Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in People Undergoing Pulmonary Metastasectomy

Background:

- Whereas malignancies of diverse histologies express a variety of cancer testis antigens
(CTAs), immune responses to these antigens appear uncommon in cancer patients, possibly
due to low-level, heterogeneous antigen expression, as well as immunosuppressive
regulatory T cells.

- In published studies we have demonstrated induction of NY-ESO-1 and MAGE-A3 in cancer
cells of various histologies but not normal respiratory epithelial cells or fibroblasts
following exposure to the DNA demethylating agent, Decitabine (DAC); up-regulation of
these CTAs facilitated CTL-mediated lysis of tumor cells. We have also demonstrated
eradication of pulmonary metastases in immunocompetent mice following systemic
treatment with DAC and subsequent adoptive transfer of CTL recognizing the murine CTA,
P1A. In a phase 1 trial, we demonstrated up-regulation of NY-ESO-1 and MAGE-A3 as well
as reactivation of p16 in thoracic malignancies following intravenous 72hr DAC
infusions. Chronic administration schedules are necessary for optimal gene induction in
solid cancers.

- Additional studies using murine tumor models suggest that DNA demethylating agents may
enhance the activity of immune checkpoint inhibitors not only by upregulating antigen
presentation, but by inhibiting activity of myeloid derived suppressor cells (MDSC).

- Presently, there is no information regarding gene modulation and antitumor activity of
oral epigenetic therapy in patients with solid tumors.

- In this study, the optimal frequency/dose of DAC-THU administration will be established
in patients with bilateral pulmonary metastases, then an additional cohort of patients
will receive DAC-THU together with celecoxib to inhibit activity of immunosuppressive
Treg and myeloid derived suppressor cells. Correlative experiments will be performed to
ascertain if oral epigenetic therapy modulates gene expression in pulmonary metastases
and enhances antitumor immunity to these neoplasms.

- This trial is intended to establish the rationale and conditions for the use of oral
DAC-THU +/- celecoxib in combination with immune checkpoint inhibitors or adoptive
immunotherapy regimens targeting CTAs in patients with thoracic malignancies.

Objectives:

-To determine the pharmacokinetics, toxicities and maximum tolerated dose of oral DAC and
THU with or without celecoxib in patients undergoing resection of pulmonary metastases

Eligibility:

- Patients with histologically or cytologically proven sarcoma, melanoma, germ cell
tumors, or epithelial malignancies with bilateral pleuro-pulmonary metastases who can
be rendered no clinical evidence of active disease (NED) or minimal residual disease
(MRD) by metastasectomy.

- Patients greater than or equal to 18 years; ECOG performance status of 0-2, without
evidence of unstable or decompensated myocardial disease; must have adequate pulmonary
reserve evidenced by post-operative FEV1 and DLCO (Bullet) 40% predicted; pCO2 < 50 mm
Hg and pO2 > 60 mm Hg on room air ABG; and be on no immunosuppressive medications
except non-systemic corticosteroids.

- Patients must have a platelet count > 100,000, ANC greater than or equal to 1500
without transfusion or cytokine support, a normal PT, and adequate hepatic function as
evidenced by a total bilirubin of < 1.5 times ULN. Serum creatinine less than or equal
to 1.6 mg/ml or creatinine clearance > 70 ml/min/1.73m(2) at the time DAC/THU +/-
celecoxib treatment commences.

Design:

- Eligible subjects with bilateral pulmonary metastases will undergo disease resection in
one hemithorax

- Following recovery from initial hemithoracic metastasectomy (approximately 2-3 weeks),
patients will begin oral DAC (0.2mg/kg)-THU (10 mg/kg) therapy 3-5 consecutive
days/week depending on dose level. THU will be administered 60 minutes prior to DAC.

- If no dose limiting systemic toxicities (primarily myelosuppression) are observed, the
frequency of DAC- THU will be sequentially increased to maximize intra-tumoral DNMT1
depletion while avoiding grade 3 or greater systemic toxicities.

- Once the frequency of DAC-THU therapy has been optimized, additional patients will also
receive oral celecoxib (400mg PO BID).

- Oral DAC-THU +/- celecoxib therapy will continue for 6 weeks. Patients will then have
repeat imaging studies. Those patients who exhibit no evidence of disease recurrence in
the operated lung with disease progression in the contralateral hemithorax will undergo
metastasectomy if there are no standard of care contraindications such as progression
of disease in extrathoracic sites. Those patients exhibiting response to therapy
evidenced by stable or regressing nodules will continue DAC-THU therapy for 4
additional weeks, followed by metastasectomy.

- Systemic toxicities and response to therapy will be recorded. Gene expression and DNA
methylation profiles in pre- and post-treatment metastases will be compared to
determine if DAC-THU therapy has altered the epigenome of the metastases. Serologic
responses to upregulated CTAs as well as cell mediated responses to
epigenetically-modified autologous EBV-transformed B and autologous tumor cells (if
available) will be assessed before and after treatment if there is evidence of CT gene
activation following DAC-THU +/- celecoxib treatment.

- DNMT and CTA expression levels in PBMC and tumor tissues will be evaluated before and
after treatment to ascertain if DAC-THU depletes systemic DNMT levels, and to determine
if alterations in DNMT/CTA expression in PBMC can serve as surrogates of respective
drug induced changes in tumor tissues.

- Following complete metastasectomy, patients will be followed in the clinic with routine
staging scans per standard of care guidelines.

- As the exact set of comparisons and analyses to be performed will be determined
following completion of the trial, and will be based on limited numbers of patients,
the analyses will be considered exploratory and hypothesis generating rather than
definitive.

- Approximately 46 patients will be accrued to this trial.

- INCLUSION CRITERIA:

- Patients with bilateral pulmonary metastases from sarcomas, melanomas, germ cell
tumors, or epithelial malignancies metastatic to the lungs, mediastinum, or pleura
who can be rendered no clinical evidence of active disease (NED) or minimal residual
disease (MRD) by standard of care metastasectomy where NED refers to diagnostic tests
failing to detect presence of disease and MRD refers to low-volume, subclinical
disease which is not amenable to standard of care biopsy for histologic confirmation
and poses no immediate threat to patient health and would not otherwise warrant
standard of care treatment but surveillance instead.

- Patients must have a minimum of two metastases per hemithorax.

- Patients with active disease outside the thorax may be eligible for study once the
extrathoracic disease is definitively treated by local modalities such as radiation,
surgery, or radiofrequency ablation.

- Patients must have adequate pulmonary reserve evidenced by predicted post-operative
FEV1 and DLCO equal to or greater than 40% predicted; pCO2 less than 50 mm Hg and pO2
greater than 60 mm Hg on room air ABG; and be on no immunosuppressive medications
except inhaled corticosteroids.

- Patients must have received first line standard systemic therapy for their metastases
(if applicable).

- Patients with intracranial metastases, which have been treated by surgery or
radiation therapy, may be eligible for study provided there is no evidence of active
disease and no requirement for anticonvulsant therapy or steroids following
treatment.

- Patients must have an ECOG performance status of 0-2.

- Patients must have recovered from non-hematologic toxicities associated with
treatment of malignancy to less than or equal to grade 1.

- Patients must be 18 years of age or older due to the unknown effects of systemic DNA
hypomethylation and immunologic responses to germ cell-restricted gene products
during childhood and adolescent development.

- Patients must have evidence of adequate bone marrow reserve, hepatic and renal
function as evidenced by the following laboratory parameters:

- Absolute neutrophil count greater than 1500/mm(3) without transfusion or
cytokine support

- Platelet count greater than 100,000/mm(3)

- Hemoglobin greater than 8g/dl (patients may receive transfusions to meet this
parameter)

- PT no more than 2 seconds above the ULN

- Total bilirubin <1.5 times upper limits of normal

- Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance
must be greater than 70 ml/min/1.73m(2).

- Seronegative for HIV antibody. Note: The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV seropositive
can have decreased immune competence and thus may be less responsive to the
experimental treatment.

- Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If
hepatitis C antibody test is positive, then patient must be tested for the presence
of antigen by RT-PCR and be HCV RNA negative.

- Patients must be aware of the neoplastic nature of their illnesses, the experimental
nature of the therapy, alternative treatments, potential benefits, and risks.

- Patients must be willing to practice birth control during and for four months
following treatment.

- Patients must be able to swallow oral medications (capsules and tablets) without
chewing, breaking, crushing, opening or otherwise altering the product formulation.

- Patients who had prior lung resection are eligible provided they fulfil the rest of
the eligibility criteria.

- Patients must be willing to sign an informed consent.

EXCLUSION CRITERIA:

- Patients with uncontrollable progression of extra-thoracic disease will be excluded
from study.

- Patients requiring corticosteroids (other than inhaled) will be excluded.

- Patients receiving warfarin anticoagulation, who cannot be transferred to other
agents such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held
for up to 24 hours will be excluded.

- Patients with uncontrolled hypertension (>160/95), unstable coronary disease
evidenced by uncontrolled arrhythmias, unstable angina, decompensated CHF (>NYHA
Class II), or myocardial infarction within 6 months of study will be excluded.

- Patients with other cardiac diseases may be excluded at the discretion of the PI
following consultation with Cardiology consultants.

- Pregnant and/or lactating women will be excluded due to the unknown, potentially
harmful effects of immune response to CT-X antigens and stem cell proteins that may
be expressed in placenta, fetus, and neonates.

- Patients with active infections, including HIV, will be excluded, due to unknown
effects DAC/THU on systemic immunity.

- For patients enrolled on celecoxib cohort: history of ulcer disease or
gastrointestinal bleeding, hypersensitivity or asthma to celecoxib, sulfa drugs,
aspirin or other NSAID.