Nivolumab Alone or in Combination With Decitabine/Tetrahydrouridine in Non-small Cell Lung Cancer

Lung Cancer Clinical Trial

Official title:

Phase II Evaluation of Nivolumab, an Immune Checkpoint Inhibitor, Alone or in Combination With Oral Decitabine/Tetrahydrouridine as Second Line Therapy for Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02795923
• Other study ID #: CASE3516
• Status: Not yet recruiting
• Phase: Phase 2
• First received: June 7, 2016
• Last updated: June 7, 2016
• Start date: September 2016
• Est. completion date: December 2018

Study information

• Verified date: June 2016
• Source: Case Comprehensive Cancer Center
• Contact: Vamsidhar Velcheti, MD
• Phone: 216-444-8665
• Email: velchev[@]ccf.org
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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 in your body 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.

Description:

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 in combination with nivolumab ii) To evaluate the Immune priming effect of THU-Dec combination therapy by functional and phenotypic circulating immune cell characterization and changes in the immune contexture in the tumor tissue 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

• Measurable disease per RECIST1.1

• Disease that can be accessed by a bronchoscopic, surgical or percutaneous biopsy, eligible for biopsy from safety perspective, and agrees to biopsy prior to study. The pre-study biopsy can be waived if there is an archival biopsy specimen that was obtained after the most recent therapy.

• Eastern cooperative oncology group (ECOG) performance status 0 - 2

• Adequate organ function as defined by the following criteria:

• Absolute neutrophil count (ANC) = 1,500/mcL

• Platelets = 100,00/mcL

• Hemoglobin = 8.5g/dL or = 5.6mmol/L

• Serum creatinine = 1.5 times upper limit of normal (ULN)

• OR 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 ULN

• OR direct bilirubin = ULN for subjects with total bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) = 2.5 times ULN

--- OR = 5 times ULN for subjects with liver metastases

• Albumin = 2mg/dL

• Patients with history of brain metastases can be eligible for study treatment at a minimum of 1 week following the completion of gamma knife or whole brain radiotherapy. 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 significant bleeding or pulmonary embolism.

• 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 epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase tyrosine-kinase inhibitors (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 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.

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

• Has known active Hepatitis B or Hepatitis C.

• Has received a live vaccine within 30 days of planned start of study therapy.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Nivolumab
Nivolumab 3mg/kg IV Q2 weeks until progression
• oral decitabine
oral decitabine ~0.2 mg/kg 60 minutes after the THU, twice weekly on consecutive days.
• Tetrahydrouridine
Oral THU ~10 mg/kg twice weekly on consecutive days

Locations

Country	Name	City	State
United States	Center for Cancer Research	Bethesda	Maryland
United States	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio
United States	University Hospitals Case Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Yogen Saunthararajah

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST1.1)	Overall response rate (ORR) is defined as the proportion of all randomized subjects whose best overall response (BOR) from baseline is either a complete response (CR) or partial response (PR) per RECIST 1.1 criteria. BOR is determined by the best response designation recorded between the date of randomization and the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For subjects without documented progression or subsequent anticancer therapy, all available response designations will contribute to the BOR determination. For subjects who continue treatment beyond progression, the BOR should be determined based on response designations recorded at the time of the initial RECIST 1.1 defined progression.	Up to 12 months	No
Secondary	Progression free survival	Progression free survival: It is defined as the time from randomization to the date of the first documented tumor progression (per RECIST 1.1) or death due to any cause. Subjects who die without a reported prior progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on the date they were randomized. Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last evaluable tumor assessment prior to initiation of the subsequent anti-cancer therapy. Progression will be assessed every 6 weeks (from the first on-study radiographic assessment) until disease progression is noted.	Up to 12 months	No
Secondary	Overall survival	Overall survival: It is defined as the time from randomization to the date of death. A subject who has not died will be censored at last known date alive. Overall survival (OS) will be followed continuously while subjects are on the study drug.	Up to 12 months	No