Acute Myeloid LeukemiaPhase 2PEMAZANCT03769532
MRD-guided Treatment in NPM1mut AML Patients
A Phase 2 study testing Pembrolizumab and Azacitidine in people with Acute Myeloid Leukemia, run by Technische Universität Dresden at 10 sites in Germany.
Trial summary
Evaluation the safety and efficacy of Pembrolizumab (PEM) when administered in combination with standard Azacitidine (AZA) in nucleophosmin (NPM1) mutated AML patients with molecular relapse defined by the presence of measurable residual disease (MRD). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia
- What is being tested?
- Pembrolizumab and Azacitidine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 10 sitesGermany
- Study dates
- 21 Aug 2019to 13 Feb 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed informed consent
- Age ≥18 years
- Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracycline ± cytarabine based)
- Detectable measurable residual disease (MRD) indicating imminent hematological relapse (NPM1mut MRD ratio >1%, confirmed by central lab)
- Patients who are not eligible for immediate allogeneic hematopoietic stem cell transplantation
- Patients who are not eligible to undergo alternative intensive treatment
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- Intended AZA therapy for molecular relapse
- Eastern cooperative oncology Group (ECOG) performance status of 0 or 1
- Demonstrate adequate organ function as defined by protocol, 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 (Section 5.9.2) 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 (Section 5.9.2) 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.
Who cannot join
- Prior allogeneic hematopoietic stem cell transplantation
- 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 monoclonal antibody (mAb) within 4 weeks prior to study day 1 or no recovering (i.e., ≤ Grade 1 or at baseline) from adverse events 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 adverse events 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.
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- Receiving immunosuppressive therapy within 7 days prior to the first dose of trial medication.
- Known history of active Bacillus Tuberculosis (TB).
- 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 (eg., 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., Hepatitis C virus (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 locations and contacts
10 sites in 1 country.
10 sites in 1 country
Germany10 sites
Klinikum Chemnitz
Chemnitz, 09116
Universitätsklinikum Dresden
Dresden, 01307
Universitätsklinikum Heidelberg
Heidelberg, 69120
Universitätsklinikum Jena
Jena, 07740
Universitätsklinikum Leipzig
Leipzig, 04103
Kliniken Maria Hilf
Mönchengladbach, 41063
Klinikum r. d. I.
München, 81675
Universitätsklinikum Münster
Münster, 48149
Robert-Bosch-Krankenhaus
Stuttgart, 70376
Universitätsklinikum Würzburg
Würzburg, 97080
About this study
Official title: MRD-guided Treatment With Pembrolizumab and Azacitidine in NPM1mut AML Patients With an Imminent Hematological Relapse
Evaluation the safety and efficacy of Pembrolizumab (PEM) when administered in combination with standard Azacitidine (AZA) in nucleophosmin (NPM1) mutated AML patients with molecular relapse defined by the presence of measurable residual disease (MRD).
Read the detailed description
Azacitidine is an effective and well established therapy in patients with acute myeloid leukemia (AML). In fact, in previous measurable residual disease (MRD) triggered studies, azacitidine allowed for a delay towards an overt hematological relapse in the majority of patients. However, the majority of patients ultimately relapsed even though they received multiple cycles of preemptive therapy. Hypomethylating agents (HMA) can enhance antitumor immune responses by upregulating tumor antigene expression, class 1 major histocompatibility complex, and co-stimulatory molecules, while concurrently dampening this antitumor effect by upregulating expression of checkpoint receptors or ligands, including programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Upregulation of these immune checkpoint molecules might be a mechanism of resistance to hypomethylating drugs. It has been shown that PD-L1 Messenger ribonucleic acid (mRNA) is up-regulated acute myeloid leukemia cluster of differentiation 34 (CD34+) cells and importantly, patients resistant to treatment with hypomethylating agents such as azacitidine have an up-regulated expression compared to responding patients. In addition, it is known that PD-1 promoter demethylation correlates with a higher PD-1 expression and a worse response rate to hypomethylating agents as well as a shorter overall survival. In this context it is of note that PD-1 promoter demethylation can be caused by hypomethylating agents and hence the mode of action of the drug itself could cause resistance to therapy in these patients. This might also explain why hypomethylating agents are not curative and can not eradicate early leukemic progenitor cells. The investigators, therefore, perform a phase II trial evaluating a combination therapy of pembrolizumab and azacitidine in nucleophosmin (NPM1) mutated AML patients with MRD and impending hematological relapse after conventional chemotherapy. This trial aims at improving response rates observed with single agent azacitidine within the studies NCT00422890 and NCT01462578.
