The purpose of this study is to assess whether treatment with the study drug tetrahydrouridine-decitabine (THU-Dec) in combination with nivolumab is more effective than treatment with nivolumab alone in patients with NSCLC.

Decitabine is an investigational (experimental) drug that works by depleting DNA methyltransferase 1 (DNMT1). DNMT1 is an enzyme, or protein that causes chemical changes, often increased in cancer. Blocking DNMT1 has been shown to reduce tumor formation. Decitabine is experimental in this study because it is not approved by the Food and Drug Administration (FDA) for patients with lung cancer. Decitabine is approved by the FDA for treating patients with a blood disease called myelodysplastic syndrome (MDS, a condition where the bone marrow does not make blood cells normally).

THU is an investigational (experimental) drug that works by blocking an enzyme that breaks down decitabine. This enzyme is highly expressed in solid tissues of the body, limiting the distribution of decitabine into these tissues, including solid cancer tissues. So, THU will increase the time cells are exposed to decitabine. The idea is that THU will also increase the time that the lung cancer cells are exposed to decitabine. THU is experimental because it is also not approved by the FDA, although it has been extensively used in clinical trials, including several cancer trials.

Primary objective: To determine if non-cytotoxic oral THU-Dec when combined with nivolumab can improve objective response rates of nivolumab

Secondary objectives:

i) To evaluate clinical efficacy end points and toxicity of oral THU-Dec when combined with nivolumab ii) evaluate the induction of a T-cell response in patients with metastatic NSCLC iii) To evaluate hypotheses regarding mechanisms of resistance and predictive biomarkers for response to nivolumab

Study design: This is a Phase 2 randomized two arm trial of nivolumab alone or in combination with THU-Dec, in previously treated patients with stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to compare the efficacy of oral THU-Dec as a way of enhancing the anti-tumor immune response to nivolumab to that of nivolumab alone. The primary efficacy endpoint is overall RECIST-defined response. To accomplish this goal 60 patients will be randomized 2:1 to THU-Dec plus nivolumab or nivolumab only respectively.

Inclusion Criteria:

• Histologically or cytologically-proven NSCLC

• Subjects must have received 1 or more prior systemic therapies for this disease, should not have had prior treatment with immunotherapy; (including immune checkpoint inhibitor drugs, or immunotherapy vaccines); Patients with epidermal growth factor receptor (EGFR) or ALK alterations will need to have progressed on a TKI treatment

• Measurable disease per RECIST1.1

• Disease that can be accessed by a bronchoscopic, surgical or percutaneous biopsy

  • Eligible for biopsy from safety perspective
  • Agrees to percutaneous biopsy prior to study, may be eligible if archival tissue from a biopsy is after most recent therapy.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

• Adequate organ function as defined by the following criteria:

  • Absolute neutrophil count ≥1,500/mcL
  • Platelets ≥100,000/mcL
  • Hemoglobin ≥8.5g/dL or ≥5.6mmol/L
  • Serum creatinine ≤1.5 times upper limit of normal
  • Measured or calculated creatinine clearance ≥ 30mL/min for subject with creatinine levels > 1.5 times institutional upper level of normal (ULN)
  • Serum total bilirubin ≤1.5 times upper limit of normal
  • Direct bilirubin ≤ upper limit of normal for subjects with total bilirubin levels > 1.5 upper limit of normal
  • AST (SGOT) ≤2.5 times upper limit of normal or ≤5 times upper limit of normal for subjects with liver metastases
  • ALT (SGPT) ≤2.5 times upper limit of normal or ≤5 times upper limit of normal for subjects with liver metastases
  • Albumin ≥ 2 mg/dL

• Patients with history of brain metastases can be eligible for study treatment at a minimum of 1 weeks following the completion of gamma knife or whole brain radiotherapy. (if patient underwent surgical resection of brain metastasis need to wait for 4 weeks before study treatment) Patients should ideally be off steroids at the start of study treatment, however patients on steroid taper and dose of no more than 2mg/day of Decadron at the time of study treatment are allowed; and steroids should be tapered off as quickly as clinically feasible.

• Subjects must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, severe peripheral vascular disease (claudication) or procedure on peripheral vasculature, coronary/peripheral artery bypass graft, New York Heart Association grade II or greater congestive heart failure, cerebrovascular accident or transient ischemic attack, clinically unstable bleeding or pulmonary embolism leading to hemodynamic compromise are not allowed
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness (HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with oral THU-Dec. Appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated.
• Pregnancy or breastfeeding (pregnant or breastfeeding women are excluded from this study because oral THU-Dec has 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 oral THU-Dec, breastfeeding should be discontinued if the mother is treated with oral THU-Dec.
• 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.
• 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 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; Patients who receive palliative radiation therapy within 1 week prior to day 1 are allowed. Patients on treatment with targeted therapy (like EGFR or ALK TKIs) may start study treatment 5 days from last treatment.
• Receiving other investigational agent
• 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,in situ cervical cancer, superficial bladder cancer or localized low grade prostate cancer not requiring active treatment
• Has active and documented history of autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Patients with psoriasis and rheumatoid arthritis with no evidence of disease flare off immunosuppression for >1year may be allowed after discussion with the study PI. 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 217 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., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
• Has received a live vaccine within 30 days of planned start of study therapy.

Participants enrolled in study

Adverse events were collected while the participants were on treatment for up to 20 months