PTC299 for Treatment of Advanced Cancer

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. Identifier: NCT00704821
Recruitment Status : Suspended
First Posted : June 25, 2008
Last Update Posted : April 9, 2012
Information provided by:
PTC Therapeutics

Brief Summary:
Formation of new blood vessels (angiogenesis) is important for tumor growth in advanced cancer. It is known that tumors make a protein called vascular endothelial growth factor (VEGF). VEGF stimulates the formation of blood vessels that supply the tumor with nutrients and oxygen. PTC299 is an oral investigational new drug that has been shown to decrease production of VEGF in animal models of human cancer. In these animal models, oral PTC299 administration decreases VEGF levels in the tumor and in the bloodstream, decreases blood vessel numbers in the tumor, and significantly slows or halts tumor growth. When given in combination with the chemotherapeutic drug, docetaxel, PTC299 increases the antitumor activity over use of docetaxel alone. Safety studies in research animals indicate good tolerability at doses and drug levels that are higher than those planned for the clinical studies. Results from Phase 1a studies in healthy volunteers indicate that PTC299 achieves levels of PTC299 in the bloodstream that are known to be active in animal models of human cancer. This Phase 1b study is designed to test the hypothesis that PTC299 will be tolerable and will show evidence of anti-VEGF and antitumor activity when administered orally to patients with cancer.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: PTC299 Phase 1

Detailed Description:
The study will be conducted in 3 stages. In Stage 1 of the study, successive groups of 3 to 6 patients will receive progressively higher PTC299 dose levels; in this stage, treatment will be given in repeated 6-week cycles consisting of 4 weeks of oral PTC299 twice per day followed by a 2-week, no-drug period. In Stage 2, additional groups of 3 to 6 patients will be enrolled at tolerable dose levels to receive treatment in repeated 6-week cycles consisting of oral PTC299 administered 2 or 3 times per day continuously (ie, without the 2-week no-drug period as in Stage 1). In Stage 3, additional groups of 3 to 6 patients will be enrolled at tolerable dose levels to receive treatment in repeated 3-week cycles consisting of oral PTC299 administered 2 or 3 times per day continuously in combination with docetaxel (75 mg/m2 intravenously every 3 weeks). All planned dose levels in all stages are expected to achieve circulating blood levels of PTC299 known to be active in animal models of human cancer. Treatment for each patient can continue as long as the therapy appears to be safely offering tumor control to that patient. Up to 76 evaluable patients will be accrued across the 3 stages.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study to Assess the Safety Profile, Pharmacokinetics, and Anti-VEGF Activity of PTC299 in Patients With Advanced Cancer
Study Start Date : June 2008
Estimated Primary Completion Date : December 2012
Estimated Study Completion Date : June 2014

Arm Intervention/treatment
Experimental: 1
Drug: PTC299
PTC299 orally administered 2 or 3 times per day.

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of PTC299 within the tested dose range. [ Time Frame: 6 Weeks ]

Secondary Outcome Measures :
  1. Overall safety profile of PTC299 alone and in combination with docetaxel [ Time Frame: 3 Weeks ]
  2. Study drug compliance [ Time Frame: 6 Weeks ]
  3. Pharmacokinetics [ Time Frame: 6 Weeks ]
  4. Circulating angiogenic activity [ Time Frame: 6 Weeks ]
  5. Tumor perfusion as assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) [ Time Frame: 6 Weeks ]
  6. Tumor metabolism as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) [ Time Frame: 6 Weeks ]
  7. Antitumor activity as assessed by computerized tomography (CT) scans and tumor markers [ Time Frame: 6 Weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥18 years.
  2. Body weight 40-100 kg.
  3. Capable of swallowing oral medication.
  4. ECOG performance status of 0 or 1.
  5. Life expectancy >3 months.
  6. Histologically or cytologically confirmed diagnosis of a solid tumor. Note: Patients with lymphomas may be enrolled. Patients with leukemia should not be included.
  7. Presence of locally advanced or metastatic disease that is not amenable to surgery, radiation therapy, or chemotherapy with curative intent.
  8. Cancer progression on or after standard therapy or cancer for which no standard therapy is available.
  9. Discontinuation of all anticancer therapies ≥3 weeks before initiation of study treatment. Note: Prior treatment with antiangiogenic therapies (eg, bevacizumab, sunitinib, sorafenib, or investigational antiangiogenic agents) is allowed.
  10. Acute toxic effects (as evaluated by CTCAE, Version 3.0) of any prior therapy resolved as shown below:

