ClinicalTrials.gov
ClinicalTrials.gov Menu

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 : October 17, 2018
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, 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 daily for 28 days in patients with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: TP-0184 Phase 1

Detailed Description:

Primary Objective:

• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-0184 administered daily for 28 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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0184 Administered Daily for 28 Days to Patients With Advanced Solid Tumors
Actual Study Start Date : July 10, 2018
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : April 2020

Arm Intervention/treatment
Experimental: Single Arm TP-0184
Daily dose of TP-0184 by oral administration
Drug: TP-0184
Oral daily dose




Primary Outcome Measures :
  1. 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

  2. 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.


Secondary Outcome Measures :
  1. 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

  2. Determine antitumor activity of TP-0184 [ Time Frame: 20 months ]
    Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03429218


Contacts
Contact: Nissa Ashenbramer, BBA 210-931-2533 nashenbramer@toleropharma.com
Contact: Susan Smith, MSN 210-414-7702 su.smith@toleropharma.com

Locations
United States, Arizona
Honor Health Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Michael Gordon, MD    480-323-1350      
Principal Investigator: Michael Gordon, MD         
United States, Kansas
University of Kansas Medical Center Research Institute Not yet recruiting
Kansas City, Kansas, United States, 66160
Contact: Joaquina Baranda, MD    913-588-6029      
Principal Investigator: Joaquina Baranda, MD         
United States, Massachusetts
Massachusetts General Hospital MGH Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Aparna Parikh, MD, MS    617-724-4000      
Principal Investigator: Aparna Parikh, MD, MS         
United States, Texas
University of Texas Southwestern UTSW Not yet recruiting
Dallas, Texas, United States, 75390-9179
Contact: Muhammad Beg, MD    214-648-4180      
Principal Investigator: Muhammad Beg, MD         
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Investigators
Study Director: James French, MD Tolero Pharmaceuticals

Responsible Party: Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03429218     History of Changes
Other Study ID Numbers: TP-0184-101
First Posted: February 12, 2018    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tolero Pharmaceuticals, Inc.:
Tolero, Phase 1, First in Human, Solid Tumors, Advanced Malignancy, Cancer