Clinical Trials /

MRD-guided Treatment in NPM1mut AML Patients

NCT03769532

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MRD-guided Treatment in NPM1mut AML Patients
  • Official Title: MRD-guided Treatment With Pembrolizumab and Azacitidine in NPM1mut AML Patients With an Imminent Hematological Relapse

Clinical Trial IDs

  • ORG STUDY ID: TUD-PEMAZA-068
  • NCT ID: NCT03769532

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
PembrolizumabPEM, Ketruda®Pembrolizumab + Azacitidine
AzacitidineAZA, Vidaza®Pembrolizumab + Azacitidine

Purpose

Evaluation the safety and efficacy of PEM when administered in combination with standard AZA in NPM1mut AML patients with molecular relapse defined by the presence of MRD.

Detailed Description

      AZA is an effective and well established therapy in patients with AML. In fact, in previous
      MRD-triggered studies, AZA 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 drugs 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 PD-1, PD-L1, and
      CTLA-4 . Upregulation of these immune checkpoint molecules might be a mechanism of resistance
      to hypomethylating drugs. It has been shown that PD-L1 mRNA is up-regulated AML CD34+ cells
      and importantly, patients resistant to treatment with HMAs 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
      HMAs as well as a shorter overall survival. In this context it is of note that PD-1 promoter
      demethylation can be caused by HMAs and hence the mode of action of the drug itself could
      cause resistance to therapy in these patients. This might also explain why HMAs are not
      curative and can not eradicate early leukemic progenitor cells. The investigators, therefore,
      perform a phase II trial evaluating a combination therapy of PEM and azacitidine in NPM1mut
      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
      RELAZA1 and RELAZA2 studies (NCT00422890, NCT01462578).
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + AzacitidineExperimentalPembrolizumab (IMP): 200 mg i.v. (fixed dose) / Azacitidine (SOC): 75 mg/m2 s.c. maximum duration of treatment: up to 24 weeks
  • Pembrolizumab
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Intended AZA therapy for molecular relapse

          -  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.

        Exclusion Criteria:

          -  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.

          -  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 (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., 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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)
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:Overall survival is defined as the number of days between date of first visit (AZA) and date of death from any cause.
Measure:Proportion of event-free patients
Time Frame:after 12 weeks of combined therapy
Safety Issue:
Description:For this endpoint apply the same definitions as for the primary endpoint.
Measure:Treatment-related mortality
Time Frame:during 24 weeks of combined therapy
Safety Issue:
Description:Any death without preceding hematologic relapse is considered to be treatment related.
Measure:Course of MRD-burden measured as quantitative NPM1/ABL ratio
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

  • AML
  • NPM1mut
  • molecular relapse
  • pembrolizumab
  • azacitidine

Last Updated