    • Neuropathy - Grade ≤2 (Stage 1 and 2)
    • Neuropathy - Grade ≤1 (Stage 3)
    • Alopecia - Grade ≤2 (all stages)
    • Fatigue - Grade ≤2 (all stages)
    • All others - Grade ≤1 (all stages)
  11. Required baseline laboratory data:

    • Absolute neutrophil count ≥1,500/mm3
    • Platelets ≥100,000/mm3
    • Hemoglobin ≥9.0 g/dL
    • Serum total bilirubin <ULN; ≤1.5x ULN is acceptable if there is liver involvement secondary to tumor
    • Serum Alanine transaminase and Aspartate transaminase <ULN; ≤2.5 x ULN is acceptable if there is liver involvement secondary to tumor
    • Serum alkaline phosphatase ≤2.5x ULN regardless of liver involvement with tumor
    • Serum albumin ≥3.0 g/dL
    • Serum creatinine ≤2.0 mg/dL
    • Urine protein <2+ by dipstick (or spot urinary protein: creatinine ratio <1.0 mg/dL:mg/dL, if quantitative method used)
    • Prothrombin time and Activated partial thromboplastin time ≤ULN
    • Serum beta-HCG negative
  12. Willingness, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ an effective method of contraception during the study periods.
  13. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, and study restrictions.
  14. Ability to provide written informed consent.
  15. Evidence of a personally signed informed consent indicating that the patient is aware of the neoplastic nature of his or her disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.
  16. An interval of >2 weeks from corticosteroid dose stabilization prior to obtaining the baseline MRI scan in patients with CNS malignancy.

Exclusion Criteria:

  1. Unstable brain or leptomeningeal disease based on history and physical examination. Note: Enrollment of subjects with central nervous system metastases is permitted if such disease is considered stable in the judgment of the investigator. A baseline magnetic resonance imaging (MRI) scan of the brain is required if there is clinical suspicion of central nervous system metastases, hemorrhage, thromboembolism, or increased intracranial pressure.
  2. Any of the following in the past 3 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, other arterial thromboembolic event, or pulmonary embolism.
  3. Known coagulopathy or bleeding diathesis.
  4. Known history of drug-induced liver injury.
  5. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg.
  6. Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections). Note: Patients with localized fungal infections of skin or nails are eligible.
  7. Pregnancy or breast-feeding.
  8. Ongoing alcohol or drug addiction.
  9. Prior exposure to PTC299.
  10. Exposure to another investigational drug within 4 weeks prior to the study treatment.
  11. Concurrent participation in another therapeutic treatment trial.
  12. History of major surgical procedure within 14 days prior to enrollment in this study.
  13. Psychological, social, familial, or geographical factors that would prevent regular follow up.
  14. Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results.
  15. History of severe hypersensitivity reactions to docetaxel or polysorbate 80. Note: This criterion applies to Stage 3 study candidates only.
  16. Presence of malignancy that is refractory to docetaxel (ie, best response with prior docetaxel was progressive disease at first assessment). Note: This criterion applies to Stage 3 study candidates only.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00704821

United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
PTC Therapeutics
Principal Investigator: Gary Schwartz, MD Memorial Sloan Kettering Cancer Center

Additional Information:
Responsible Party: Leslie Callahan, RN, MS, PTC Therapeutics, Inc. Identifier: NCT00704821     History of Changes
Other Study ID Numbers: PTC299-ONC-004-AST
First Posted: June 25, 2008    Key Record Dates
Last Update Posted: April 9, 2012
Last Verified: April 2012

Keywords provided by PTC Therapeutics:
Post-transcriptional control

Additional relevant MeSH terms:
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action