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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03429218
Recruitment Status : Recruiting
First Posted : February 12, 2018
Last Update Posted : July 10, 2020
Sponsor:
Information provided by (Responsible Party):
Sumitomo Dainippon Pharma Oncology, Inc

Tracking Information
First Submitted Date  ICMJE February 5, 2018
First Posted Date  ICMJE February 12, 2018
Last Update Posted Date July 10, 2020
Actual Study Start Date  ICMJE July 10, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2020)
  • Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events [ Time Frame: 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) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 5, 2018)
  • Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events [ Time Frame: 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 ≥2 weeks due to treatment emergent adverse events or related severe laboratory test values
  • Determine maximum tolerated dose (MTD) [ Time Frame: 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2018)
  • Recommended Phase 2 Dose of TP-0184 [ Time Frame: 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 [ Time Frame: 20 months ]
    Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors
Official Title  ICMJE A Phase I, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0184 Administered Once Weekly for 4 Weeks to Patients With Advanced Solid Tumors
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Solid Tumors
Intervention  ICMJE Drug: TP-0184
Oral dose once weekly for 4 weeks
Study Arms  ICMJE Experimental: Single Arm TP-0184
Weekly dose of TP-0184 by oral administration
Intervention: Drug: TP-0184
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 18, 2020)
20
Original Estimated Enrollment  ICMJE
 (submitted: February 5, 2018)
40
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nissa Ashenbramer, BBA 210-639-2144 nashenbramer@toleropharma.com
Contact: Susan Smith, MSN 210-414-7702 su.smith@toleropharma.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03429218
Other Study ID Numbers  ICMJE TP-0184-101
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sumitomo Dainippon Pharma Oncology, Inc
Study Sponsor  ICMJE Sumitomo Dainippon Pharma Oncology, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Stephen Anthony, DO Sumitomo Dainippon Pharma Oncology, Inc
PRS Account Sumitomo Dainippon Pharma Oncology, Inc
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP