Advanced Solid Tumors
Conditions
Keywords
Sumitomo Dainippon Pharma Oncology SDPO, Phase 1, First in human, Solid Tumors, Advanced Malignancy, Cancer
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
Interventions
DRUGTP-0184
Oral dose once weekly for 4 weeks
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 values |
| Determine 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Outcome results
None listed