Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in People Undergoing Pulmonary Metastasectomy

• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

Most patients who have surgery for cancer that has metastasized (spread) to the lungs later get more metastases that cannot be treated with surgery or chemotherapy. The drug resistance may be due to DNA changes in cancer cells that activate some genes and turn others off. Researchers want to test a combination of drugs for people with metasteses. Decitabine (DAC) may reverse the DNA changes. Tetrahydrouridine (THU) makes DAC last longer. Celecoxib may slow the progression of cancer.

Objectives:

To determine a safe dose of DAC and THU by mouth. To see if DAC-THU with or without celecoxib reactivates genes in lung metastases.

Eligibility:

Adults 18 years and older, with cancer in both lungs that can be treated with surgery.

Design:

Participants will be screened with:

Blood, lung, and heart tests

Scans

Tests for viruses

Pregnancy test

Participants will have blood and stool tests.

They will have surgery to remove metasteses in 1 lung.

About 3 weeks later, they will have lung scans. If the disease is not back, participants will get DAC and THU with or without celecoxib, by mouth for 6 weeks.

Participants will have more scans. If the disease is not worse, they will continue the study drugs for 4 more weeks.

Participants will have more scans and heart and lung tests. They will have surgery to remove metasteses from the other lung.

Participants will have weekly blood and urine tests, plus several blood draws the first 2 days of taking the drugs.

Participants will have exams and blood tests before each surgery.

Participants will have follow-up visits 1 and 3 months after the second surgery.

Condition or disease	Intervention/treatment	Phase
Neoplasm Metastasis; Sarcoma; Neoplasms, Germ Cell and Embryonal; Melanoma	Drug: decitabine (DAC); Drug: Tetrahydrouridine (THU); Drug: Celecoxib	Phase 1

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Evaluation of Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in Patients Undergoing Pulmonary Metastasectomy
• Study Start Date: July 7, 2016
• Actual Primary Completion Date: April 26, 2017
• Actual Study Completion Date: April 26, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose escalation cohort; dose escalation cohort	Drug: decitabine (DAC); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks; Drug: Tetrahydrouridine (THU); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks
Experimental: Expansion cohort; expansion cohort at MTD	Drug: decitabine (DAC); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks; Drug: Tetrahydrouridine (THU); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks
Active Comparator: expansion cohort with celecoxib; expansion cohort at MTD with celecoxib	Drug: decitabine (DAC); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks; Drug: Tetrahydrouridine (THU); Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks; Drug: Celecoxib; 400 mg orally twice a day every day for while on DAC-THU therapy

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose [ Time Frame: 4 weeks after the start of study therapy ]
2. Table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen [ Time Frame: 30 days after treatment initiation ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:
• Patients with bilateral pulmonary metastases from sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to the lungs, mediastinum, or pleura who can be rendered no clinical evidence of active disease (NED) or minimal residual disease (MRD) by standard of care metastasectomy where NED refers to diagnostic tests failing to detect presence of disease and MRD refers to low-volume, subclinical disease which is not amenable to standard of care biopsy for histologic confirmation and poses no immediate threat to patient health and would not otherwise warrant standard of care treatment but surveillance instead.
• Patients must have a minimum of two metastases per hemithorax.
• Patients with active disease outside the thorax may be eligible for study once the extrathoracic disease is definitively treated by local modalities such as radiation, surgery, or radiofrequency ablation.
• Patients must have adequate pulmonary reserve evidenced by predicted post-operative FEV1 and DLCO equal to or greater than 40% predicted; pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG; and be on no immunosuppressive medications except inhaled corticosteroids.
• Patients must have received first line standard systemic therapy for their metastases (if applicable).
• Patients with intracranial metastases, which have been treated by surgery or radiation therapy, may be eligible for study provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids following treatment.
• Patients must have an ECOG performance status of 0-2.
• Patients must have recovered from non-hematologic toxicities associated with treatment of malignancy to less than or equal to grade 1.
• Patients must be 18 years of age or older due to the unknown effects of systemic DNA hypomethylation and immunologic responses to germ cell-restricted gene products during childhood and adolescent development.

• Patients must have evidence of adequate bone marrow reserve, hepatic and renal function as evidenced by the following laboratory parameters:

  • Absolute neutrophil count greater than 1500/mm(3) without transfusion or cytokine support
  • Platelet count greater than 100,000/mm(3)
  • Hemoglobin greater than 8g/dl (patients may receive transfusions to meet this parameter)
  • PT no more than 2 seconds above the ULN
  • Total bilirubin <1.5 times upper limits of normal
  • Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m(2).
• Seronegative for HIV antibody. Note: The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus may be less responsive to the experimental treatment.
• Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
• Patients must be aware of the neoplastic nature of their illnesses, the experimental nature of the therapy, alternative treatments, potential benefits, and risks.
• Patients must be willing to practice birth control during and for four months following treatment.
• Patients must be able to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation.
• Patients who had prior lung resection are eligible provided they fulfil the rest of the eligibility criteria.
• Patients must be willing to sign an informed consent.

EXCLUSION CRITERIA:

• Patients with uncontrollable progression of extra-thoracic disease will be excluded from study.
• Patients requiring corticosteroids (other than inhaled) will be excluded.
• Patients receiving warfarin anticoagulation, who cannot be transferred to other agents such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held for up to 24 hours will be excluded.
• Patients with uncontrolled hypertension (>160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated CHF (>NYHA Class II), or myocardial infarction within 6 months of study will be excluded.
• Patients with other cardiac diseases may be excluded at the discretion of the PI following consultation with Cardiology consultants.
• Pregnant and/or lactating women will be excluded due to the unknown, potentially harmful effects of immune response to CT-X antigens and stem cell proteins that may be expressed in placenta, fetus, and neonates.
• Patients with active infections, including HIV, will be excluded, due to unknown effects DAC/THU on systemic immunity.
• For patients enrolled on celecoxib cohort: history of ulcer disease or gastrointestinal bleeding, hypersensitivity or asthma to celecoxib, sulfa drugs, aspirin or other NSAID.

Contacts and Locations

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: David S Schrump, M.D.; National Cancer Institute (NCI)

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02839694 History of Changes
• Other Study ID Numbers: 160146; 16-C-0146
• First Posted: July 21, 2016
• Last Update Posted: July 4, 2018
• Last Verified: April 26, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Lung Resection; Surgery; Bilateral Lung Metastases

Additional relevant MeSH terms:

Neoplasms; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Neoplastic Processes; Pathologic Processes; Neoplasms by Histologic Type; Celecoxib; Decitabine; Tetrahydrouridine; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents