Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Adenocarcinoma

Pancreatic Neoplasms

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Decitabine

Tetrahydrouridine

Antimetabolites

Enzyme Inhibitors

Tetrahydrouridine (THU) is supplied as 250 mg/capsule, Decitabine (Dec) as 5 mg/capsule.

Starting dose is by weight:

THU is supplied as 250 mg/capsule Weight 40-60kg = 2 capsules of Tetrahydrouridine. Weight 61-80kg = 3 capsules of THU. Weight 81-100kg or higher = 4 capsules of THU.

Timing between THU and Dec, Frequency of administration: Oral THU capsules followed 60 minutes later by oral Dec capsules are ingested 2X/week on consecutive days. Treatment on protocol monitoring continues for 52 weeks, however, subjects will have the option to continue beyond this period if it judged to be in their interests.

Starting dose is by weight:

DEC is supplied as 5 mg/capsule. Weight 40-60kg = 2 capsules of Decitabine. DEC capsules are ingested \~60 minutes after THU capsules. Weight 61-80kg = 3 capsules of DEC. DEC capsules are ingested \~60 minutes after THU capsules. Weight 81-100kg or higher = 4 capsules of DEC. DEC capsules are ingested \~60 minutes after THU capsules.

Timing between THU and Dec, Frequency of administration: Oral THU capsules followed 60 minutes later by oral Dec capsules are ingested 2X/week on consecutive days. Treatment on protocol monitoring continues for 52 weeks, however, subjects will have the option to continue beyond this period if it judged to be in their interests.

Devendra P Sohal, MD, MPH

Patients with pancreatic cancer which has stopped responding to one or more chemotherapy drugs are asked to take part in this study. The study hopes to find out whether decitabine, the drug being studied, will have an effect on pancreatic cancer. The decitabine is being given at a lower dose than its approved use. It is also being given with another drug, tetrahydrouridine (THU), to improve the exposure of your pancreatic cancer cells to decitabine.

The purpose of this study is to determine if the drug combination of decitabine and tetrahydrouridine can recognize a certain DNA target in your cancer. All cells have DNA within them, and tumor cells have abnormal DNA.

Primary Objective The primary goal of this pilot study is to detect decitabine therapy induced DNMT1 protein level decreases with an effect size of 1 using a paired t-test and alpha=0.05. The effect size is defined as the difference in mean DNMT1-protein levels between post-treatment and pre-treatment divided by the standard deviation and is thus a metric of change in the natural units of the distribution, its standard deviation. Our goal is thus to detect drops in DNMT1 of at least one standard deviation.

Secondary Objectives Secondary goals include correlating DNMT1 decreases with clinical response (measured by Response Evaluation Criteria in Solid Tumors \[RECIST1.1\]), using logistic regression; time to relapse, using a Cox model; tolerability and safety assessment by toxicity characterization using CTCAEv4.

Study Design Single-arm, open-label, proof-of-concept clinical trial in patients with metastatic pancreatic cancer that has progressed on one or more lines of systemic therapy.

p53/p16-Independent Epigenetic Therapy With Oral Decitabine/Tetrahydrouridine for Pancreatic Cancer

p53/p16-Independent Epigenetic Therapy With Oral Decitabine/Tetrahydrouridine for Advanced Pancreatic Cancer That Has Progressed Through One or More Lines of Therapy

Differences will be calculated using a paired t-test and alpha=0.05. The effect size is defined as the difference in mean DNMT1-protein levels between post-treatment and pre-treatment divided by the standard deviation and is thus a metric of change in the natural units of the distribution, its standard deviation. Our goal is thus to detect drops in DNMT1 of at least one standard deviation.

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started) The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.

Overall Survival will be calculated as time in days from enrollment (signing of the informed consent) to death.

Progression-free Survival will be calculated as time in days from enrollment (signing of the informed consent) to the earlier of:

* Death, or
* Disease progression, by clinical or imaging parameters.

Yogen Saunthararajah

Professor, Hematology and Oncology

Nervous System Diseases

Carcinoma

Central Nervous System Neoplasms

Nervous System Neoplasms

The study's starting dose of CldC is 50 mg/m2/day. The dose of CldC will be escalated / de-escalated for patients. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.

Cytochlor

A fixed dose of H4U at 720 mg/m2/day will be used, regardless of the dose of CldC administered. H4U will be delivered by an IV bolus infusion over a period of 5 minutes, followed 5 minutes later by an IV bolus infusion of CldC. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.

One treatment of 3 Gy will be given daily 5 days per week (10 fractions) for a total of 30 Gy over two weeks.

Radiation Therapy

Fazilat Ishkanian, MD

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as cytochlor and tetrahydrouridine, may make tumor cells more sensitive to radiation therapy.

PURPOSE: This phase I trial is studying the side effects and best dose of cytochlor when given together with tetrahydrouridine and external-beam radiation therapy in treating patients with cancer that has spread to the brain.

OBJECTIVES:

Primary

* Establish the safety and toxicity profile of cytochlor and H4U when given in combination with external-beam radiotherapy for 2 weeks after treatment with the drugs alone in the previous week.

Secondary

* Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with cytochlor and H4U.
* Perform detailed pharmacokinetic studies to determine the levels of cytochlor and its metabolites in serum and in urine in weeks 1, 2, and 3 during treatment.

OUTLINE: This is a dose-escalation study of cytochlor.

Patients receive cytochlor IV and tetrahydrouridine (H4U) IV over 5 minutes on 3 days in week 1 and on days 1-5 in weeks 2 and 3. Patients also undergo external-beam radiotherapy 5 days a week in weeks 2 and 3 initiated 3-4 hours after infusions of cytochlor and H4U. Treatment may repeat in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed monthly for 3 months, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.

Cytochlor, Tetrahydrouridine, and External-Beam Radiation Therapy in Treating Patients With Cancer That Has Spread to the Brain

Translational Phase I Trial of Escalating Doses of 5-Chloro-2'-Deoxycytidine (CldC) With a Fixed Dose of Tetrahydrouridine Combined With External Brain Radiation for Metastatic Carcinoma to the Brain

Baseline Levels of CD will be obtained by assaying CD in serum prior to initiation of treatment on Wednesday of week 1. Follow-up assays of CD in serum will be made on the Fridays of weeks 1 to 3 after each day's treatment with CldC + H4U. In weeks 2 and 3 this will take place prior to RT

Brian Lally

Assistant Professor of Clinical

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Oral Squamous Cell Carcinoma

Cisplatin

cisplatin

cytochlor

tetrahydrouridine

radiation therapy

Luis E. Raez, MD, FACP

May Abdel-Wahab, MD, PhD

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Radiosensitizing drugs, such as cytochlor and tetrahydrouridine, may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as cisplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Combining radiosensitizers with chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of cytochlor when given together with tetrahydrouridine, cisplatin and radiation therapy in treating patients with advanced squamous cell carcinoma of the oral cavity (mouth) or oropharynx (throat).

OBJECTIVES:

Primary

* Determine the dose range of cytochlor to be used in phase II trials, based on safety, toxicity, and tissue selectivity, in patients with advanced squamous cell carcinoma of the oral cavity or oropharynx.
* Determine the safety and toxicity profile of cytochlor, tetrahydrouridine, and concurrent radiotherapy followed by radiotherapy alone in these patients.
* Determine the percentage of cancer cells vs normal cells that incorporate cytochlor in the DNA of patients treated with this regimen.
* Determine the percentage replacement of thymine by 5-chlorouracil in tumors vs normal tissue of patients treated with this regimen.

Secondary

* Determine the tissue selectivity of this regimen in these patients.
* Determine the level of cytochlor and its metabolites within the serum and urine of these patients during combination treatment and before radiotherapy alone is initiated.
* Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of cytochlor.

Patients receive tetrahydrouridine IV over 5 minutes followed by cytochlor IV for 3 days on week 1 and 5 days a week on weeks 2-4 and cisplatin IV over 30-60 minutes once in weeks 2 and 5. Patients also undergo radiotherapy 5 days a week during weeks 2-7. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of cytochlor until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 1 of 3 or 3 of 6 patients experience dose-limiting toxicity.

