First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors

Primary Objective:

• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-0184 administered once weekly for 4 weeks, over a range of doses in patients with advanced solid tumors.

Secondary Objectives:

• To establish the pharmacokinetics of orally administered TP-0184
• To observe patients for any evidence of antitumor activity of TP-0184 by objective radiographic assessment
• To study the pharmacodynamics of TP-0184 therapy
• To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-0184

Inclusion criteria

• Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
• Be 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 ≤1
• 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: Calculated creatinine clearance ≥ 30 mL/min
• Have acceptable hematologic status:

• Granulocyte ≥1500 cells/mm3
• Platelet count ≥100,000 (plt/mm3)
• Hemoglobin ≥8 g/dL (Patients may not have received prior transfusions within 2 weeks of the first dose of TP-0184)
• 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 3 months (males) and 6 months (females) after the last study drug dose. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Have read and signed the Institutional Review Board (IRB)-approved informed consent form (ICF) prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new ICF must be signed.)

Exclusion criteria

• History of congestive heart failure (CHF); cardiac disease, myocardial infarction within the past 6 months prior to Cycle 1 Day 1; left ventricular ejection fraction (LVEF) <45% by echocardiogram (ECHO), unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1 Day 1
• Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of >450 msec in men and >470 msec in women
• Have a seizure disorder 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 (defined as resting O2 saturation of ≤90% breathing room air)
• Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 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 28 days or 5 half lives, whichever occurs first, 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 that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption
• Have hemochromatosis or a transferrin saturation (TS) >50% in men or >45% in women at baseline or noted during the study via scheduled iron panel monitoring