Study of TP-3654 in Patients With Advanced Solid Tumors

Primary Objective:

• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-3654 in patients with advanced solid tumors.

Secondary Objectives:

• To establish the pharmacokinetic (PK) profile of orally administered TP-3654
• To observe patients for any evidence of antitumor activity of TP-3654 by objective radiographic assessment
• To study the pharmacodynamic effects of TP-3654 therapy
• To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-3654

Inclusion criteria

• 1. Have a histologically confirmed diagnosis of advanced metastatic, progressive or unresectable solid tumor

• Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.

• Have 1 or more tumors measurable or evaluable as outlined by modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2

• Have a life expectancy greater than or equal to 3 months

• Be greater than or equal to 18 years of age

• Have a negative pregnancy test (if female of childbearing potential) and not currently nursing

• Have acceptable liver function:

a. Bilirubin less than or equal to 1.5x upper limit of normal (ULN) (unless associated with Gilbert's syndrome b. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase less than or equal to 2.5x upper limit of normal (ULN) *If liver metastases are present, then less than or equal to 5x ULN is allowed.

• Have acceptable renal function:

a. Calculated creatinine clearance greater than or equal to 30 mL/min

• Have acceptable hematologic status:

a. Absolute Neutrophil Count (ANC) greater than or equal to 1500 x10^9/L b. Platelet count greater than or equal to 100,000 x 10^9/L c. Hemoglobin greater than or equal to 8 g/dL

• Have acceptable coagulation status:
• Prothrombin time (PT) within 1.5 x normal limits
• Activated partial thromboplastin time (aPTT) within 1.5 x 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 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 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 informed consent form must be signed.)

Exclusion criteria

• 1. 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 <45% by echocardiogram, 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

• 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 02 saturation of less than or equal to 90% breathing room air). The use of supplemental oxygen with nasal cannula to reach >90% saturation will not preclude study participation.

• 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

• 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)

8, Are unwilling or unable to comply with procedures required in this protocol

• Have known infection with human immunodeficiency virus, 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 a medical conditional such as Crohn's disease or 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.