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Lung CancerPhase 2PRECISENCT02664181

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

A Phase 2 study testing Nivolumab, oral decitabine and Tetrahydrouridine in people with Lung Cancer and Non-small Cell Lung Cancer, run by Case Comprehensive Cancer Center at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Lung Cancer, Non-small Cell Lung Cancer
What is being tested?
Nivolumab, oral decitabine and Tetrahydrouridine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
2 sitesUnited States
Study dates
6 Jun 2017to 19 May 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Center for Cancer Research

    Bethesda, Maryland, 20892

  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44118

Other trials in United States

About this study

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

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.

Read the detailed description

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

Secondary objectives:

  1. 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.

Being tested
Nivolumab, oral decitabine, Tetrahydrouridine
Keywords
Cancer, Nivolumab, Decitabine, Tetrahydrouridine
Medical subject headings
Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Also called Opdivo

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

  • oral decitabineDrug

    Also called decitabine, DEC, Dacogen

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

  • TetrahydrouridineDrug

    Also called THU

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

Study groups in NCT02664181
Study groupRoleWhat they receive
Oral THU/decitabine + NivolumabExperimentalOral 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
Receives: Drug: Nivolumab; Drug: oral decitabine; Drug: Tetrahydrouridine
NivolumabActive comparatorNivolumab 3mg/kg IV Q2 weeks until progression; This is the standard of care for patients with NSCLC who have progressed on prior chemotherapy.
Receives: Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 52 weeks after beginning therapy

Secondary outcomes (3)

  1. Time-to-Progression

    Time-to-Progression 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.

    Measured: Up to 77 weeks after beginning treatment

  2. 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.

    Measured: Up to 171 weeks after beginning treatment

  3. Overall Survival - Long Term Follow-up (LTFU)

    Survival LTFU is planned to be done until death or withdrawal of consent, or until the final clinical trial report is published

    Measured: Up to 5 years from end of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jan 2016 (estimated)
  2. Study start6 Jun 2017
  3. Primary completion2 Jul 2019
  4. Study completion19 May 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02664181
Sponsor's protocol ID
CASE3516
Acronym
PRECISE
Status last verified
Aug 2024
First submitted
22 Jan 2016
Last updated
3 Sep 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab, oral decitabine and Tetrahydrouridine in people with Lung Cancer and Non-small Cell Lung Cancer, run by Case Comprehensive Cancer Center at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response by Response Evaluation Criteria in Solid Tumors (RECIST1.1) (time frame: Up to 52 weeks after beginning therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02664181.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2024.

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