MRD-guided treatment with pembrolizumab and azacitidine in NPM1mut AML patients with an imminent hematological relapse

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Technische Universitaet Dresden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

16 Sep 2019 → 31 Mar 2025

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

MSD Sharp & Dohme GmbH

External identifiers

EU CT number

2024-513956-14-00

EudraCT number

2017-004110-25

ClinicalTrials.gov

NCT03769532

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate the safety and efficacy of pembrolizumab (PEM) when administered in combination with standard azacitidine (AZA) in NPM1mut AML patients with molecular relapse defined by the presence of MRD

Secondary objectives 4

1. Overall survival
2. Proportion of event-free patients after 12 weeks of combined therapy
3. Treatment-related mortality during 24 weeks of combined therapy
4. Course of MRD-burden measured as quantitative NPM1/ABL ratio over time

Conditions and MedDRA coding

Acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Signed informed consent.
2. Age ≥18 years.
3. Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracycline ± cytarabine based).
4. Detectable MRD indicating imminent hematologic relapse (NPM1mut MRD ratio >1%, confirmed by central lab).
5. Patients who are not eligible for immediate alloSCT.
6. Patients who are not eligible to undergo alternative intensive treatment.
7. Intended AZA therapy for molecular relapse.
8. ECOG performance status of 0 or 1.
9. Demonstrate adequate organ function as defined in the table below, all labs should be performed within the screening period.
10. 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.
11. 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.
12. 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 22

1. Prior alloSCT.
2. 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.
3. 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.
4. 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.
5. Prior treatment with an anti-programmed cell death protein (anti PD-1, anti PD-L1 or anti PD L2 agent).
6. Known hypersensitivity to any of the drugs within this study, their constituents or to drugs with similar chemical structure.
7. Receiving immunosuppressive therapy within 7 days prior to the first dose of trial medication.
8. Known history of active TB (Bacillus Tuberculosis).
9. 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.
10. 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.
11. Autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
12. 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.
13. Known history of, or any evidence of active, non-infectious pneumonitis.
14. Liver cirrhosis or malignant liver tumor.
15. Known severe congestive heart failure, incidence of clinically unstable cardiac or pulmonary disease.
16. Active infection requiring systemic therapy.
17. 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.
18. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. 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.
20. Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
21. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
22. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the trial will be proportion of event-free patients after 24 weeks of combination treatment (i.e. after up to 6 cycles of AZA for 7 d Q4W and up to 8 PEM infusions Q3W). Events are defined as: (i) First hematologic relapse after start of combined therapy, (ii) Death from any cause, (iii) AML-treatment other than PEM and AZA or HMA only.

Secondary endpoints 4

1. Overall survival.
2. Proportion of event-free patients after 12 weeks of combined therapy
3. Treatment-related mortality during 24 weeks of combined therapy
4. Course of MRD-burden measured as quantitative NPM1/ABL ratio over time

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Technische Universitaet Dresden

Sponsor organisation

Technische Universitaet Dresden

Address

Mommsenstrasse 11, Raecknitz/zschertnitz Raecknitz/zschertnitz

City

Dresden

Postcode

01069

Country

Germany

Scientific contact point

Organisation

Technische Universitaet Dresden

Contact name

Dr. Jan Moritz Middeke

Public contact point

Organisation

Technische Universitaet Dresden

Contact name

Dr. Jan Moritz Middeke

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications