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Oral Decitabine and Tetrahydrouridine as Epigenetic Priming for, Pembrolizumab-Mediated Immune Checkpoint Blockade in Patients With Inoperable, or Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancers and Esophageal Carcinomas

Trial Status: Active

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the leading cause of cancer-related death in the United States. Most people with lung cancer are already in the advanced stages of the disease by the time they see a doctor. Researchers want to see if combining an approved drug with two new drugs can help. Objective: To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective in people with non-small cell lung cancer that cannot be removed by surgery. Eligibility: People 18 years and older who have NSCLC that cannot be removed by surgery Design: Participants will be screened with - Medical history - Physical exam - Blood and urine tests - Tests of heart and lung function They may have a small tumor sample taken (biopsy). They may have tumor scans. Before starting treatment, participants will repeat the screening tests. They will also give a stool sample. The study will be done in 3-week cycles for up to 6 cycles. - Participants will take the 2 study drugs by mouth 3-5 days a week. - Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle. Participants will keep a study medication diary. During cycle 1, participants will have blood taken multiple times on days 1 and 2. Every 3 cycles, participants will repeat screening tests. Participants will have a mandatory tumor biopsy. When they finish treatment, participants will have a physical exam and blood tests.

Inclusion Criteria

  • - INCLUSION CRITERIA: - Histologically or cytologically confirmed, inoperable or unresectable, locally advanced, or metastatic NSCLC or esophageal cancers including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ) carcinomas, or MPM. - NSCLC patients with no prior systemic treatment or those with prior first line treatment including an immune checkpoint inhibitor, are eligible for study. - Patients with esophageal and gastro-esophageal junction (GEJ) cancers are potentially eligible for study if they have received or refused first line standard of care cytotoxic therapy, and subsequent targeted therapy if appropriate. - Patients with MPM are eligible for study if they have received, refused or are ineligible for first line chemotherapy. - Patients who received DNA demethylating agents or PD-1/PD-L1 inhibitors for another malignancy may be eligible for study if there were no dose-limiting immune related events, and there has been either no clinical evidence of disease or minimal residual disease that has been stable for at least three years. - 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 (Dose Exoansion: NSCLC with high PD-L1) must have greater than or equal to 50% expression in cancer cells. - Patients in Cohort 3 (Dose Expansion: NSCLC with low PD-L1) must have 0-49% expression. Note: Patients in this cohort must have been offered and refused standard of care platinum-based chemotherapy - Patients in Cohort 4 (Dose Expansion: EsC) may have any level of expression. - Patients in Cohort 5 (Dose Expansion: MPM) may have any level of expression. - 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 cancers harboring any targetable mutation for which there is approved first or second line therapy, unless standard care of therapy refused. - 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.

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: ACTIVE
Contact: National Cancer Institute Referral Office
Phone: 888-624-1937

Background:

-Non-small cell lung cancers (NSCLC) esophageal carcinomas (EsC) and malignant

pleural mesotheliomas (MPM) account for approximately 185,000 deaths annually in the United

States, with over two thirds of patients presenting with advanced, incurable disease.

1st-line platinum-based chemotherapy for advanced NSCLC, EsC or MPM produces transient

responses at best, with most patients succumbing to disease within 12-16 months following

diagnosis.

- Recent randomized clinical trials have demonstrated response rates approximating 20% in

unselected patients with advanced NSCLC or EsC, and nearly 45% in patients with tumors

exhibiting high level expression of programmed death ligand 1 (PD-L1) following

administration of pembrolizumab, a humanized monoclonal anti- PD-1 antibody.

- Approximately 17% of unselected MPM patients have exhibited objective responses

following administration of pembrolizumab or other PD-1 inhibitors.

- Preclinical studies have demonstrated that epigenetic drugs such as DNA demethylating

agents and histone deacetylase (HDAC) inhibitors can prime cancer cells and tumor

microenvironments thereby enhancing efficacy of immune checkpoint inhibitors.

- Although a potent DNA demethylating agent, Decitabine has poor bioavailability and

inconsistent distribution in solid tumors due to 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/solid-tissue-distribution of low dose oral DAC, thereby enhancing

systemic DNA demethylation with acceptable toxicities.

- Preliminary results of recent clinical trial suggest that oral DAC-THU can increase the

frequency and magnitude of responses to immune checkpoint inhibitors in lung cancer

patients with low or absent intra-tumoral PD-L1 expression.

- These data support further evaluation of oral DAC-THU in combination with immune

checkpoint inhibitors for therapy of thoracic malignancies.

Objectives:

Phase I

-To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in

combination with pembrolizumab in patients with inoperable, or unresectable locally advanced

or metastatic NSCLC, EsC, or MPM.

Phase II

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

pembrolizumab in patients with inoperable, or unresectable, locally advanced or metastatic

NSCLC, EsC, or MPM.

Eligibility:

Inclusion Criteria

- Male or female, 18 years or older with histologically or cytologically-proven,

inoperable, or unresectable locally advanced, or metastatic NSCLC, EsC, or MPM.

- Measurable disease.

- Patients with high PD-L1 expression ( (Bullet) 50%) and low PD-L1 expression (0-49%) in

cancer cells by immunohistochemistry are eligible.

- NSCLC patients with no prior systemic treatment, or those with prior first line

treatment including an immune checkpoint inhibitor are eligible for study.

- MPM patients who have received, refused, or are ineligible for first line chemotherapy

are eligible.

- Patients with EsC including Seiwert-Stein Type I and Type II gastro-esophageal junction

(GEJ) carcinomas who have received or refused standard of care first line therapy and/or

targeted therapy are eligible.

- Patients who received DNA demethylating agents or PD-1/PD-L1 inhibitors for another

malignancy may be eligible for study if there were no dose-limiting immune related

events, and there has been either no clinical evidence of disease or minimal residual

disease that has been stable for at least three years.

- 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 or second 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 with incremental dose escalation of oral DAC-THU to define MTD.

- Simon 2-stage design for Phase II studies will be used to determine clinical response at

the MTD.

- Patients will receive oral DAC-THU- on T-W for two weeks out of every 3 for 9 weeks

- 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 NSCLC patients with high (50% or greater) intratumoral PD-L1 expression and 10 NSCLC

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 NSCLC 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 NSCLC 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. Up to 10 EsC patients, including those considered

to be part of the Phase I component after the MTD has been identified, will be enrolled

into a separate cohort to examine responses to DAC-THU/pembrolizumab at the MTD. If 2 or

more of these 10 EsC patients respond to treatment, these findings may warrant an

amendment or a separate Phase II trial to determine response rates to

DAC-THU/pembrolizumab in EsC patients. Similarly, if 2 or more of 10 MPM patients

respond to treatment, these findings may warrant an amendment or a separate Phase II

trial to determine response rates to DACTHU/pembrolizumab in MPM.

- 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 at least 30 days after treatment has been

discontinued, start of new anti-cancer treatment or until death, whichever occurs first.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
David S. Schrump

  • Primary ID 170140
  • Secondary IDs NCI-2018-03586, 17-C-0140, NCI-2017-01384
  • Clinicaltrials.gov ID NCT03233724