First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors
- Registration Number
- NCT03429218
- Lead Sponsor
- Sumitomo Pharma America, Inc.
- Brief Summary
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.
- Detailed 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
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Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
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Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.
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Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1
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Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of ≤1
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Have a life expectancy ≥3 months
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Be ≥18 years of age
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Have a negative pregnancy test (if female of childbearing potential)
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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.
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Have acceptable renal function: Calculated creatinine clearance ≥ 30 mL/min
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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)
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Have acceptable coagulation status:
- Prothrombin time (PT) within 1.5x normal limits
- Activated partial thromboplastin time (aPTT) within 1.5x normal limits
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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.
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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.)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single Arm TP-0184 TP-0184 Weekly dose of TP-0184 by oral administration
- Primary Outcome Measures
Name Time Method Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events Day 1 - 28 A DLT is defined as any one of the following events observed within Cycle 1 regardless of investigator attribution unless there is a clear alternative explanation:
* Grade 3 or greater febrile neutropenia
* Grade 4 neutropenia for ≥7 consecutive days
* Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or that requires a platelet transfusion
* Grade 3 or 4 nonhematologic AEs including nausea, vomiting, diarrhea, and electrolyte imbalances persisting for more than 48 hours despite optimal medical management
* Dosing delays ≥1 week due to treatment emergent adverse events or related severe laboratory test valuesDetermine maximum tolerated dose (MTD) 20 months If a patient experiences a DLT, up to three additional patients will be treated at that dose level. If no additional DLTs are observed in the expanded six-patient cohort, the dose will be escalated in a new cohort of three patients. If two or more patients at a given dose level experience a DLT during the first cycle, then the MTD will have been exceeded and up to a total of six patients will be treated at the next lower dose level. If 0 or 1 of 6 patients experiences a DLT at this previous lower dose level, this dose will be declared the MTD.
- Secondary Outcome Measures
Name Time Method Recommended Phase 2 Dose of TP-0184 23 months To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-0184, MTD data to be reviewed
Determine antitumor activity of TP-0184 20 months Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria
Trial Locations
- Locations (5)
University of Texas Southwestern UTSW
🇺🇸Dallas, Texas, United States
Massachusetts General Hospital MGH
🇺🇸Boston, Massachusetts, United States
Northside Hospital
🇺🇸Atlanta, Georgia, United States
University of Kansas Medical Center Research Institute
🇺🇸Kansas City, Kansas, United States
Honor Health
🇺🇸Scottsdale, Arizona, United States