First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors
- Clements University Hospital
Muhammad Beg, M.D.
A Phase I, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0903 Administered Daily for 21 Days to Patients With Advanced Solid Tumors
TP-0903 is a novel oral inhibitor that targets AXL kinase. Preclinical studies have shown
promising antitumor activity of TP-0903 as a single agent against a variety of tumor types in
both in vitro and in vivo studies.
This first-in-human study is conducted to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of TP-0903 administered orally to patients with advanced solid tumors.
The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.
This is a phase 1, first-in-human, open-label, dose-escalation, safety, pharmacokinetics, and
pharmacodynamic study of TP-0903 administered once daily for the first 21 out of 28 days.
There are 2 stages in this study. In Stage 1, sequential cohorts of three (3) patients will be treated with escalated doses until the MTD is established. In the absence of dose-limiting toxicities (DLTs), the dose will be increased using a modified Fibonacci dose escalation scheme. Once the MTD has been established, 2 additional cohorts of up to 10 patients each (20 additional patients total) may be enrolled at the MTD dose level for confirmation of safety (Stage 2).
Patients who successfully complete a 4-week treatment cycle without evidence of significant treatment-related toxicity or progressive disease will be permitted to continue to receive treatment with the same dose and dosing schedule.
- Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
- Are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition
- Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1
- Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of ≤2
- Have a life expectancy ≥3 months
- Be ≥18 years of age
- Have a negative pregnancy test (if female of childbearing potential)
- Have acceptable liver function:
- Bilirubin ≤1.5x upper limit of normal (ULN)
- Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase ≤2.5x upper limit of normal (ULN) *If liver metastases are present, then ≤5x ULN is allowed.
- Have acceptable renal function:
- Serum creatinine ≤1.5x ULN, OR
- Calculated creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- Have acceptable hematologic status:
- Granulocyte ≥1500 cells/mm3
- Platelet count ≥100,000 (plt/mm3)
- Hemoglobin ≥9 g/dL
- Have no clinically significant abnormalities on urinalysis
- Have acceptable coagulation status:
- Prothrombin time (PT) within 1.5x normal limits
- Activated partial thromboplastin time (aPTT) within 1.5x normal limits
- Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation and for at least 30 days after the last study drug dose.
- Have read and signed the IRB-approved informed consent form prior to any study related procedure.
- Have New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) or during Cardiac Stress Testing within 14 days prior to Day 1 (Appendix C)
- Have a corrected QT interval (QTc) of >470 msec
- Have a seizure disorders requiring anticonvulsant therapy
- Presence of symptomatic central nervous system metastatic disease or disease that requires local therapy such as radiotherapy, surgery, or increasing dose of steroids within the prior 2 weeks.
- Have severe chronic obstructive pulmonary disease with hypoxemia
- Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Day 1
- Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
- Are pregnant or nursing.
- Received treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one month prior to study entry (6 weeks for nitrosoureas or Mitomycin C).
- Are unwilling or unable to comply with procedures required in this protocol
- Have known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible.
- Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor
- Are currently receiving any other investigational agent
- Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
- Have undergone significant surgery to the gastrointestinal tract