Clinical Trials /

Safety of TT-00420 Monotherapy in Patients With Advanced Solid Tumors and Triple Negative Breast Cancer

NCT03654547

Description:

This is a first-in-human, phase I clinical research study with TT-00420, an investigational, oral, multi-target, dual mechanism kinase inhibitor targeting both mitosis and tumor micro-environment, for the treatment of triple negative breast cancer (TNBC) and other advanced solid tumors. The study consists of a dose escalation part followed by a MTD expansion part.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety of TT-00420 Monotherapy in Patients With Advanced Solid Tumors and Triple Negative Breast Cancer
  • Official Title: A Phase I, First-In-Human, Multicenter, Open-Label Study of TT-00420, Administered Orally in Adult Patients With Advanced Solid Tumors and Triple Negative Breast Cancers

Clinical Trial IDs

  • ORG STUDY ID: TT420X2101
  • NCT ID: NCT03654547

Conditions

  • Advanced Solid Tumors
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
TT-00420TT420Dose Escalation

Purpose

This is a first-in-human, phase I clinical research study with TT-00420, an investigational, oral, multi-target, dual mechanism kinase inhibitor targeting both mitosis and tumor micro-environment, for the treatment of triple negative breast cancer (TNBC) and other advanced solid tumors. The study consists of a dose escalation part followed by a MTD expansion part.

Detailed Description

      Dose Escalation Cohorts: Eligible adult patients with advanced solid tumors will be enrolled
      into Dose Escalation cohorts. Starting dose of TT-00420 mono-therapy will be 1 mg p.o., q.d.
      TT-00420 capsule will be administered once daily on a continuous schedule. A treatment cycle
      consists of 28 days. An ABLRM guided by the EWOC principle will evaluate the risk of
      under-dose or over-dose for the dose tested in each cohort and provide the recommendation
      dose for next cohort. Dose limiting toxicity (DLT) will be evaluated per the pre-defined DLT
      criteria and managed by the pre-defined rules detailed in the protocol. Maximum Tolerated
      Dose (MTD) and/or Dose Recommend for Dose Expansion (DRDE) will be determined in Dose
      Escalation cohorts.

      Dose Expansion Cohorts:

      TNBC Cohort:

      TNBC Dose-Expansion cohort will be opened to enroll the patients with advanced TNBC and
      evaluate the safety, PK and preliminary efficacy of TT-00420 to identify the optimal
      biological dose (OBD), when feasible, in patients with advanced TNBC.

      SAT Cohort:

      A parallel basket SAT Dose Expansion Cohort will be open to enroll patients with selected
      advanced tumors (SAT) to evaluate the safety, PK and preliminary efficacy of TT-00420 to
      identify the optimal biological dose (OBD), when feasible, in patients with SATs.

      Recruitment in dose expansion cohorts may be put on hold if any significant safety finding(s)
      that was not observed in dose escalation cohorts is identified. Bayesian modeling will be
      updated with the new findings to evaluate if the previously determined MTD or DRDE still
      suitable for further enrollment.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalEligible adult patients with advanced solid tumors will be enrolled into Dose Escalation cohorts and treated with TT-00420 at different dose cohorts. Starting dose will be 1 mg p.o., q.d. An ABLRM guided by the EWOC principle will evaluate the risk of under-dose or over-dose for the dose tested in each cohort and provide the recommendation dose for next cohort. Dose Escalation Teleconference will be held after the last evaluable patient complete Cycle 1 treatment in each dose cohort to evaluate DLT, determine MTD and/or DRDE.
  • TT-00420
Dose ExpansionExperimentalTNBC Cohort: TNBC Dose-Expansion cohort will be opened to enroll the patients with advanced TNBC and evaluate the safety, PK and preliminary efficacy of TT-00420 and identify the optimal biological dose (OBD), when feasible, in patients with advanced TNBC. SAT Cohort: A parallel basket SAT Dose Expansion Cohort will be open to enroll patients with SATs to evaluate the safety, PK and preliminary efficacy of TT-00420 and identify the optimal biological dose (OBD), when feasible, in patients with SATs.
  • TT-00420

Eligibility Criteria

        Inclusion Criteria:

          1. Aged 18 years to 75 years at the time of provision of informed consent

          2. Dose Escalation Cohorts: Histopathological or cytologically documented locally
             advanced or metastatic solid tumors who have no available standard therapeutic
             treatment options Dose Expansion Cohorts: Histopathological or cytologically
             documented locally advanced or metastatic TNBC or SATs

          3. TNBC Dose Expansion Cohort:

               1. Histologically proven invasive breast carcinoma with triple negative receptor
                  status per institutional standard and with confirmed negative for ER and PR by
                  IHC (<10% positive tumor nuclei)

               2. relapsed/refractory to at least one line of systemic chemotherapy

          4. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors

          5. ECOG performance status of 0 or 1

          6. Adequate organ function confirmed at Screening and within 10 days of initiating
             treatment, as evidenced by:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L

               -  Hemoglobin (Hgb) ≥ 9 g/dl

               -  Platelets (plt) ≥ 100 x 10^9/L

               -  AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver
                  metastases are present

               -  Total bilirubin ≤ 1.5 x ULN, or direct bilirubin < ULN for patients with total
                  bilirubin levels >1.5 ULN

               -  Serum creatinine ≤ 1.5 x ULN or calculated 24-hour clearance ≥ 50 mL/min

               -  Negative pregnancy test within 72 hours before starting study treatment in all
                  pre-menopausal women and women < 12 months after the onset of menopause

          7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the
             study and until at least 6 months after ceasing study treatment

          8. Able to sign informed consent and to comply with the protocol

        Exclusion Criteria:

          1. Women who are pregnant or lactating

          2. Women of child-bearing potential (WOCBP) who does not use adequate birth control

          3. Patients with any hematologic malignancy. This includes leukemia (any form), lymphoma,
             and multiple myeloma.

