The Immune Checkpoint Inhibitor Pembrolizumab in Combination With Oral Decitabine and Tetrahydrouridine as First-Line Therapy for Inoperable, Locally Advanced or Metastatic Non-small Cell Lung Cancer

Background:

- Lung cancer is the leading cause of cancer-related mortality in the United States, with
over two thirds of patients presenting with advanced stage of disease. 1st-line
platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) produces
transient responses at best, with most patients succumbing to disease within 12-16
months following diagnosis.

- A recent randomized clinical trial demonstrated a response rate approximating 45% in
treatment naive patients with advanced NSCLC with high level PD-L1 expression of
programmed death ligand 1 (PD-L1) following administration of pembrolizumab, a humanized
monoclonal anti- PD-1 antibody.

- Additional studies suggest that responses to immune checkpoint inhibitors may be
augmented by epigenetic drugs such as DNA demethylating agents and histone deacetylase
(HDAC) inhibitors.

- Although a potent DNA hypomethylating agent, Decitabine has significant limitations
regarding chronic treatment of solid tumors due to poor bioavailability resulting from
rapid inactivation by cytidine deaminase (CDA) which is present in high levels in many
organs.

- Recent studies in rodents and nonhuman primates, as well as a Phase 1 clinical trial
(NCT#01685515) in patients with sickle cell disease have demonstrated that oral
tetrahydrouridine (THU), an inhibitor of CDA, significantly enhances
bioavailability/solidtissue- distribution of low dose oral DAC, thereby enhancing
systemic DNA demethylation without dose limiting toxicities.

- Results of an ongoing clinical trial suggest that oral DAC-THU can increase the
frequency and magnitude of responses to immune checkpoint inhibitors when used as
second-line therapy in lung cancer patients with low or absent intra-tumoral PD-L1
expression.

- Collectively these data support implementation of such strategies for front-line therapy
of NSCLC.

Objectives:

- Phase I - To define pharmacokinetics, toxicities and maximum tolerated dose of oral
DAC-THU in combination with pembrolizumab in first-line therapy of inoperable, or
unresectable locally advanced, or metastatic NSCLC

- Phase II - To determine clinical response by RECIST criteria to oral DAC-THU in
combination with pembrolizumab

Eligibility:

- Inclusion Criteria

- Male or female, 18 years or older with histologically or cytologically-proven,
inoperable or unresectable locally advanced, or metastatic NSCLC

- Measurable disease

- Patients with high PD-L1 expression (greater than or equal to 50%) and low PD-L1
expression (0-49%) in lung cancer cells by immunohistochemistry are eligible.
Patients with low PD-L1 expression in tumor cells must have been offered and
refused first line platinum based chemotherapy.

- Willingness to undergo tumor biopsies if safely accessible per PI discretion before
and after treatment

- ECOG performance status 0 - 2

- No evidence of unstable or decompensated myocardial disease; adequate pulmonary
reserve

- Adequate renal, hepatic and hematopoietic function

- Exclusion Criteria

- Patients with any targetable mutation for which there is approved first line therapy.

- Serious cardiovascular conditions.

- Active Hepatitis A, Hepatitis B or Hepatitis C

- Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)- related
illness

- Other active infection requiring systemic therapy

- Pregnant or breastfeeding women

- Patients who are receiving systemic corticosteroids.

- Patients receiving another investigational agent

- Another malignancy.

Design:

- The phase I component will be a standard 3+3 design combining high and low PD-L1
expressers starting with oral DAC-THU q M-T-W each week with incremental dose escalation
in 4 cohorts dose levels.

- Pembrolizumab will be administered on Wednesday, Thursday or Friday at a fixed
intravenous dose of 200 mg every 3 weeks.

- One cycle is three weeks; one course is 9 weeks. Treatment evaluation using RECIST 1.1
every 10 +/- 1 weeks.

- Those patients exhibiting disease progression or unacceptable toxicities will be removed
from study. Patients exhibiting stable disease or disease regression will be offered an
additional course of therapy followed by treatment evaluation. Treatment will continue
in this manner until off-study criteria have been met.

