Rational EpigenetiC Immunotherapy for SEcond Line Therapy in Patients With NSCLC: PRECISE Trial

NCT02664181 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: CASE3516
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 2

Brief 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 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.

Conditions

Lung Cancer; Non-small Cell Lung Cancer

Keywords

Cancer; Nivolumab; Decitabine; Tetrahydrouridine

Outcome Measures

Primary Outcomes (1)

• Objective Response 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 52 weeks after beginning therapy

Secondary Outcomes (3)

• Time-to-Progression

  Up to 77 weeks after beginning treatment

• Overall Survival

  Up to 171 weeks after beginning treatment

• Overall Survival - Long Term Follow-up (LTFU)

  Up to 5 years from end of treatment

Study Arms (2)

Oral THU/decitabine + Nivolumab

EXPERIMENTAL

Oral THU \~10 mg/kg, followed by oral decitabine \~0.2 mg/kg 60 minutes after the THU, twice weekly on consecutive days. This drug combination is administered with Nivolumab 3mg/kg IV Q2 weeks until progression

Drug: Nivolumab; Drug: oral decitabine; Drug: Tetrahydrouridine

Nivolumab

ACTIVE COMPARATOR

Nivolumab 3mg/kg IV Q2 weeks until progression; This is the standard of care for patients with NSCLC who have progressed on prior chemotherapy.

Drug: Nivolumab

Interventions

Nivolumab DRUG

Nivolumab will be given at 3mg/kg by IV every two weeks until progression

Also known as: Opdivo

Nivolumab; Oral THU/decitabine + Nivolumab

oral decitabine DRUG

oral decitabine \~0.2 mg/kg 60 minutes after the THU, twice weekly on consecutive days.

Also known as: decitabine, DEC, Dacogen

Oral THU/decitabine + Nivolumab

Tetrahydrouridine DRUG

Oral THU \~10 mg/kg twice weekly on consecutive days

Also known as: THU

Oral THU/decitabine + Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Center for Cancer Research

Bethesda, Maryland, 20892, United States

Location

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44118, United States

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms

Interventions

Nivolumab; Decitabine; Tetrahydrouridine

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Uridine

Results Point of Contact

• Title: Dr. Nathan Pennell
• Organization: Cleveland Clinic, Case Comprehensive Cancer Center

TaussigResearch@ccf.org

1-866-223-8100

Study Officials

• Nathan Pennell, MD,PhD

  Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: January 22, 2016
• First Posted: January 26, 2016
• Study Start: June 6, 2017
• Primary Completion: July 2, 2019
• Study Completion: May 19, 2024
• Last Updated: September 3, 2024
• Results First Posted: December 10, 2020

Record last verified: 2024-08

Locations

US (2)