Clinical Trials /

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

NCT03429218

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors
  • Official Title: A Phase I, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0184 Administered Daily for 21 Days to Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: TP-0184-101
  • NCT ID: NCT03429218

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
TP-0184Single Arm TP-0184

Purpose

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 daily for 21 days 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 daily for 21 days, 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
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm TP-0184ExperimentalDaily dose of TP-0184 by oral administration
  • TP-0184

Eligibility Criteria

        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

          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 a negative pregnancy test (if female of childbearing potential)

         10. Have acceptable liver function:

               1. Bilirubin ≤1.5x upper limit of normal (ULN)

               2. Aspartate aminotransferase (AST/SGOT), alanine amino-transferase (ALT/SGPT) and
                  alkaline phosphatase ≤2.5x ULN. If liver metastases are present, then ≤5x ULN is
                  allowed.

         11. Have acceptable renal function:

               1. Serum creatinine ≤1.5x ULN, OR

               2. Calculated creatinine clearance ≥ 30 mL/min

         12. Have acceptable hematologic status:

               1. Granulocyte ≥1500 cells/mm3

               2. Platelet count ≥100,000 (plt/mm3)

               3. Hemoglobin ≥9 g/dL (Patients may not have received prior transfusions within 2
                  weeks of the first dose of TP-0184)

         13. Have no clinically significant abnormalities on urinalysis

         14. Have acceptable coagulation status:

               1. Prothrombin time (PT) within 1.5x normal limits

               2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits

         15. 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 including for 30 days after the last dose of study
             drug (see Section 4.6.3). Should a woman become pregnant or suspect she is pregnant
             while participating in this study, she should inform her treating physician
             immediately.

         16. Have read and signed the 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. Cardiac disease, myocardial infarction within the past 6 months prior to Cycle 1 Day
             1, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 14
             days prior to Cycle 1 Day 1 (Appendix C)

          2. Have a corrected QT interval (QTcF, Fridericia's method) of >450 msec in men and 470
             msec in women

          3. Have a seizure disorders 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 ≤88% 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events
Time Frame:Day 1 - 28
Safety Issue:
Description: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 ≥2 weeks due to treatment emergent adverse events or related severe laboratory test values

Secondary Outcome Measures

Measure:Recommended Phase 2 Dose of TP-0184
Time Frame:23 months
Safety Issue:
Description:To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-0184, MTD data to be reviewed
Measure:Determine antitumor activity of TP-0184
Time Frame:20 months
Safety Issue:
Description:Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tolero Pharmaceuticals, Inc.

Trial Keywords

  • Tolero
  • Phase 1
  • First in human
  • Solid Tumors
  • Advanced Malignancy
  • Cancer

Last Updated

May 20, 2019