Patients are followed at 1 month, monthly for 3 months, every 3 months for up to 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study within 2 years.

Cytochlor and Tetrahydrouridine as Radiosensitizers and Cisplatin Combined With Radiation Therapy in Treating Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity (Mouth) or Oropharynx (Throat)

Translational Phase I Trial of Escalating Doses of 5-Chloro-2'-Deoxycytidine (CldC) With a Fixed Dose of Tetrahydrouridine Combined With a Fixed Dose of Cisplatin Concomitant With Definitive Radiation in Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity and Oropharynx

National Cancer Institute (NCI)

University of Miami

Symptoms and General Pathology

Blood and Lymph Conditions

Neoplasm Metastasis

Syndrome

Recurrence

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Neoplastic Processes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Patients receive FdCyd IV over 3 hours and THU IV over 3 hours on days 1-10. Courses repeat every 21days in the absence of disease progression or unacceptable toxicity.

5-fluoro-2-deoxycytidine

laboratory biomarker analysis

reverse transcriptase-polymerase chain reaction

DNA methylation analysis

Robert Chen, MD

This phase I trial is studying the side effects and best dose of 5-Fluoro-2'-deoxycytidine (FdCyd) when given together with tetrahydrouridine (THU) in treating patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). FdCyd may inhibit cancer cell growth by increasing the production in cells of compounds that suppress growth or by otherwise killing cells. Although FdCyd is stable as a drug solution, it is rapidly inactivated by an enzyme present in people. THU is included in the treatment to inhibit the enzyme, prolonging the time FdCyd remains in the body

OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of FdCyd administered with a fixed dose of THU in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), once daily on days 1-10 of a 21-day treatment cycle. II. To describe the toxicities of FdCyd/THU in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). III. To document all clinical responses and hematologic improvement in patients treated with FdCyd/THU. IV. To obtain preliminary information regarding the effect of FdCyd/THU on deoxyribonucleic acid (DNA) methylation patterns in peripheral blood mononuclear cells and bone marrow aspirates, including malignant myeloid cells; the ratio of gamma- to beta-globin messenger ribonucleic acid (mRNA) in blood cells; and serum cytokines. OUTLINE: This is a dose-escalation study of FdCyd. Patients receive FdCyd intravenously (IV) over 3 hours and THU IV over 3 hours on days 1-10. Courses repeat every 21days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

A Phase I Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU) in Myeloid Leukemia and MDS

Toxicities will be summarized by Common Terminology Criteria for Adverse Events (CTCAE) grade and attribution using the version current at the initiation of the protocol.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
p53/p16-Independent Epigenetic Therapy With Oral Decitabine/Tetrahydrouridine for Pancreatic Cancer	NCT02847000	Metastatic Panc...	Tetrahydrouridi... Decitabine	18 Years -	Case Comprehensive Cancer Center
Cytochlor, Tetrahydrouridine, and External-Beam Radiation Therapy in Treating Patients With Cancer That Has Spread to the Brain	NCT00521183	Brain and Centr...	Cytochlor Tetrahydrouridi... Radiation Thera...	21 Years -	University of Miami
Cytochlor and Tetrahydrouridine as Radiosensitizers and Cisplatin Combined With Radiation Therapy in Treating Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity (Mouth) or Oropharynx (Throat)	NCT00077051	Head and Neck C...	cisplatin cytochlor tetrahydrouridi... radiation thera...	21 Years - 120 Years	University of Miami
5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes	NCT01041443	Adult Acute Mye... de Novo Myelody... Previously Trea... Recurrent Adult... Secondary Acute... Secondary Myelo... Untreated Adult...	5-fluoro-2-deox... tetrahydrouridi... laboratory biom... reverse transcr... DNA methylation...	18 Years -	City of Hope Medical Center
5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes	NCT01041443	Adult Acute Mye... de Novo Myelody... Previously Trea... Recurrent Adult... Secondary Acute... Secondary Myelo... Untreated Adult...	5-fluoro-2-deox... tetrahydrouridi... laboratory biom... reverse transcr... DNA methylation...	18 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for tetrahydrouridine