Dose Escalation Trial Of 2-Deoxy-D-Glucose (2DG) In Subjects With Advanced Solid Tumors

Study Overview

Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) in Subjects With Advanced Solid Tumors

The objectives of this study are to evaluate the safety, tolerability, pharmacokinetics, and biologic effect (FDG PET, preliminary efficacy) of daily oral doses of 2DG with and without weekly docetaxel in subjects with advanced solid tumors.

2-deoxy-D-glucose (2DG) is a synthetic glucose analog under development by Threshold Pharmaceuticals, Inc. that exploits the differences in metabolism between normal and malignant cells. Malignant cells utilize glucose at a much higher rate than normal cells and are therefore more dependent on aerobic and anaerobic glycolysis. If glycolysis could be blocked preferentially in malignant cells, 2DG would have potential for anti-tumor therapy. Hypoxic cells are especially dependent on anaerobic glycolysis and are generally resistant to anti-tumor therapies such as chemotherapy and radiotherapy. Therefore, combining 2DG with chemotherapy may be a way to simultaneously target both hypoxic and aerobic cells in tumors. Four factors may play a role in the preferential toxicity of 2DG in malignant cells: (1) increased uptake and retention of glucose analogs by malignant cells; (2) relative hypoxia of tumor cells relative to normal cells; (3) malignant cells may be more sensitive to glucose deprivation than normal cells; and (4) inhibition of glycolysis may increase sensitivity to some cytotoxic agents. Preliminary data in human tumor xenografts support this hypothesis. Because 2DG is most likely to be effective in combination with chemotherapy, this trial was designed to evaluate the maximum tolerated dose (MTD) of 2DG both alone and in combination with chemotherapy. Docetaxel was chosen because there is evidence in human tumor xenografts of delayed tumor growth for 2DG in combination with paclitaxel compared to paclitaxel alone and it has been reported that taxanes may enhance uptake of 2DG into malignant cells. Patients with advanced solid tumors were chosen because they are appropriate candidates for a Phase I clinical trial and because their tumors are likely to have areas of hypoxia.

Lung Cancer
Breast Cancer
Pancreatic Cancer
Head and Neck Cancer
Gastric Cancer

DRUG: 2-deoxy-D-glucose (2DG)

TH-CR-101

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2004-11-12	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2009-04-28
First Submitted that Met QC Criteria 2004-11-12	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2009-04-29
First Posted (ESTIMATED) 2004-11-15	Results First Posted N/A	Last Verified 2009-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment

Primary Outcome Measures	Measure Description	Time Frame
Significant Toxicity
Disease Progression

Secondary Outcome Measures	Measure Description	Time Frame
Response Rate
Death

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Males and females, at least 18 years of age
Histologically confirmed, locally advanced or metastatic solid malignancy
Previously treated with at least one chemotherapy regimen for advanced or metastatic disease OR no curative standard treatment is available
Recovered from reversible toxicities of prior therapy
Life expectancy of at least 3 months
ECOG performance status of 0, 1, or 2
Measurable or nonmeasurable disease by RECIST criteria
Ability to understand the purposes and risks of the study and having signed a written informed consent form
All women of childbearing potential and all men must agree to use effective means of contraception from entry into the study through 3 months after the last dose

Previous or current CNS metastases (screening CT or MRI is not required in asymptomatic subjects)
Active clinically significant infection requiring antibiotics
Known glucose-6-phosphate dehydrogenase deficiency or history of anemia of unknown etiology
History of clinically significant unexplained episodes of hypotension, fainting, dizziness, or lightheadedness
History or symptoms of cardiovascular disease, particularly coronary artery disease, arrhythmias, or conduction defects with risk of cardiovascular instability, uncontrolled hypertension, clinically significant pericardial effusion, or congestive heart failure
History of transient ischemic attack, stroke, or seizure disorder or any other CNS disease considered to be significant by the investigator
Known autonomic dysfunction or chronic orthostatic hypotension
Evidence of hypoglycemia, clinically significant renal disease, clinically significant liver disease (other than liver metastases), diabetes mellitus, gastrointestinal disorder (that could affect absorption or elimination of orally-administered medications), or obstructive uropathy with significant post-void residual during the past 5 years
Known HIV infection
Other primary malignancies (other than treated basal cell carcinoma of the skin or treated in situ cervical cancer) within the past 5 years
Major surgery within 4 weeks of the start of study treatment, without complete recovery
Antitumor therapy within 21 days of the start of study treatment
Disease progression/relapse on docetaxel therapy within the past 12 months
A history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
Known sensitivity to methylparaben or propylparaben
Inability to discontinue prohibited medications for 24 hours before and after dosing on Day 1 of Weeks 1, 2, and 3 and Day 5 of Week 1. In addition, patients who cannot discontinue medications known to induce or inhibit CYP 3A4, such as cyclosporine, terfenadine, ketoconazole, erythromycin, and troleandomycin, for the duration of the study are not eligible.
Peripheral neuropathy >= Grade 2
Hemoglobin <9 g/dL
ANC <1500/μL
Platelet count <100,000/μL
Total bilirubin >1.5 mg/dL
Abnormal liver function
Serum creatinine >1.5 mg/dL unless creatinine clearance is >= 60 mL/min
Serum potassium < lower limit of normal
Elevated fasting blood glucose
Pregnant or nursing women
Participation in an investigational drug or device study within 28 days of the first day of dosing on this study
Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
Unwillingness or inability to comply with the study protocol for any other reason
Subjects who live alone

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Luis Raez, MD, University of Miami Sylvester Comprehensive Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN, Rocha Lima CM, Schlesselman JJ, Tolba K, Langmuir VK, Kroll S, Jung DT, Kurtoglu M, Rosenblatt J, Lampidis TJ. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Feb;71(2):523-30. doi: 10.1007/s00280-012-2045-1. Epub 2012 Dec 11.

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Clinical Trial Record