Clinical Trials /

Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL

NCT03572634

Description:

TP-0903 is an inhibitor of AXL kinase. TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell epithelial-to-mesenchymal transitions. AXL was identified as a potential therapeutic target in chronic lymphocytic leukemia (CLL). TP 0903 was shown to induce apoptosis in CLL B-cells taken directly from patients.TP-0903 was equally potent against CLL cells regardless of risk-factor. TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. TP-0903 has demonstrated profound single agent activity in CLL B cells taken directly from patients even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory solid tumors (TP-0903-101). This proposed study is designed to identify the maximum tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of TP-0903 in patients with previously treated CLL. Treatment cycles may be repeated if the patient continues to show benefit and if TP-0903 is reasonably well tolerated. The study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL
  • Official Title: A Combined Phase 1/2 Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of TP-0903 in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)

Clinical Trial IDs

  • ORG STUDY ID: TP-0903-102
  • NCT ID: NCT03572634

Conditions

  • Chronic Lymphocytic Leukemia
  • CLL
  • SLL
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
TP-0903Group 1-TP 0903 monotherapy

Purpose

TP-0903 is an inhibitor of AXL kinase. TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell epithelial-to-mesenchymal transitions. AXL was identified as a potential therapeutic target in chronic lymphocytic leukemia (CLL). TP 0903 was shown to induce apoptosis in CLL B-cells taken directly from patients.TP-0903 was equally potent against CLL cells regardless of risk-factor. TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. TP-0903 has demonstrated profound single agent activity in CLL B cells taken directly from patients even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory solid tumors (TP-0903-101). This proposed study is designed to identify the maximum tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of TP-0903 in patients with previously treated CLL. Treatment cycles may be repeated if the patient continues to show benefit and if TP-0903 is reasonably well tolerated. The study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903.

Detailed Description

      This is a combined Phase 1/2 study of oral TP-0903 in patients with previously treated
      CLL/SLL. In both Phase 1 and Phase 2, study participants will be assigned to one of two
      defined patient groups:

        -  Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or have
           progressed on, B-cell receptor antagonists and/or BCL-2 antagonists

        -  Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who have
           progressed on ibrutinib yet the treating provider considers continuation of ibrutinib
           therapy to be in the best interest of the patient.

      Both groups of patients will be treated identically with TP 0903 and will undergo the same
      study assessments.

      Phase 1 Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 6 patients
      simultaneously. Group 2 will start at one dose level below the Group 1 starting dose. In each
      group, escalation of the TP-0903 dose will follow a standard 3+3 design with sequential
      cohorts of three patients treated with incrementally higher doses of TP 0903 until a
      dose-limiting toxicity (DLT) is observed and the maximum tolerated dose (MTD) is established.
      In the absence of DLTs, the dose will be increased using a modified Fibonacci dose escalation
      scheme.

      Once the MTD or preliminary RP2D is identified, an expansion cohort of up to 6 patients will
      be enrolled in each patient group to confirm safety/suitability of the preliminary RP2D, to
      collect additional biomarker data, and to further explore efficacy.

      It is expected that up to 27 patients will be enrolled in each patient group for a total of
      up to 54 patients (TP-0903 monotherapy and combination therapy with ibrutinib).

      Additional dose levels, schedules, or disease indications of TP 0903 may be explored, as
      appropriate, based on the modulation of key biomarkers and the safety profile and clinical
      signals of activity.

      Phase 2 In Phase 2, patients will be enrolled in Group 1 (TP 0903 monotherapy) and Group 2
      (TP-0903 combination therapy with ibrutinib) based on the Simon 2 stage design. In Stage 1,
      up to 13 patients will be enrolled into each patient group (total of 26 patients). If there
      are no responses among these 13 patients in each group, the study will be stopped. Otherwise,
      Stage 2 will open to enroll 14 additional patients in each group for a total of 27 patients
      per group. If 4 or more responses are observed among 27 patients, the conclusion will be that
      the study treatment is worthy of further investigation.

      If both patient groups enroll through Stage 2, it is anticipated that the total enrollment
      for Phase 2 will be 54 patients.
    

Trial Arms

NameTypeDescriptionInterventions
Group 1-TP 0903 monotherapyExperimentalAdult patients with CLL/SLL who: are intolerant to, or have had progressive disease on B-cell receptor antagonists, BCL-2 antagonists or other investigational treatments for CLL/SLL
  • TP-0903
Group 2-TP-0903 and ibrutinib combination therapyExperimentalAdult patients with CLL/SLL who: have progression of disease on ibrutinib, yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Be ≥18 years old
    
              2. Have an established, pathologically confirmed diagnoses of CLL/ Small Lymphocytic
                 Lymphoma (SLL) requiring therapy according to the 2018 IWCLL guidelines
    
              3. Have received at least one prior therapy for CLL/SLL and can be classified in one of
                 two patient groups:
    
                   -  Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or
                      have progressed on B-cell receptor antagonists and/or BCL-2 antagonists or other
                      investigational treatments for CLL/SLL
    
                   -  Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who
                      have progressed on ibrutinib, yet the treating provider considers continuation of
                      ibrutinib therapy to be in the best interest of the patient
    
