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First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors

This study is currently recruiting participants.
Verified October 2017 by Tolero Pharmaceuticals, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02729298
First Posted: April 6, 2016
Last Update Posted: October 4, 2017
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.
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.
  Purpose

TP-0903 is a novel oral inhibitor that targets AXL kinase. Preclinical studies have shown promising antitumor activity of TP-0903 as a single agent against a variety of tumor types in both in vitro and in vivo studies.

This first-in-human study is conducted to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of TP-0903 administered orally to patients with advanced solid tumors.

The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.


Condition Intervention Phase
Advanced Solid Tumors Drug: TP-0903 Phase 1

Study Type: Interventional
Study Design: 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-0903 Administered Daily for 21 Days to Patients With Advanced Solid Tumors

Further study details as provided by Tolero Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events [ Time Frame: Cycle 1 (Day 1 through Day 28) ]

    A DLT is defined as any one of the following events observed within Cycle 1:

    Grade 3 or greater febrile neutropenia, Grade 4 nANC for 7 or greater consecutive days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or that requires a platelet transfusion, Grade 3 or 4 non-hematologic AEs including nausea, vomiting, diarrhea, and electrolyte imbalances persisting for more than 48 hours despite optimal medical management, dosing delays of 2 weeks or greater due to treatment emergent adverse events or related severe laboratory test values



Secondary Outcome Measures:
  • Area under the plasma concentration-time curve from zero to infinity [AUC(0-inf)] of oral TP-0903 [ Time Frame: Blood will be taken from subjects at Cycle 1/Day 1 and Cycle1/Day 21at predose and 0.5, 1, 2, 4, 8, 24 hrs post dose and at 48 hrs post dose Day 21. ]
    Derived PK parameters by non-compartment analysis on Cycle 1, Days 1 and 21.

  • Area under the plasma concentration-time curve from zero to last measured time point [AUC(0-last)] of oral TP-0903 [ Time Frame: Blood will be taken from subjects at Cycle 1/Day 1 and Cycle1/Day 21at predose and 0.5, 1, 2, 4, 8, 24 hrs post dose and at 48 hrs post dose Day 21. ]
    Derived PK parameters by non-compartment analysis on Cycle 1, Days 1 and 21.

  • Peak plasma concentration (Cmax) of oral TP-0903 [ Time Frame: Blood will be taken from subjects at Cycle 1/Day 1 and Cycle1/Day 21at predose and 0.5, 1, 2, 4, 8, 24 hrs post dose and at 48 hrs post dose Day 21. ]
    Derived PK parameters by non-compartment analysis on Cycle 1, Days 1 and 21.

  • Activity of TP-0903 on predictive biomarkers [ Time Frame: PBMCs and serum will be obtained prior to first dose on Day 1/Cycle 1 and at 2 and 24 hours after dosing and on Day 8 ]
    Assess biomarkers in tumor tissue, PBMCs and serum. The pharmacodynamic relationships of TP-0903 exposure with exploratory biomarkers will be quantified using the Spearman rank correlation statistic.

  • Objective response rate using RECIST v1.1 [ Time Frame: Patients will be assessed on Day 22 after every two treatment cycles through study completion ]
    Baseline tumor assessment will be performed at screening and repeated at Cycle 2 and every even cycle thereafter.


Estimated Enrollment: 46
Actual Study Start Date: December 14, 2016
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TP-0903
Single daily dose by oral administration on Days 1-21 of a 28 day cycle
Drug: TP-0903

Stage 1: Single oral daily doses on Days 1-21 of each 28 day cycle. Starting dose is 1.5 mg/m2 with subsequent dose escalation using a modified Fibonacci dose escalation schema.

Stage 2: Upon confirmation of MTD, 2 additional cohorts of up 10 patients each (20 additional patients total) will receive single oral daily doses of this dose on Days 1-21 of each 28 day cycle.


Detailed Description:

This is a phase 1, first-in-human, open-label, dose-escalation, safety, pharmacokinetics, and pharmacodynamic study of TP-0903 administered once daily for the first 21 out of 28 days.

There are 2 stages in this study. In Stage 1, sequential cohorts of three (3) patients will be treated with escalated doses until the MTD is established. In the absence of dose-limiting toxicities (DLTs), the dose will be increased using a modified Fibonacci dose escalation scheme. Once the MTD has been established, 2 additional cohorts of up to 10 patients each (20 additional patients total) may be enrolled at the MTD dose level for confirmation of safety (Stage 2).

Patients who successfully complete a 4-week treatment cycle without evidence of significant treatment-related toxicity or progressive disease will be permitted to continue to receive treatment with the same dose and dosing schedule.

  Eligibility

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, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
  • Are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition
  • Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1
  • Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of ≤2
  • Have a life expectancy ≥3 months
  • Be ≥18 years of age
  • Have a negative pregnancy test (if female of childbearing potential)
  • 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.
  • Have acceptable renal function:

    • Serum creatinine ≤1.5x ULN, OR
    • Calculated creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
  • Have acceptable hematologic status:

    • Granulocyte ≥1500 cells/mm3
    • Platelet count ≥100,000 (plt/mm3)
    • Hemoglobin ≥9 g/dL
  • Have no clinically significant abnormalities on urinalysis
  • Have acceptable coagulation status:

    • Prothrombin time (PT) within 1.5x normal limits
    • Activated partial thromboplastin time (aPTT) within 1.5x normal limits
  • 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 30 days after the last study drug dose.
  • Have read and signed the IRB-approved informed consent form prior to any study related procedure.

Exclusion Criteria:

  • Have New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) or during Cardiac Stress Testing within 14 days prior to Day 1 (Appendix C)
  • Have a corrected QT interval (QTc) of >470 msec
  • Have a seizure disorders 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
  • Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to 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 one month 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
  Contacts and Locations
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): NCT02729298


Contacts
Contact: Holly Beever, BS, RN 210-365-9014 hbeever@toleropharma.com
Contact: Susan Smith, MSN su.smith@toleropharma.com

Locations
United States, Arizona
HonorHealth Research Institute Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Joyce Schaffer, RN    480-323-1339    clinicaltrials@honorhealth.com   
Principal Investigator: Vivek Khemka, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Yolanda Pitts       yolanda.pitts@utsouthwestern.edu   
Principal Investigator: Muhammad Beg, MD         
University of Texas Science Center at San Antonio (UTHSCSA) Recruiting
San Antonio, Texas, United States, 78229
Contact: CTRC    210-450-2872      
Principal Investigator: John Sarantopoulos, MD         
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Investigators
Study Director: Stephen P Anthony, DO Tolero Pharmaceuticals
  More Information

Responsible Party: Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02729298     History of Changes
Other Study ID Numbers: TP-0903-101
First Submitted: March 28, 2016
First Posted: April 6, 2016
Last Update Posted: October 4, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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