- Once the MTD for DAC/THU has been identified, the MTD dose level will be expanded by 4
patients to confirm its safety. Then, including these 10 patients at the MTD, a total of
10 patients with high (50% or greater) intratumoral PD-L1 expression and 10

patients with low (0-49%) intratumoral PL-L1 expression will be accrued to the first stage of
each of two separate phase II cohorts using individual Simon optimal designs. If 5 or more
patients of the 10 first stage patients in the high PD-L1 cohort respond to treatment, the
cohort will be expanded to 23 patients. If 11 of 23 of these patients respond to treatment,
the trial will be deemed positive for NSCLC with high PD-L1 expression. If 2 or more of the
10 first stage patients in the low PD-L1 expression cohort respond to treatment, the cohort
will be expanded to 29 patients. If 6 or more of these 29 patients experience a response, the
trial will be deemed positive for NSCLC with low PD-L1 expression.

- Biopsies of index lesions will be obtained at baseline and at treatment evaluation
following the first course of therapy for analysis of pharmacodynamic endpoints.

- Patients will be followed for toxicity for 100 days after treatment has been
discontinued, start of new anti-cancer treatment or until death, whichever occurs first.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed, inoperable or
unresectable, locally advanced, or metastatic NSCLC

- Patients who have received no prior systemic treatment.

- Patients must have analysis of PD-L1 expression in cancer cells quantitated by
immunohistochemistry analysis.

- Patients in Cohort 1 (dose escalation) may have any level of expression

- Patients in Cohort 2 (high PD-L1) must have greater than or equal to 50% expression

- Patients in Cohort 3 (low PD-L1) must have 0-49% expression

- Patients must have measurable disease, per RECIST 1.1.

- Willingness to undergo tumor biopsies if safely accessible per PI discretion before
and after treatment.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of Decitabine (DAC) and Tetrahydrouridine (THU) in
combination with Pembrolizumab in patients <18 years of age, children are excluded
from this study, but will be eligible for future pediatric trials.

- ECOG performance status of less than or equal to 2

- Patients must be without evidence of unstable or decompensated myocardial disease; and
must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than or equal
to 35% predicted; oxygen saturation equal to or greater than 90% on room air by pulse
oximetry or ABG (to be drawn if pulse oximetry < 90% on room air)

- No immunosuppressive medications except non-systemic corticosteroids

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL (without transfusion
or cytokine support)

- absolute lymphocyte count greater than or equal to 800/mcL

- platelets greater than or equal to 100,000/mcL

- PT no more than 2 seconds above the ULN

- total bilirubin < 1.5 X institutional upper limit of normal OR direct bilirubin
less than or equal to ULN for patients with total bilirubin > 1.5 ULN

- serum albumin greater than or equal to 2.0 mg/dL

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional ULN

- creatinine less than or equal to 1.6 mg/ml OR creatinine clearance (eGFR) greater
than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal at the time DAC-THU and pembrolizumab treatment commences.

- Patients with history of brain metastases except those with meningeal carcinomatosis
or leptomeningeal disease may be eligible for treatment a minimum of 1 week following
completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical
resection of brain metastasis provided post-treatment MR scan reveals no evidence of
active disease, and no ongoing need for systemic steroids.

- Patients with laboratory evidence of autoimmune disease (e.g. positive ANA or lupus
anticoagulant) without associated symptoms; vitiligo, or mild autoimmunity not
impacting the function of organs, such as Hashimoto or psoriasis may be eligible for
study.

- The effects of DAC-THU and pembrolizumab on the developing human fetus are unknown.
For this reason and because antineoplastic agents as well as other therapeutic agents
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation and
for 60 days after completion of the study treatment. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients with lung cancers harboring any targetable mutation for which there is
approved for first line therapy.

- Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral
vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (<
6 months prior to enrollment), unstable angina, congestive heart failure (New York
Heart Association Classification Class greater than or equal to II), serious cardiac
arrhythmia, clinically significant bleeding or clinically significant pulmonary
embolism

- Active Hepatitis A, Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness due to unknown effects of DAC-THU on systemic immunity.

- Other active infection requiring systemic therapy.

- Pregnant women are excluded from this study because DAC-THU may have the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
DACTHU, breastfeeding should be discontinued if the mother is treated with DAC-THU.
These potential risks may also apply to other agents used in this study

- Other severe acute or chronic medical or psychiatric conditions or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the patient inappropriate for entry into
this study.

- Patients who are receiving systemic corticosteroids.

- Patients with history of or active autoimmune disease including thyroiditis, colitis,
nephritis, neuropathy or pneumonitis.

- Patients receiving another investigational agent.

- An 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 or anal cancer, or
ductal carcinoma in-situ

- 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.

- Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the trial.

- Thrombocytosis defined as platelet count >1,200,000/mcL.