- Conditions
- Acute Myeloid Leukemia
- Being tested
- Pembrolizumab, Azacitidine
- Keywords
- AML, NPM1mut, molecular relapse, pembrolizumab, azacitidine
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabDrug
Also called PEM, Keytruda®
Pembrolizumab (IMP): 200mg i.v. (fixed dose), every 3 weeks (Q3W), 8 doses
AzacitidineDrug
Also called AZA, Vidaza®
Azacitidine (SOC): 75 mg/m2 s.c., day 1-7 every 4 weeks (Q4W), 6 cycles
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab + Azacitidine | Experimental | Pembrolizumab (IMP): 200 mg i.v. (fixed dose) / Azacitidine (SOC): 75 mg/m2 s.c.
maximum duration of treatment: up to 24 weeks Receives: Drug: Pembrolizumab; Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of event-free patients
Events are:
- First hematological relapse after start of combined therapy
- Death from any cause
- AML-treatment other than Pembrolizumab and Azacitidine or hypomethylating agents only
Measured: after 24 weeks of combination treatment (i.e. after up to 6 cycles of AZA for 7 days every 4 weeks and up to 8 PEM infusions every 3 weeks)
Secondary outcomes (4)
Overall survival (OS)
Overall survival is defined as the number of days between date of first visit (AZA) and date of death from any cause.
Measured: through study completion, an average of 1 year
Proportion of event-free patients
For this endpoint apply the same definitions as for the primary endpoint.
Measured: after 12 weeks of combined therapy
Treatment-related mortality
Any death without preceding hematologic relapse is considered to be treatment related.
Measured: during 24 weeks of combined therapy
Course of MRD-burden measured as quantitative NPM1/Abelson murine leukemia viral oncogene homolog 1 (ABL) ratio
The NPM1/ABL-ratio will be log-transformed with base 10. With the log transformation a near normal distributed variable will be derived to be able to use parametric methods for analysis. Values below limit of detection (LOD) will be substituted by LOD/2 before log-transformation.
Measured: through study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Dec 2018
- Study start21 Aug 2019
- Primary completion13 Feb 2025
- Study completion13 Feb 2025
Why it stopped: Feasibility
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by Technische Universität DresdenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- Technische Universität Dresden
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Jan Moritz Middeke, MD, Principal investigator, Technische Universität Dresden (TUD)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03769532
- Sponsor's protocol ID
- TUD-PEMAZA-068
- Acronym
- PEMAZA
- Status last verified
- Aug 2025
- First submitted
- 5 Dec 2018
- Last updated
- 24 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- MRD-guided Treatment With Pembrolizumab and Azacitidine in NPM1mut AML Patients With an Imminent Hematological Relapse
- ClinicalTrials.gov ID
- NCT03769532
- Acronym / sponsor ID
- PEMAZA / TUD-PEMAZA-068
- Conditions
- Acute Myeloid Leukemia
- Keywords
- AML, NPM1mut, molecular relapse, pembrolizumab, azacitidine
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Feasibility
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Technische Universität DresdenUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 21 Aug 2019 (actual)
- Primary completion
- 13 Feb 2025 (actual)
- Study completion
- 13 Feb 2025 (actual)
- First posted
- 7 Dec 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Evaluation the safety and efficacy of Pembrolizumab (PEM) when administered in combination with standard Azacitidine (AZA) in nucleophosmin (NPM1) mutated AML patients with molecular relapse defined by the presence of measurable residual disease (MRD).
Detailed description
Azacitidine is an effective and well established therapy in patients with acute myeloid leukemia (AML). In fact, in previous measurable residual disease (MRD) triggered studies, azacitidine allowed for a delay towards an overt hematological relapse in the majority of patients. However, the majority of patients ultimately relapsed even though they received multiple cycles of preemptive therapy. Hypomethylating agents (HMA) can enhance antitumor immune responses by upregulating tumor antigene expression, class 1 major histocompatibility complex, and co-stimulatory molecules, while concurrently dampening this antitumor effect by upregulating expression of checkpoint receptors or ligands, including programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Upregulation of these immune checkpoint molecules might be a mechanism of resistance to hypomethylating drugs. It has been shown that PD-L1 Messenger ribonucleic acid (mRNA) is up-regulated acute myeloid leukemia cluster of differentiation 34 (CD34+) cells and importantly, patients resistant to treatment with hypomethylating agents such as azacitidine have an up-regulated expression compared to responding patients. In addition, it is known that PD-1 promoter demethylation correlates with a higher PD-1 expression and a worse response rate to hypomethylating agents as well as a shorter overall survival. In this context it is of note that PD-1 promoter demethylation can be caused by hypomethylating agents and hence the mode of action of the drug itself could cause resistance to therapy in these patients. This might also explain why hypomethylating agents are not curative and can not eradicate early leukemic progenitor cells. The investigators, therefore, perform a phase II trial evaluating a combination therapy of pembrolizumab and azacitidine in nucleophosmin (NPM1) mutated AML patients with MRD and impending hematological relapse after conventional chemotherapy. This trial aims at improving response rates observed with single agent azacitidine within the studies NCT00422890 and NCT01462578.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab + Azacitidine | Experimental | Drug: Pembrolizumab, Drug: AzacitidinePembrolizumab (IMP): 200 mg i.v. (fixed dose) / Azacitidine (SOC): 75 mg/m2 s.c. maximum duration of treatment: up to 24 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Signed informed consent
- Age ≥18 years
- Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracycline ± cytarabine based)
- Detectable measurable residual disease (MRD) indicating imminent hematological relapse (NPM1mut MRD ratio >1%, confirmed by central lab)
- Patients who are not eligible for immediate allogeneic hematopoietic stem cell transplantation
Key exclusion criteria (22 listed)
- Prior allogeneic hematopoietic stem cell transplantation
- 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 monoclonal antibody (mAb) within 4 weeks prior to study day 1 or no recovering (i.e., ≤ Grade 1 or at baseline) from adverse events 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 adverse events 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PembrolizumabAlso: PEM, Keytruda®Pembrolizumab (IMP): 200mg i.v. (fixed dose), every 3 weeks (Q3W), 8 doses | Drug | Pembrolizumab + Azacitidine |
| AzacitidineAlso: AZA, Vidaza®Azacitidine (SOC): 75 mg/m2 s.c., day 1-7 every 4 weeks (Q4W), 6 cycles | Drug | Pembrolizumab + Azacitidine |
Primary outcome
Proportion of event-free patients
Time frame: after 24 weeks of combination treatment (i.e. after up to 6 cycles of AZA for 7 days every 4 weeks and up to 8 PEM infusions every 3 weeks)
Events are: * First hematological relapse after start of combined therapy * Death from any cause * AML-treatment other than Pembrolizumab and Azacitidine or hypomethylating agents only
4 secondary outcomes
Overall survival (OS)
Time frame: through study completion, an average of 1 year
Proportion of event-free patients
Time frame: after 12 weeks of combined therapy
Treatment-related mortality
Time frame: during 24 weeks of combined therapy
Course of MRD-burden measured as quantitative NPM1/Abelson murine leukemia viral oncogene homolog 1 (ABL) ratio
Time frame: through study completion, an average of 1 year
Results and safety
The study was stopped early (reason given: Feasibility). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Aug 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jan Moritz Middeke, MD principal investigator
Technische Universität Dresden (TUD)
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pembrolizumab and Azacitidine in people with Acute Myeloid Leukemia, run by Technische Universität Dresden at 10 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 24 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Feasibility). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of event-free patients (time frame: after 24 weeks of combination treatment (i.e. after up to 6 cycles of AZA for 7 days every 4 weeks and up to 8 PEM infusions every 3 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Aug 2025.