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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00096707
Recruitment Status : Completed
First Posted : November 15, 2004
Last Update Posted : April 29, 2009
Sponsor:
Information provided by:
Threshold Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE November 12, 2004
First Posted Date  ICMJE November 15, 2004
Last Update Posted Date April 29, 2009
Study Start Date  ICMJE February 2004
Actual Primary Completion Date July 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Significant Toxicity
  • Disease Progression
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Response Rate
  • Death
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) in Subjects With Advanced Solid Tumors
Official Title  ICMJE Phase I Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) Alone and in Combination With Docetaxel in Subjects With Advanced Solid Malignancies
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Cancer
  • Breast Cancer
  • Pancreatic Cancer
  • Head and Neck Cancer
  • Gastric Cancer
Intervention  ICMJE Drug: 2-deoxy-D-glucose (2DG)
Study Arms  ICMJE Not Provided
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: June 23, 2005)
50
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2008
Actual Primary Completion Date July 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00096707
Other Study ID Numbers  ICMJE TH-CR-101
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Not Provided
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Threshold Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Luis Raez, MD University of Miami Sylvester Comprehensive Cancer Center
PRS Account Threshold Pharmaceuticals
Verification Date April 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP