TP-0184 is a potent inhibitor of ALK2 or ACRV1 kinase, a constitutively active
serine/threonine receptor kinase due to activating mutations or upregulated upstream
signaling pathways. This is a Phase 1, open-label, dose-escalation, safety, pharmacokinetics,
and pharmacodynamic study, with a purpose of determining the maximum tolerated dose (MTD) and
dose-limiting toxicities (DLTs) of oral TP-0184 administered once weekly for 4 weeks 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:
1. Have a histologically confirmed diagnosis of advanced metastatic or progressive solid
tumor
2. Be refractory to, or intolerant of, established therapy known to provide clinical
benefit for their condition.
3. Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1
4. Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO])
performance of ≤1
5. Have a life expectancy ≥3 months
6. Be ≥18 years of age
7. Have a negative pregnancy test (if female of childbearing potential)
8. Have acceptable liver function:
1. Bilirubin ≤1.5x upper limit of normal (ULN)
2. 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.
9. Have acceptable renal function: Calculated creatinine clearance ≥ 30 mL/min
10. Have acceptable hematologic status:
1. Granulocyte ≥1500 cells/mm3
2. Platelet count ≥100,000 (plt/mm3)
3. Hemoglobin ≥8 g/dL (Patients may not have received prior transfusions within 2
weeks of the first dose of TP-0184)
11. Have acceptable coagulation status:
1. Prothrombin time (PT) within 1.5x normal limits
2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits
12. 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.
13. 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:
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
(LVEF) <45% by echocardiogram (ECHO), unstable arrhythmia, or evidence of ischemia on
electrocardiogram (ECG) within 14 days prior to Cycle 1 Day 1
2. Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of >450
msec in men and >470 msec in women
3. Have a seizure disorder requiring anticonvulsant therapy
4. 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
5. Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting
O2 saturation of ≤90% breathing room air)
6. Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to
Cycle 1 Day 1
7. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy
8. Are pregnant or nursing
9. 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)
10. Are unwilling or unable to comply with procedures required in this protocol
11. 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.
12. 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
13. Are currently receiving any other investigational agent
14. Have exhibited allergic reactions to a similar structural compound, biological agent,
or formulation
15. 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
16. 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
