PTC299 for Treatment of Advanced Cancer

This study has suspended participant recruitment.
Sponsor:
Information provided by:
PTC Therapeutics
ClinicalTrials.gov Identifier:
NCT00704821
First received: June 23, 2008
Last updated: April 6, 2012
Last verified: April 2012
  Purpose

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 Intervention Phase
Advanced Cancer
Drug: PTC299
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by PTC Therapeutics:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of PTC299 within the tested dose range. [ Time Frame: 6 Weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Overall safety profile of PTC299 alone and in combination with docetaxel [ Time Frame: 3 Weeks ] [ Designated as safety issue: Yes ]
  • Study drug compliance [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
  • Pharmacokinetics [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
  • Circulating angiogenic activity [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
  • Tumor perfusion as assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
  • Tumor metabolism as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]
  • Antitumor activity as assessed by computerized tomography (CT) scans and tumor markers [ Time Frame: 6 Weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 76
Study Start Date: June 2008
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
PTC299
Drug: PTC299
PTC299 orally administered 2 or 3 times per day.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00704821

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

Additional Information:
No publications provided

Responsible Party: Leslie Callahan, RN, MS, PTC Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT00704821     History of Changes
Other Study ID Numbers: PTC299-ONC-004-AST
Study First Received: June 23, 2008
Last Updated: April 6, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by PTC Therapeutics:
Cancer
PTC299
VEGF
Angiogenesis
Post-transcriptional control
Docetaxel

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on October 23, 2014