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

Sumitomo Pharma

Status and phase

Completed

Phase 1

Conditions

Advanced Solid Tumors

Treatments

Drug: TP-0184

Study type

Interventional

Funder types

Industry

Identifiers

NCT03429218

TP-0184-101

Details and patient eligibility

About

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.

Full description

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

Enrollment

24 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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:
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.
Have acceptable renal function: Calculated creatinine clearance ≥ 30 mL/min
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)
Have acceptable coagulation status:
1. Prothrombin time (PT) within 1.5x normal limits
2. 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