MRD-Guided Pembrolizumab and Azacitidine Therapy in NPM1-Mutated Acute Myeloid Leukemia with Imminent Hematological Relapse
- Trial ID
- 2024-513956-14-00
- Protocol
- TUD-PEMAZA-068
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and efficacy of pembrolizumab when administered in combination with standard azacitidine in patients with NPM1-mutated acute myeloid leukemia (AML) experiencing a molecular relapse, as indicated by the presence of measurable residual disease (MRD). This is clinically relevant as it aims to address the therapeutic needs of patients at risk of hematological relapse, potentially improving outcomes by targeting the disease at a molecular level before clinical relapse occurs.
Secondary objectives include: - Assessing overall survival, which is crucial for understanding the long-term benefits of the treatment. - Determining the proportion of event-free patients after 12 weeks of combined therapy, providing insight into the short-term efficacy of the treatment regimen. - Evaluating treatment-related mortality during 24 weeks of combined therapy, which is essential for understanding the safety profile of the treatment. - Monitoring the course of MRD-burden as measured by the quantitative NPM1/ABL ratio over time, offering valuable data on the treatment's impact on disease progression at a molecular level.
Participants
The clinical trial focuses on evaluating the safety and efficacy of pembrolizumab in combination with azacitidine for patients with **acute myeloid leukemia** (AML) who have experienced a molecular relapse. The study population includes both male and female participants aged 18 years and older, all of whom have been diagnosed with NPM1mut AML and are in complete morphologic remission following conventional chemotherapy. Participants must have detectable minimal residual disease (MRD) indicating an imminent hematologic relapse and are not eligible for immediate allogeneic stem cell transplantation or alternative intensive treatment. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, ensuring they are in relatively good health. Participants are required to demonstrate adequate organ function and must not be part of a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of **pembrolizumab** in combination with standard **azacitidine** in patients with **acute myeloid leukemia** (AML) who have a molecular relapse indicated by measurable residual disease (MRD). This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence on October 17, 2024, and conclude by December 31, 2025, with a total duration of 24 months for each participant. The study involves a series of visits, beginning with a screening visit to confirm eligibility based on criteria such as age, MRD status, and organ function. Participants will then undergo treatment cycles, with **azacitidine** administered subcutaneously and **pembrolizumab** via intravenous infusion. The primary endpoint is the proportion of event-free patients after 24 weeks of combination treatment, defined by the absence of hematologic relapse, death, or the need for alternative AML treatments. Secondary endpoints include overall survival and treatment-related mortality. Follow-up visits will occur regularly to monitor the MRD burden and assess the patient's response to treatment. The end-of-study visit will evaluate the long-term outcomes and any adverse events. Participants are expected to be involved for the full 24-week treatment period, with conditions for early termination including significant adverse reactions or withdrawal of consent. The trial aims to provide insights into the potential benefits of combining **pembrolizumab** and **azacitidine** for patients with AML at risk of relapse.
Treatment
The clinical trial involves the administration of **AZACITIDINE**, a cytostatic and hypomethylating agent, in the form of a **powder for suspension for injection**. The active substance, azacitidine, is of chemical origin. The medication is administered via the **subcutaneous** route. The dosing regimen includes a maximum daily dose of 75 mg/m², with a total maximum dose of 3150 mg/m² over a treatment period of up to 24 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
In addition to azacitidine, the trial also includes the administration of **KEYTRUDA**, which contains the active substance **pembrolizumab**. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is provided as a **concentrate for solution for infusion**. The medication is administered via **intravenous infusion**. The dosing schedule for pembrolizumab involves a maximum daily dose of 200 mg, with a total maximum dose of 1600 mg over a 24-week treatment period. The trial aims to evaluate the safety and efficacy of pembrolizumab when used in combination with azacitidine in patients with NPM1mut acute myeloid leukemia (AML) experiencing molecular relapse, as indicated by the presence of minimal residual disease (MRD).
Efficacy
The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of event-free patients after 24 weeks of combination treatment with pembrolizumab and azacitidine in patients with **NPM1mut acute myeloid leukemia (AML)**. Events are defined as the first hematologic relapse after the start of combined therapy, death from any cause, or the initiation of AML treatment other than pembrolizumab and azacitidine or hypomethylating agents only.
Secondary endpoints include overall survival, the proportion of event-free patients after 12 weeks of combined therapy, treatment-related mortality during 24 weeks of combined therapy, and the course of minimal residual disease (MRD) burden measured as the quantitative NPM1/ABL ratio over time. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to evaluate the treatment's impact on disease progression and patient survival.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent.
- Age ≥18 years.
- Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracycline ± cytarabine based).
- Detectable MRD indicating imminent hematologic relapse (NPM1mut MRD ratio >1%, confirmed by central lab).
- Patients who are not eligible for immediate alloSCT.
- Patients who are not eligible to undergo alternative intensive treatment.
- Intended AZA therapy for molecular relapse.
- ECOG performance status of 0 or 1.
- Demonstrate adequate organ function as defined in the table below, all labs should be performed within the screening period.
- Negative pregnancy test in women of childbearing potential (negative urine or serum pregnancy within 3 days prior to receiving study treatment). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.9.2 – Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Male subjects with procreative capacity must agree to use an adequate method of contraception as outlined in Section 5.9.2 – Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion Criteria
- Prior alloSCT.
- Treatment with any investigational drug within 4 weeks to study therapy or less than 5 half-lives preceding the first dose of trial medication, whichever is longer.
- Anti-cancer mAb within 4 weeks prior to study day 1 or no recovering (i.e., ≤ Grade 1 or at baseline) from adverse events (AE) due to agents administered more than 4 weeks earlier.
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or no recovering (i.e., ≤ Grade 1 or at baseline) from AE due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Prior treatment with an anti-programmed cell death protein (anti PD-1, anti PD-L1 or anti PD L2 agent).
- Known hypersensitivity to any of the drugs within this study, their constituents or to drugs with similar chemical structure.
- Receiving immunosuppressive therapy within 7 days prior to the first dose of trial medication.
- Known history of active TB (Bacillus Tuberculosis).
- Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- Autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Known history of, or any evidence of active, non-infectious pneumonitis.
- Liver cirrhosis or malignant liver tumor.
- Known severe congestive heart failure, incidence of clinically unstable cardiac or pulmonary disease.
- Active infection requiring systemic therapy.
- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
- Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 17 Oct 2024 | 28 |
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 |
|---|---|---|---|---|---|---|
AZACITIDINE | Other | — | SUBCUTANEOUS | 75 | 24 | SUB05624MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 200 | 24 | PRD4323105 |