Patients with NPM1mut AML >= 18 years in CR presenting with MRD after conventional chemotherapy MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive
Sponsors
Technische Universität Dresden
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Signed informed consent - Age =18 years - Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracyclines ± cytarabin based) - Detectable measurable residual disease (MRD) indicating imminent hematological relapse (NPM1mut status >1%) - Patients who are not eligible for immediate allogeneic hematopoietic stem cell transplantation - Patients who are not eligible to undergo alternative intensive treatment - Intended AZA therapy for molecular relapse - ECOG performance status of 0 or 1 - Adequate organ function as defined by protocol - No allogeneic stem cell transplantation (allo SCT) within 5 years prior to study treatment - Female subject of childbearing potential should have a negative urine or serum pregnancy within 3 days prior to receiving the first dose of study medication. 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 (Section 5.9.2), for the course of the study through 120 days after the last dose of study medication - Male subjects with procreative capacity must agree to use an adequate method of contraception (Section 5.9.2), starting with the first dose of study therapy through 120 days after the last dose of study therapy Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 14 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 14
Exclusion criteria
Exclusion criteria: - Current treatment with any investigational drug or within 4 weeks or less than 5 half-lives preceding the first dose of trial medication, whichever is longer - Known hypersensitivity to any of the drugs used or their constituents or to drugs with similar chemical structure - Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Known history of active TB (Bacillus Tuberculosis) - Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (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 who has not recovered (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. - Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later - 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 - Active 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 - Severe hepatic impairment (AST and ALT may not exceed three times the normal) or liver cirrhosis or malignant liver tumor - Dialysis dependent renal dysfunction - 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 p
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and efficacy of PEM when administered in combination with AZA in NPM1mut patients with molecular relapse. This objective is based on the hypothesis that PEM in combination with AZA is safe and more effective than AZA alone to prevent hematological relapse of NPM1mut patients with molecular relapse. ;Secondary Objective: - Toxicity of the treatment with pembrolizumab and azacytidine - Proportion of event-free patients after 12 weeks of combination treatment - Treatment-related mortality during 24 weeks of combined therapy - Course of MRD-burden measured as quantitative NPM1/ABL ratio over time Exploratory: - Qualitative and quantitative changes in cellular subsets of the immune system during treatment with pembrolizumab and azacytidine - Impact of PD-1 and PD-L1 expression on outcome - Mutational pattern and burden of selected genes (panel) and their influence on response ;Primary end point(s): Proportion of event-free patients after 24 weeks of combination treatment, events are defined as - Hematological relapse - Death from any cause - AML-treatment other then pembrolizumab and azacitidine or hypomethylating agents only;Timepoint(s) of evaluation of this end point: after 24 weeks of combination treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall survival (OS) - Toxicity of the treatment with pembrolizumab and azacytidine - Proportion of event-free patients after 12 weeks of combination treatment - Treatment-related mortality during 24 weeks of combined therapy - Course of MRD-burden measured as quantitative NPM1/ABL ratio over time;Timepoint(s) of evaluation of this end point: after 12 weeks after 24 weeks after 12 months | — |
Countries
Germany
Contacts
Public Contactcoordinating investigator
Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
Outcome results
None listed