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.
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).
- 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
- 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.
- 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
- 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
- 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.