          4. Patients with

               1. a history of primary central nervous system tumors or

               2. carcinomatous meningitis Note: Patients with treated brain metastases that are
                  off corticosteroid and have been clinically stable 28 days are eligible for
                  enrollment

          5. Patients with the following mood disorders as judged by the Investigator or a
             psychiatrist, or as result of patient's mood assessment questionnaire:

               -  Medically documented history of or active major depressive episode, bipolar
                  disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of
                  suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm
                  to others)

               -  ≥ CTCAE grade 3 anxiety

               -  The psychiatric judgment, if available, overrules the mood assessment
                  questionnaire result/investigator judgment

          6. Impaired cardiac function or clinically significant cardiac diseases, including but
             not limited to any of the following:

               1. LVEF < 45% as determined by MUGA scan or ECHO

               2. Congenital long QT syndrome

               3. QTc ≥ 450 msec on screening ECG

               4. Unstable angina pectoris ≤ 3 months prior to starting study drug

               5. Acute myocardial infarction ≤ 3 months prior to starting study drug

          7. Patients with

               1. unresolved diarrhea ≥ CTCAE grade 2, or

               2. impairment of gastrointestinal (GI) function, or

               3. GI disease that may significantly alter the absorption of TT-00420 (e.g.,
                  ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption
                  syndrome, or small bowel resection).

          8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
             uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], active or uncontrolled
             infection) that could cause unacceptable safety risks or compromise compliance with
             the protocol

          9. Patients who have received chemotherapy, targeted therapy or immunotherapy ≤ 4 weeks
             (6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not
             recovered from side effects of such therapy

         10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
             radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
             recovered from side effects of such therapy

         11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
             who have not recovered from side effects of such therapy

         12. Patients who have been treated with any hematopoietic colony-stimulating growth
             factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin
             or darbepoetin therapy, if initiated before enrollment, may be continued

         13. Patients who are currently receiving treatment with therapeutic doses of warfarin
             sodium (Coumadin®) or any other coumarin-derivative anticoagulants

         14. Patients who have received corticosteroids ≤ 2 weeks prior to starting study drug or
             who have not recovered from the side effects of such treatment

         15. Patients who are currently receiving treatment with medication that has known risk to
             prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot
             either be discontinued or switched to a different medication prior to starting study
             drug

         16. Patients who are receiving high to moderate CYP3A inhibitors and inducers as listed in
             Appendix F

         17. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
             mandatory)

         18. Known history of active infection with Hepatitis B (e.g., HBsAg reactive), or
             Hepatitis C (e.g., HCV RNA (qualitative) is detected)

         19. Has received a live-virus vaccination within 30 days of planned first dose Note:
             Seasonal flu vaccines are permitted.

         20. Inability to swallow or tolerate oral medication

         21. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that, in the opinion of the investigator, might confound the results of the trial,
             interfere with the patient's participation and compliance in the trial
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) and/or Dose Limiting Toxicity (DLT)
Time Frame:At the end of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:FIH Dose Finding

Secondary Outcome Measures

Measure:Dose Recommended for Dose Expansion (DRDE)
Time Frame:At the end of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Dose Recommended for Dose Expansion
Measure:Optimal Biological Dose (OBD)
Time Frame:At the end of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Dose Recommended for Dose Expansion
Measure:Number of Participants With Abnormal Laboratory Values
Time Frame:Up to 30 days from study discontinuation
Safety Issue:
Description:Safety and tolerability of TT-00420
Measure:Number of Participants With Adverse Events That Are Related to Treatment
Time Frame:Up to 30 days from study discontinuation
Safety Issue:
Description:Safety and tolerability of TT-00420
Measure:Peak Plasma Concentration (Cmax) of TT-00420
Time Frame:through study completion, an average of 6 months
Safety Issue:
Description:PK parameters of TT-00420
Measure:Time at which Cmax was first observed (Tmax) of TT-00420
Time Frame:through study completion, an average of 6 months
Safety Issue:
Description:PK parameters of TT-00420
Measure:Half-life (T1/2) of TT-00420
Time Frame:through study completion, an average of 6 months
Safety Issue:
Description:PK parameters of TT-00420
Measure:Objective Response Rate (ORR)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:ORR of TT-00420 in patients with TNBC or SAT treated in Dose Expansion cohorts
Measure:Disease Control Rate (DCR)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:DCR of TT-00420 in patients with TNBC or SAT treated in Dose Expansion cohorts
Measure:Duration of Response (DOR)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:DOR of TT-00420 in patients with TNBC or SAT treated in Dose Expansion cohorts
Measure:Progression Free Survival (PFS)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:PFS of TT-00420 in patients with TNBC or SAT treated in Dose Expansion cohorts
Measure:Overall Survival (OS)
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:OS of TT-00420 in patients with TNBC or SAT treated in Dose Expansion cohorts

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:TransThera Biosciences Co., Ltd

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