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.
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.
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.
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
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.