PRIMARY OBJECTIVES:
I. To assess the safety of the combination of azacitidine and MK3475 (pembrolizumab) in
patients with higher risk myelodysplastic syndrome (MDS).
II. To explore the clinical activity (response, survival effect) of the combination of
azacitidine with MK-3475 in patients with higher risk MDS.
EXPLORATORY OBJECTIVES:
I. To study the biological effects of the combination of azacitidine and pembrolizumab in
patients with MDS treated on this study.
OUTLINE:
Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on
days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days, every 12 weeks
for 1 year, then annually thereafter.
Inclusion Criteria:
- Voluntary signed informed consent before performance of any study related procedure
not part of normal medical care indicating that the patient is aware of the
investigation and nature of this study in keeping with institutional policies and with
the understanding that the consent may be withdrawn with the subject at any time
without prejudice to future medical care
- Intermediate 1 (INT-1) or higher risk MDS defined by International Prognostic Scoring
System (IPSS) criteria
- Patients can or cannot have receive prior therapy with hypomethylating agent but will
be allocated to specific patient cohorts based on their prior exposure. Patients that
had received prior hypomethylating agent therapy should have at least received 6
cycles of therapy and not achieved any response or had progressed after any given
number of cycles
- Eastern Cooperative Oncology Group (ECOG) performance of 0 to 2
- Male patients, even if surgically sterilized, should agree to practice effective
barrier contraception for the entire study treatment period and through 120 days after
the last dose of the study treatment or agree to completely abstain from heterosexual
intercourse. Female patients who are postmenopausal for at least one year before the
screening visit or are surgical sterile or if they are of child bearing potential must
have a negative pregnancy test within 72 hours of treatment of the start date and
agree to practice two effective methods of contraception forms at the same time from
the time of signing the informed consent through 120 days of the last dose of the
study treatment or agree to completely abstain from heterosexual intercourse
- Willingness and ability to comply with scheduled visits treatment plans, laboratory
tests and other study procedures
- Serum creatinine or measured or calculated creatine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrcL]) =<
2.0 x upper limit of normal (ULN) or >= 60 mL/min for subject with creatinine levels >
1.5 x institutional ULN (performed within 10 days of treatment initiation). Creatinine
clearance should be calculated per institutional standard
- Serum total bilirubin =< 2.0 x ULN (unless considered due to Gilbert's disease or
leukemia disease) or direct bilirubin =< ULN for subjects with total bilirubin levels
> 1.5 ULN (performed within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (unless considered due to Gilbert's disease or leukemia disease) or =< 5 x ULN for
subjects with liver metastases (performed within 10 days of treatment initiation)
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours 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 should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy
- Patients must receive a minimum dose of azacitidine of 75mg/(m)(2) dose
Exclusion Criteria:
- Significant medical psychiatric cognitive or other conditions that may compromise the
patient ability to understand the patient information to give informed consent to
comply with the study protocol or to complete the study
- Any severe or concurrent disease or condition including uncontrolled systemic
infection, congestive heart failure, angina pectoris or cardiac arrhythmia and
autoimmune processes that in the opinion of the investigator would make the patient
inappropriate for study participation
- Patients with known hypersensitivity to 5-azacitdine or MK3475 or any of their
excipients
- Prior history of stem cell transplantation
- For patients in the relapse or refractory cohort, any other therapy not being a
hypomethylating agent after hypomethylating agents (HMA) failure or more than 4 months
since completion of last cycle of hypomethylating agent. Please note that
hypomethylating agent may include second generation compounds such as SGI-110, oral
decitabine or oral azacitidine and will also include combinations with investigational
agents
- Treatment with other investigational agents including chemotherapy, immunotherapy, or
radiation therapy within a month prior to the start of this clinical trial
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment
- Has a 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
- Has a known history of active TB (Bacillus tuberculosis)
- Has had a prior 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
- Has had 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
- Has a 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
- Has 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
- Has 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has a 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
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is 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
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)
- Has received a 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
