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

ID: NCT03233724
Status: Recruiting
Phase: Phase 1/Phase 2
Start Date: March 01, 2018
First Submitted: July 28, 2017
Last Updated: February 23, 2018
Results: N/A
Sponsors & Collaborators: National Cancer Institute (NCI)
Location: United States
Conditions: Carcinoma, Non-Small-Cell Lung, Lung Cancer, Non-Small Cell Lung Cancer
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Study Description

Brief Summary

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.

Detailed Description

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.

- Presently, there is no information regarding gene modulation and antitumor activity of oral DAC-THU in patients with cancer, and specifically no information pertaining to potentiation of responses to FDA approved immune checkpoint inhibitor regimens by DAC-THU in cancer patients.

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, 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, PD-L1 expressing, treatment na(SqrRoot) ve, inoperable locally advanced, or metastatic NSCLC

- Measurable disease

- Disease that can be safely accessed and willingness to undergo biopsy 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

- 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 starting with oral DAC-THU q Su-MT each week with incremental dose escalation in 4 cohorts.

- Pembrolizumab will be administered on Wednesday (or Th if necessary) 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 cohort will be expanded to 10 patients. If 5 or more patients respond to treatment, the cohort will be expanded to 23 patients. If 11 of 23 patients respond to treatment, the trial will be deemed positive.

- 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.
Condition or disease Intervention/treatment Phase

Carcinoma, Non-Small-Cell Lung

Lung Cancer

Non-Small Cell Lung Cancer

Drug: Decitabine (DAC)
Other Names
Drug: Tetrahydrouridine (THU)
Other Names
Drug: Pembrolizumab
Other Names
Phase 1/Phase 2

Tracking Information

First Submitted DateJuly 28, 2017
Last Update Posted DateFebruary 23, 2018
Anticipated Start DateMarch 01, 2018
Anticipated Completion DateApril 15, 2020
Anticipated Primary Completion DateDecember 01, 2018
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • 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]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

Not Available

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleThe 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
Official TitlePhase I/II Evaluation of 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
Brief Summary

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.

Detailed Description

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.

- Presently, there is no information regarding gene modulation and antitumor activity of oral DAC-THU in patients with cancer, and specifically no information pertaining to potentiation of responses to FDA approved immune checkpoint inhibitor regimens by DAC-THU in cancer patients.

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, 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, PD-L1 expressing, treatment na(SqrRoot) ve, inoperable locally advanced, or metastatic NSCLC

- Measurable disease

- Disease that can be safely accessed and willingness to undergo biopsy 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

- 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 starting with oral DAC-THU q Su-MT each week with incremental dose escalation in 4 cohorts.

- Pembrolizumab will be administered on Wednesday (or Th if necessary) 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 cohort will be expanded to 10 patients. If 5 or more patients respond to treatment, the cohort will be expanded to 23 patients. If 11 of 23 patients respond to treatment, the trial will be deemed positive.

- 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.

Study TypeInterventional
Study PhasePhase 1/Phase 2
Estimated Enrollment
44
Allocation
Non-Randomized
Interventional Model
Single Group Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Carcinoma, Non-Small-Cell Lung
Lung Cancer
Non-Small Cell Lung Cancer
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Decitabine (DAC)

Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Other Names
Drug: Tetrahydrouridine (THU)

Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Other Names
Drug: Pembrolizumab

200 mg IV once a day every Wednesday or Thursday every 3 weeks.

Other Names
Study Groups/Cohorts
Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts

Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study

Study Arms
Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Decitabine (DAC)
Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Tetrahydrouridine (THU)
Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Pembrolizumab
200 mg IV once a day every Wednesday or Thursday every 3 weeks.

Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Decitabine (DAC)
Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Pembrolizumab
200 mg IV once a day every Wednesday or Thursday every 3 weeks.

Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Tetrahydrouridine (THU)
Administered orally at increasing frequency or dose from 3 - 5 times per week for 3 weeks

Arm Intervention/Treatment
Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Decitabine (DAC)
Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Tetrahydrouridine (THU)
Experimental Dose Escalation Cohort
Subjects enrolled to dose escalation cohorts
Drug : Pembrolizumab
Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Decitabine (DAC)
Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Pembrolizumab
Experimental Dose Expansion
Subjects enrolled at the MTD after the MTD is established and subjects on Phase II portion of the study
Drug : Tetrahydrouridine (THU)

Recruitment Information

Recruitment Status:Recruiting
Enrollment44
Completion DateApril 15, 2020
Eligibility Criteria: - INCLUSION CRITERIA:
- Patients must have histologically or cytologically confirmed, treatment naive inoperable, locally advanced, or metastatic NSCLC
- Patients must have 50% or greater PD-L1 expression in cancer cells by immunohistochemistry analysis.
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
- Disease that can be safely accessed via bronchoscopic, thoracoscopic or percutaneous biopsy, and willingness to undergo biopsy before and after treatment.
- Age >=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 (Karnofsky greater than or equal to 60%), without evidence of unstable or decompensated myocardial disease; adequate pulmonary reserve evidenced by FEV1 and DLCO greater than or equal to 35% predicted; pCO2 < 50 mm Hg and pO2 > 60 mm Hg on room air ABG
- 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 sensitizing EGFR or ALK mutations, or PD-L1 expression less than 50%
- 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.
- 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.
GenderAll
Age18 Years to 99 Years
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03233724
Other Study ID Numbers
170140
17-C-0140
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
National Cancer Institute (NCI)
Collaborators
Not Available
Investigators
Principal Investigator
David S Schrump, M.D.
National Cancer Institute (NCI)