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

NCT02839694 | Withdrawn Phase 1

• 2 other identifiers: 16014616-C-0146
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Neoplasm Metastasis; Sarcoma; Neoplasms, Germ Cell and Embryonal; Melanoma

Keywords

Lung Resection; Surgery; Bilateral Lung Metastases

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose

  4 weeks after the start of study therapy

• Table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen

  30 days after treatment initiation

Study Arms (3)

Dose escalation cohort

EXPERIMENTAL

dose escalation cohort

Drug: decitabine (DAC); Drug: Tetrahydrouridine (THU)

Expansion cohort

EXPERIMENTAL

expansion cohort at MTD

Drug: decitabine (DAC); Drug: Tetrahydrouridine (THU)

expansion cohort with celecoxib

ACTIVE COMPARATOR

expansion cohort at MTD with celecoxib

Drug: decitabine (DAC); Drug: Tetrahydrouridine (THU); Drug: Celecoxib

Interventions

decitabine (DAC) DRUG

Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks

Dose escalation cohort; Expansion cohort; expansion cohort with celecoxib

Tetrahydrouridine (THU) DRUG

Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks

Dose escalation cohort; Expansion cohort; expansion cohort with celecoxib

Celecoxib DRUG

400 mg orally twice a day every day for while on DAC-THU therapy

expansion cohort with celecoxib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Neoplasm Metastasis; Sarcoma; Neoplasms, Germ Cell and Embryonal; Melanoma

Interventions

Decitabine; Tetrahydrouridine; Celecoxib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Uridine; Benzenesulfonamides; Sulfonamides; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2016
• First Posted: July 21, 2016
• Study Start: July 7, 2016
• Primary Completion: April 26, 2017
• Study Completion: April 26, 2017
• Last Updated: July 5, 2018

Record last verified: 2017-04-26