              4. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
    
              5. Have adequate hematologic function:
    
                   -  Absolute neutrophil count (ANC) ≥500/µL
    
                   -  Platelet count ≥30,000/µL
    
                   -  Hemoglobin ≥8 g/dL in the absence of transfusions within the previous 2 weeks
    
              6. Have adequate organ function:
    
                   -  Creatinine clearance ≥30 mL/min
    
                   -  Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤2.5 ×
                      upper limit of normal (ULN)
    
                   -  Have a total bilirubin level ≤1.5 × ULN (unless secondary to Gilbert syndrome,
                      hemolysis, or leukemia)
    
              7. Have acceptable coagulation status:
    
                 • Activated partial thromboplastin (aPTT) and prothrombin time (PT) ≤1.5 × ULN
    
              8. Have a negative pregnancy test (if female of childbearing potential)
    
              9. 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. Should a woman become pregnant or suspect that she is pregnant while
                 participating in this study, she should inform her treating physician immediately.
    
             10. 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
                 rescreened for study participation or a protocol amendment alters the care of an
                 ongoing patient, a new ICF must be signed.)
    
             11. Are able to comply with the requirements of the entire study
    
            Exclusion Criteria:
    
              1. Have undergone prior autologous or allogeneic stem cell transplant within ≤3 months,
                 have not recovered from transplant associated toxicities, or requires graft versus
                 host immunosuppressive therapy
    
              2. Have known central nervous system (CNS) involvement
    
              3. Have Richter's transformation of CLL
    
              4. Have received any monoclonal antibody therapy directed at treatment of the patient's
                 malignancy within 2 weeks prior to anticipated first dose
    
              5. Have received any anticancer therapy including chemotherapy, radiotherapy, or an
                 investigational anticancer drug within less than 5 half lives of the last dose of that
                 treatment
    
                 • This exclusion criterion is not applicable to patients requiring continuation on
                 ibrutinib. (Note: Certain patients with a rapidly rising white blood cell count while
                 on ibrutinib may need to remain on this drug for medical reasons. These patients will
                 need to be approved by the Medical Monitor and treated in accordance with the
                 protocol.)
    
              6. Have received >20 mg/day of prednisone and 0.1 mg/day of mineralocorticoids within 7
                 days prior to anticipated first dose
    
              7. Have a corrected QT interval of >450 msec (males) and >470 msec (females) using
                 Fridericia's correction formula
    
              8. Have a significant history of renal, neurologic, psychiatric, endocrinologic,
                 metabolic, immunologic, hepatic, or cardiovascular disease or any other medical
                 condition that, in the opinion of the Investigator, would adversely affect his/her
                 participation in the study
    
              9. Are pregnant and/or nursing, or refuse to use appropriate contraceptives during the
                 course of the study and for at least 30 days after the last dose of study drug
    
             10. History of another malignancy in the last 5 years except for the following adequately
                 treated:
    
                   -  Local basal cell or squamous cell carcinoma of the skin
    
                   -  Carcinoma in situ of the cervix or breast
    
                   -  Papillary, noninvasive bladder cancer
    
                   -  Early stage prostate cancer for which observation is clinically indicated
    
                   -  Other Stage 1 or 2 cancers currently in complete remission
    
                   -  Any other cancer that has been in complete remission for 2 years or surgically
                      cured. Medical Monitor may be contacted for additional determination of
                      acceptable prior cancer history
    
             11. Have known gastrointestinal disorders (eg, malabsorption syndrome), complications (eg,
                 dysphagia), or surgery that could make consumption or absorption of oral medications
                 problematic
    
             12. Have an uncontrolled systemic infection (viral, bacterial, or fungal) or fever and
                 neutropenia within 7 days prior to anticipated first dose
    
             13. Have active and uncontrolled autoimmune cytopenias for 2 or more weeks including
                 autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)
    
             14. Have received prior therapy with an AXL inhibitor
    
             15. Have exhibited allergic reactions to a similar structural compound, biological agent,
                 or formulation
    
             16. Are unwilling or unable to comply with procedures required in this protocol
    
             17. Have a history of severe adverse reaction (eg. hypersensitivity reaction, anaphylaxis)
                 to sulfonamides
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:PHASE 1: Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events.
    Time Frame:28 days
    Safety Issue:
    Description:A DLT is defined as a drug-related toxicity that is observed to occur within the first 28 days of treatment

    Secondary Outcome Measures

    Measure:PHASE 1: Area under the plasma concentration-time curve from zero to infinity of oral TP-0903 in the defined patient groups
    Time Frame:28 days
    Safety Issue:
    Description:Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1
    Measure:PHASE 1: Peak plasma concentration (Cmax) of oral TP-0903 in the defined patient groups
    Time Frame:28 days
    Safety Issue:
    Description:Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1
    Measure:PHASE 2: To determine the Duration of Response
    Time Frame:2 years
    Safety Issue:
    Description:Time from tumor response to disease progression
    Measure:PHASE 2: Rate of overall survival
    Time Frame:2 years
    Safety Issue:
    Description:The time from first dose to objective tumor progression or death

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Tolero Pharmaceuticals, Inc.

    Trial Keywords

    • Tolero
    • Phase 1/2
    • First in human
    • Previously treated Chronic Lymphocytic Leukemia (CLL)
    • Previously treated Small Lymphocytic Lymphoma (SLL)
    • AXL inhibitor
    • Cancer
    • Advanced Cancer
    • Relapsed / Refractory CLL

    Last Updated

    June 10, 2019