of systemic corticosteroids for a minimum of 5 days before the first administration of cusatuzumab. Treatment of adrenal insufficiency with physiologic replacement doses of corticosteroids are allowed.
- Prior treatment with a hypomethylating agent for treatment of AML or MDS
- Criterion modified per Amendment 1 5.1. Active malignancies (ie, progressing or requiring treatment in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: ● Non-melanoma skin cancer treated within the last 24 months that is considered completely cured ● Adequately treated breast lobular carcinoma in situ and breast ductal carcinoma in situ ● Adequately treated cervical carcinoma in situ without evidence of disease ● History of localized breast cancer and receiving antihormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy ● Malignancy that is considered cured with minimal risk of recurrence
- Criterion modified per Amendment 1 6.1. Any active systemic infection
- Criterion modified per Amendment 1 7.1. A history of human immunodeficiency virus (HIV) antibody positive or tests positive for HIV at screening
- Criterion modified per Amendment 1 8.1. Active hepatitis B or C infection or other clinically active liver disease Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (ie, 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 real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR. Known Hepatitis C infection or positive serologic testing for Hepatitis C (anti-HCV antibody)
- New York Heart Association Class IV heart failure or ongoing unstable angina
- Known allergies, hypersensitivity, or intolerance to cusatuzumab or azacitidine or its excipients (ie, mannitol, an excipient of azacitidine).
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments.
- Criterion modified per Amendment 1 12.1. Major surgery, (eg, requiring general anesthesia) within 4 weeks prior to initiation of the study.
- Women who are breastfeeding.
- Received a live, attenuated vaccine within 4 weeks prior to initiation of study treatment. NOTE: Investigators should ensure that all study enrollment (inclusion/exclusion) criteria have been met at screening and prior to the first dose of study intervention. If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study intervention is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 02 Mar 2020 | 1 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cusatuzumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 20.00 | 8 | PRD10916358 |
AZACITIDINE | Test | — | SUBCUTANEOUS USE | 75.00 | 8 | SUB05624MIG |
AZACITIDINE | Test | — | INTRAVENOUS USE | 75.00 | 8 | SUB05624MIG |