PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

The researchers propose a Simon-two stage design for this study. The researchers will test
pembrolizumab at the FDA approved dose (in head and neck cancer) of 200mg dose administered
via intravenous infusion over 30 minutes given every 3 weeks. Nine patients will be enrolled
in the first stage of the Simon-two stage design, and 15 in the second stage. A treatment
cycle is 3 weeks and the core study period is 6 cycles. Response assessment by established
consensus criteria will be used to assess response after 6 cycles in order to determine if
the trial will progress to the second stage and for the purpose of determining the primary
endpoint. In addition, allowed will be a maximum of ten patients with accelerated or blast
phase disease (MPN-AP/BP) who are refractory or intolerant to conventional therapies such as
decitabine, and in which hematopoietic stem cell transplant is not a therapeutic option
(exploratory cohort), to enroll in the study as a separate exploratory cohort. These patients
can be enrolled during stage 1 or 2 and will be analyzed separately from the primary cohort
population.

Exploratory biomarkers will be obtained from enrolled patients at baseline, cycle 3 and cycle
7 and at 1 year of therapy. Patients that obtain at least a clinical improvement after 6
cycles of therapy can continue receiving pembrolizumab until evidence of disease progression,
unacceptable toxicity, and patient or physician decision for a maximum of 2 years.

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial.

- Be ≥ 18 years of age on day of signing consent.

- Must have a diagnosis of chronic phase (CP) (defined as peripheral blood and bone
marrow <10% blasts) primary myelofibrosis (PMF) or post essential thrombocythemia
(post-ET) or polycythemia vera (post-PV) myelofibrosis by World Health Organization
(WHO) criteria OR a diagnosis of a myeloproliferative neoplasm in accelerated/blast
phase (MPN-AP/BP) defined as either a peripheral blood or bone marrow with =10% blasts
.

- If the diagnosis is MF-CP, must have Dynamic International Prognostic Scoring System
(DIPSS) intermediate-2/high risk disease and either be intolerant/resistant to
ruxolitinib as determined by the treating investigator or ineligible for ruxolitinib
therapy as determined by the treating investigator .

- If the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment
with a DNMT1 inhibitor therapy (azacytidine, decitabine) as determined by the treating
investigator .

- Either not eligible or unwilling to proceed with hematopoietic stem cell
transplantation (HSCT)

- Have a performance status of 0 or 1 on the ECOG Performance Scale.

- Demonstrate adequate organ function as defined in Table 1, all screening labs should
be 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 (Reference
Section 5.7.2). 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.

Exclusion Criteria:

- 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.

- Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or
child) who is investigational site or sponsor staff directly involved with this trial,
unless prospective IRB approval (by chair or designee) is given allowing exception to
this criterion for a specific subject.

- 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)

- Hypersensitivity to pembrolizumab or any of its excipients.

- 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.

1. Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.

2. 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 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.

- 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.
"Anti-CD137 or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
(including ipilimumab or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways)

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 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.