Clinical Trials /

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

NCT02729298

Description:

TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. 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 Phase 1a study is conducted to identify the maximum tolerated dose (MTD) of TP-0903 administered orally to patients with advanced solid tumors and to identify the safety profile and Recommended Phase 2 Dose (RP2D) of TP-0903. Once the MTD has been established, additional patients with specific tumor types (advanced solid tumors that have progressed after achieving a best documented response of at least stable disease (ie, SD, PR, or CR documented per iRECIST following at least 2 cycles (8 weeks) of immunotherapy, EGFR+ Non Small Cell Lung Cancer [NSCLC] and have demonstrated recent progression following a best documented response of at least stable disease (ie, SD, PR, or CR documented per RECIST v1.1 on ≤2 lines of oral TKIs (Prior chemotherapy ± immunotherapy is allowed as long as the patient is clearly demonstrating current progression on an EGFR TKI.), BRAF-, KRAS-, or NRAS-mutated Colorectal Carcinoma [CRC] for whom there is no standard therapy remaining, persistent/recurrent Ovarian Cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy, and BRAF-mutated Melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor) will be enrolled at the MTD in the Phase 1b study. Data collected from patients enrolled in each of these additional cohorts will be used for to confirm safety, explore potential biomarkers, and evaluate potential signals of activity when TP-0903 is administered to specific groups of heavily pretreated patients or given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI). The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1a / 1b, 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

Clinical Trial IDs

  • ORG STUDY ID: TP-0903-101
  • NCT ID: NCT02729298

Conditions

  • Advanced Solid Tumors
  • EGFR Positive Non-small Cell Lung Cancer
  • Colorectal Carcinoma
  • Recurrent Ovarian Carcinoma
  • BRAF-Mutated Melanoma

Interventions

DrugSynonymsArms
TP-0903Advanced Solid Tumors

Purpose

TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. 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 Phase 1a study is conducted to identify the maximum tolerated dose (MTD) of TP-0903 administered orally to patients with advanced solid tumors and to identify the safety profile and Recommended Phase 2 Dose (RP2D) of TP-0903. Once the MTD has been established, additional patients with specific tumor types (advanced solid tumors that have progressed after achieving a best documented response of at least stable disease (ie, SD, PR, or CR documented per iRECIST following at least 2 cycles (8 weeks) of immunotherapy, EGFR+ Non Small Cell Lung Cancer [NSCLC] and have demonstrated recent progression following a best documented response of at least stable disease (ie, SD, PR, or CR documented per RECIST v1.1 on ≤2 lines of oral TKIs (Prior chemotherapy ± immunotherapy is allowed as long as the patient is clearly demonstrating current progression on an EGFR TKI.), BRAF-, KRAS-, or NRAS-mutated Colorectal Carcinoma [CRC] for whom there is no standard therapy remaining, persistent/recurrent Ovarian Cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy, and BRAF-mutated Melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor) will be enrolled at the MTD in the Phase 1b study. Data collected from patients enrolled in each of these additional cohorts will be used for to confirm safety, explore potential biomarkers, and evaluate potential signals of activity when TP-0903 is administered to specific groups of heavily pretreated patients or given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI). The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.

Detailed Description

      This is a phase 1a / 1b, 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 phases in this study. In Phase 1a (dose escalation), 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, dosing will change from BSA-dependent to a flat dose based
      on the average of the dose administered in the MTD expansion safety cohort. Once the MTD has
      been established, in Ph 1b (expansion), 5 additional cohorts of up to 20 patients each with
      specific tumor types (up to 100 additional patients total) may be enrolled at the MTD dose
      level to confirm safety, explore potential biomarkers, and evaluate potential signals of
      activity when TP-0903 is administered to specific groups of heavily pretreated patients or
      given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI). Ten patients in
      each of these 5 Expansion Cohorts will be required to consent to undergo pre- and post-dose
      tumor biopsies. All patients who undergo these biopsies will comprise the 'Biopsy Cohorts'
      (Phase 1b).

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Advanced Solid TumorsExperimentalPhase 1a Single daily dose of TP-0903 by oral administration on Days 1-21 of a 28 day cycle AND Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.
  • TP-0903
EGFR+ NSCLCExperimentalPhase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.
  • TP-0903
BRAF-, KRAS-, or NRAS-Mutated CRCExperimentalPhase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.
  • TP-0903
Persistent/Recurrent Ovarian CancerExperimentalPhase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.
  • TP-0903
BRAF-Mutated MelanomaExperimentalPhase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.
  • TP-0903

Eligibility Criteria

        Inclusion Criteria:

        To be eligible for participation in the study, patients must meet all of the following
        inclusion criteria:

          1. Patients enrolled in the Phase 1a study must:

               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

          2. Patients enrolled in the Phase 1b study must meet criteria for one of the following
             tumor types:

               1. Have tumors that have progressed after achieving a best documented response of at
                  least stable disease (ie, SD, PR, or CR documented per iRECIST following at least
                  2 cycles (8 weeks) of immunotherapy and are felt to be appropriate for this type
                  of treatment*

               2. Have EGFR+ NSCLC and have demonstrated recent progression following a best
                  documented response of at least stable disease (ie, SD, PR, or CR documented per
                  per RECIST v1.1 on ≤2 lines of oral TKIs and are felt to be appropriate for this
                  type of treatment* Prior chemotherapy ± immunotherapy is allowed as long as the
                  patient is clearly demonstrating current progression on an EGFR TKI.

               3. Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy
                  remaining

               4. Have persistent/recurrent ovarian cancer who would be platinum refractory/
                  resistant and have had any number of lines of prior therapy

               5. Have BRAF-mutated melanoma that has not responded to immunotherapy or a
                  combination BRAF/MEK inhibitor

          3. Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1 or
             iRECIST

          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)

                  *Patients receiving immunotherapy should have a bilirubin level <3.0x 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.

                    -  Patients receiving immunotherapy should have AST and ALT levels <5.0x ULN.

          9. Have acceptable renal function:

             a. 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 ≥9 g/dL

         11. Have no clinically significant abnormalities on urinalysis

         12. Have acceptable coagulation status:

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

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

         13. 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 (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.

         14. 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.)

         15. Patients enrolled in each of the five Expansion Cohorts must be willing to consider
             pre-study and on-study biopsies, if safe and medically feasible, as determined by
             local interventional radiology (3 to 5 core samples requested at each biopsy
             timepoint)

        Patients meeting any one of these exclusion criteria will be prohibited from participating
        in this study:

          1. 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)

          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 2 weeks prior to Day 1

          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
             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)

             a. This exclusion criterion is not applicable for patients with EGFR+ NSCLC or
             immunotherapy-resistant tumors who are enrolled in expansion cohorts at the MTD.

         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 a history of severe adverse reaction (eg, hypersensitivity reaction, anaphylaxis)
             to sulfonamides

         17. Patients scheduled to receive immunotherapy or TKI regimens plus TP-0903 must not be
             currently taking high-dose steroids (ie, physiologic dose approximately equivalent to
             15 mg/day of prednisone)
      
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:Cycle 1 (Day 1 through Day 28)
Safety Issue:
Description:A DLT is defined as any one of the following events observed within Cycle 1: Grade 3 or greater febrile neutropenia, Grade 4 ANC 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

Measure:Area under the plasma concentration-time curve from zero to infinity [AUC(0-inf)] of oral TP-0903
Time Frame:Cycles 1 and 2 (Day 1 through 23)
Safety Issue:
Description:Derived PK parameters by non-compartment analysis on Cycle 1.
Measure:Area under the plasma concentration-time curve from zero to last measured time point [AUC(0-last)] of oral TP-0903
Time Frame:Cycles 1 and 2 (Day 1 through 23)
Safety Issue:
Description:Derived PK parameters by non-compartment analysis on Cycle 1
Measure:Peak plasma concentration (Cmax) of oral TP-0903
Time Frame:Cycles 1 and 2 (Day 1 through 23)
Safety Issue:
Description:Derived PK parameters by non-compartment analysis on Cycle 1.
Measure:Activity of TP-0903 on predictive biomarkers
Time Frame:End of every cycle (each cycle is 28 days) and End of Study (within 14 days of the last dose of study drug or within 14 days of the decision to discontinue study treatment)
Safety Issue:
Description:Assess biomarkers in tumor tissue, PBMCs, plasma and serum. The pharmacodynamic relationships of TP-0903 exposure with exploratory biomarkers will be quantified using the Spearman rank correlation statistic.
Measure:Objective response rate using RECIST v1.1 and iRECIST
Time Frame:End of every cycle (each cycle is 28 days) and End of Study (within 14 days of the last dose of study drug or within 14 days of the decision to discontinue study treatment)
Safety Issue:
Description:Baseline tumor assessment will be performed at screening and repeated at Cycle 2 and every even cycle thereafter.

Details

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

Trial Keywords

  • Tolero
  • Phase 1a / 1b
  • First in human
  • Solid Tumors with immunotherapy progression
  • AXL inhibitor
  • Advanced Malignancy
  • Cancer
  • EGFR+ NSCLC with progression on ≤2 lines of oral TKIs
  • BRAF-Mutated CRC
  • KRAS-Mutated CRC
  • NRAS-Mutated CRC
  • Persistent/Recurrent Ovarian Cancer
  • BRAF-Mutated Melanoma with immunotherapy progression

Last Updated

May 21, 2019