PTC299 for Treatment of Advanced Cancer

NCT00704821 | Terminated Phase 1

• 1 other identifier: PTC299-ONC-004-AST
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

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 participants with cancer.

Conditions

Advanced Cancer

Keywords

Cancer; PTC299; VEGF; Angiogenesis; Post-transcriptional control; Docetaxel

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of PTC299 within the tested dose range.

  To analyze the MTD of PTC299 within the tested dose range for use in further clinical trials in participants with advanced cancer.

  6 Weeks

Secondary Outcomes (12)

• Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

  From Baseline up to Week 246

• Number of Participants With a Clinically Relevant Abnormal Clinical Laboratory Parameter

  From Baseline up to Week 246

• Number of Participants With a Clinically Significant Abnormal Electrocardiogram (ECG)

  From Baseline up to Week 246

• Number of Participants With a Dose-limiting Toxicity (DLT)

  From Baseline up to Week 246

• Change From Baseline in the Circulating Concentrations of Vascular Endothelial Growth Factor (VEGF)

  Baseline; Stage 1: Days 1, 14, and 28 in Cycle 1 and Days 1 and 28 of next cycles; Stage 2: Days 1, 21, and 42 in Cycle 1 and Day 42 of next cycles; Stage 3: Day 1 of each cycle; Stage 4: Days 1, 8, 15, and 22 in Cycle 1 and Day 1 of next cycles

Study Arms (4)

Stage 1

EXPERIMENTAL

In Stage 1, PTC299 will be given orally twice a day (BID) each day at about the same time each day for the first 28 days of each cycle. Each cycle will constitute a 4-week (28 days) period followed by a ≥2-week (14-day) washout period. Participants will be assigned to 0.3 milligrams (mg)/kilograms (kg)/dose BID, 0.6 mg/kg/dose BID, or 1.2 mg/kg/dose BID sequentially based on safety evaluations by the Sponsor's medical monitor in Cycle 1. Treatment cycles can continue if therapy appears to be safely offering tumor control to participant.

Drug: PTC299

Stage 2

EXPERIMENTAL

In Stage 2, PTC299 will be given BID or 3 times a day (TID) orally each day at about the same time each day; therefore, 84 (for BID) or 126 (for TID) doses of PTC299 will be delivered during the 6-week (42-day) period in each cycle. Each participant will be assigned to 100 mg/dose BID, 100 mg/dose TID, 120 mg/dose TID, 160 mg/dose TID, or 200 mg/dose TID sequentially based on safety evaluations by the Sponsor's medical monitor in Cycle 1. Treatment cycles can continue if therapy appears to be safely offering tumor control to participant.

Drug: PTC299

Stage 3

EXPERIMENTAL

In Stage 3, PTC299 will be given BID or TID (for total of 42 \[for BID\] or 63 \[for TID\] doses) orally about same time per day starting on Day 1 in each 3-week (21-day) cycle. Starting dose will be 1 dose level below maximum tolerated dose (MTD) from Stage 2 or 80 mg/dose BID if 100 mg/dose TID in Stage 2 exceeds MTD. Dose escalation will be based on safety evaluations by Sponsor's medical monitor in Cycle 1. Treatment cycles can continue if therapy appears to be safely offering tumor control to participant. Participants will also receive docetaxel as a 1-hour IV infusion on Day 1 per cycle at starting dose of 75 mg/m\^2 with body surface area calculation based on body weight. Dose will be sequentially reduced to 60 and 50 mg/m\^2 in participants with a docetaxel-related dose-limiting toxicity (DLT). Participants will be medicated with oral corticosteroids with docetaxel administration. Recommended dose is 8 mg BID dexamethasone for 3 days starting 1 day prior to docetaxel administration.

Drug: PTC299; Drug: Docetaxel

Stage 4

EXPERIMENTAL

In Stage 4, PTC299 will be given orally each day continuously starting on first day of each cycle at about same time per day; so, 42 doses of PTC299 will be delivered for 3 weeks (21-day) in Cycle 1 (BID dosing), and 84 doses will be delivered for 3-weeks (21-day) in Cycle 2 and beyond (TID dosing). For Cycle 1, participants will be assigned to 600, 800, or 1000 mg/dose BID sequentially based on safety evaluations by Sponsor's medical monitor at enrollment. For Cycle 2 and beyond, participants will receive PTC299 160 mg/dose TID. During Cycle 1, Cohort 1 participants will eat a meal containing of ≤15 grams (g) of dietary fat and Cohort 2 participants will eat a meal containing of ≤25 g of dietary fat prior to each dose of PTC299. If ≤2 of 6 participants had experienced DLT during Cycle 1 in either diet plan, then the dose will be escalated to 800 mg BID in Cohort 3 at the optimal diet. Treatment cycles can continue if therapy appears to be safely offering tumor control to participant.

Drug: PTC299

Interventions

PTC299 DRUG

Oral

Stage 1; Stage 2; Stage 3; Stage 4

Docetaxel DRUG

Intravenous infusion

Stage 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years.
• Body weight 40-100 kg.
• Capable of swallowing oral medication.
• The Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy \>3 months.
• Histologically or cytologically confirmed diagnosis of a solid tumor. Note: Participants with lymphomas may be enrolled. Participants with leukemia should not be included.
• Presence of locally advanced or metastatic disease that is not amenable to surgery, radiation therapy, or chemotherapy with curative intent.
• Cancer progression on or after standard therapy or cancer for which no standard therapy is available.
• Discontinuation of all anticancer therapies ≥3 weeks before initiation of study treatment. Note: Prior treatment with antiangiogenic therapies (for example, bevacizumab, sunitinib, sorafenib, or investigational antiangiogenic agents) is allowed.
• 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)

You may not qualify if:

• Unstable brain or leptomeningeal disease based on history and physical examination. Note: Enrollment of participants 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.
• 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, any other arterial thromboembolic event, or pulmonary embolism.
• Known coagulopathy or bleeding diathesis.
• Known history of drug-induced liver injury.
• Resting systolic blood pressure \>180 millimeters of mercury (mmHg) or diastolic blood pressure \>110 mmHg.
• Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections). Note: Participants with localized fungal infections of skin or nails are eligible.
• Pregnancy or breast-feeding.
• Ongoing alcohol or drug addiction.
• Prior exposure to PTC299.
• Exposure to another investigational drug within 4 weeks prior to the study treatment.
• Concurrent participation in another therapeutic treatment trial.
• History of major surgical procedure within 14 days prior to enrollment in this study.
• Psychological, social, familial, or geographical factors that would prevent regular follow up.
• 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 participant; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results.
• History of severe hypersensitivity reactions to docetaxel or polysorbate 80. Note: This criterion applies to Stage 3 study candidates only.

Sponsors & Collaborators

• PTC Therapeutics: lead

Study Sites (1)

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Links

• PTC Therapeutics, Inc. Webpage

MeSH Terms

Conditions

Neoplasms

Interventions

emvododstat; Docetaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Gary Schwartz, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2008
• First Posted: June 25, 2008
• Study Start: July 3, 2008
• Primary Completion: February 24, 2012
• Study Completion: February 24, 2012
• Last Updated: May 10, 2019

Record last verified: 2019-04

Locations

US (1)