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The Immune Checkpoint Inhibitor Pembrolizumab in Combination With Oral Decitabine and Tetrahydrouridine as First-Line Therapy for Inoperable, Locally Advanced or Metastatic Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT03233724
Recruitment Status : Recruiting
First Posted : July 31, 2017
Last Update Posted : August 29, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

July 28, 2017
July 31, 2017
August 29, 2018
April 11, 2018
December 31, 2019   (Final data collection date for primary outcome measure)
  • Maximum tolerated dose [ Time Frame: After 3 weeks at cycle 1 at each dose level dose level ]
    safety
  • Overall response rate [ Time Frame: Every 9 weeks until at disease progression ]
    determine if this combination is associated with a response rate which exceeds that of Pembrolizumab alone in patients who have PD-Ll expression of at least 50 % and those who do not
  • Maximum tolerated dose [ Time Frame: After 3 weeks at cycle 1 at each dose level dose level ]
  • Overall response rate [ Time Frame: Every 9 weeks until at disease progression ]
Complete list of historical versions of study NCT03233724 on ClinicalTrials.gov Archive Site
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The Immune Checkpoint Inhibitor Pembrolizumab in Combination With Oral Decitabine and Tetrahydrouridine as First-Line Therapy for Inoperable, Locally Advanced or Metastatic Non-small Cell Lung Cancer
Phase I/II Evaluation of the Immune Checkpoint Inhibitor, Pembrolizumab in Combination With Oral Decitabine and Tetrahydrouridine as First-Line Therapy for Inoperable, or Unresectable Locally Advanced or Metastatic Non-small Cell Lung Cancer

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.

Background:

  • Lung cancer is the leading cause of cancer-related mortality in the United States, with over two thirds of patients presenting with advanced stage of disease. 1st-line platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) produces transient responses at best, with most patients succumbing to disease within 12-16 months following diagnosis.
  • A recent randomized clinical trial demonstrated a response rate approximating 45% in treatment naive patients with advanced NSCLC with high level PD-L1 expression of programmed death ligand 1 (PD-L1) following administration of pembrolizumab, a humanized monoclonal anti- PD-1 antibody.
  • Additional studies suggest that responses to immune checkpoint inhibitors may be augmented by epigenetic drugs such as DNA demethylating agents and histone deacetylase (HDAC) inhibitors.
  • Although a potent DNA hypomethylating agent, Decitabine has significant limitations regarding chronic treatment of solid tumors due to poor bioavailability resulting from 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/solidtissue- distribution of low dose oral DAC, thereby enhancing systemic DNA demethylation without dose limiting toxicities.
  • Results of an ongoing clinical trial suggest that oral DAC-THU can increase the frequency and magnitude of responses to immune checkpoint inhibitors when used as second-line therapy in lung cancer patients with low or absent intra-tumoral PD-L1 expression.
  • Collectively these data support implementation of such strategies for front-line therapy of NSCLC.

Objectives:

  • Phase I - To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in combination with pembrolizumab in first-line therapy of inoperable, or unresectable locally advanced, or metastatic NSCLC
  • Phase II - To determine clinical response by RECIST criteria to oral DAC-THU in combination with pembrolizumab

Eligibility:

  • Inclusion Criteria

    • Male or female, 18 years or older with histologically or cytologically-proven, inoperable or unresectable locally advanced, or metastatic NSCLC
    • Measurable disease
    • Patients with high PD-L1 expression (greater than or equal to 50%) and low PD-L1 expression (0-49%) in lung cancer cells by immunohistochemistry are eligible. Patients with low PD-L1 expression in tumor cells must have been offered and refused first line platinum based chemotherapy.
    • 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 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 starting with oral DAC-THU q M-T-W each week with incremental dose escalation in 4 cohorts dose levels.
  • 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 patients with high (50% or greater) intratumoral PD-L1 expression and 10

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 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 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.

  • 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 100 days after treatment has been discontinued, start of new anti-cancer treatment or until death, whichever occurs first.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Carcinoma, Non-Small-Cell Lung
  • Lung Cancer
  • Non-Small Cell Lung Cancer
  • Drug: Decitabine (DAC)
    Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks
  • Drug: Tetrahydrouridine (THU)
    Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks
  • Drug: Pembrolizumab
    200 mg IV once a day every Wednesday or Thursday every 3 weeks.
  • Experimental: 2/Dose Expansion
    DAC-THU + pembrolizumab at the dose established in Arm 1
    Interventions:
    • Drug: Decitabine (DAC)
    • Drug: Tetrahydrouridine (THU)
    • Drug: Pembrolizumab
  • Experimental: 1/Dose Escalation
    DAC-THU + pembrolizumab at escalating doses
    Interventions:
    • Drug: Decitabine (DAC)
    • Drug: Tetrahydrouridine (THU)
    • Drug: Pembrolizumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
75
44
December 31, 2020
December 31, 2019   (Final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:
  • Patients must have histologically or cytologically confirmed, inoperable or unresectable, locally advanced, or metastatic NSCLC
  • Patients who have received no prior systemic treatment.
  • 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 (high PD-L1) must have greater than or equal to 50% expression
  • Patients in Cohort 3 (low PD-L1) must have 0-49% expression
  • Patients must have 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 lung cancers harboring any targetable mutation for which there is approved for first line therapy.
  • 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.
Sexes Eligible for Study: All
18 Years to 99 Years   (Adult, Older Adult)
No
Contact: Tricia Kunst, R.N. (240) 760-6234 kunstt@mail.nih.gov
United States
 
 
NCT03233724
170140
17-C-0140
Not Provided
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
August 21, 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP