Clinical Trials /

TP-0903 for the Treatment of FLT3 Mutated Acute Myeloid Leukemia

NCT04518345

Description:

This phase IB/II trial studies the best dose of TP-0903 and how well it works when given alone or with azacitidine in treating patients with FLT3 gene mutated acute myeloid leukemia. TP-0903 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TP-0903 alone or with azacitidine may kill more cancer cells.

Related Conditions:
  • Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TP-0903 for the Treatment of FLT3 Mutated Acute Myeloid Leukemia
  • Official Title: A Phase 1b/2 Study of TP-0903 in Patients With Acute Myeloid Leukemia and FLT3 Mutations

Clinical Trial IDs

  • ORG STUDY ID: OSU-19229
  • SECONDARY ID: NCI-2020-04292
  • NCT ID: NCT04518345

Conditions

  • Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (dubermatinib)
DubermatinibTP 0903, TP-0903, TP0903Treatment (dubermatinib)

Purpose

This phase IB/II trial studies the best dose of TP-0903 and how well it works when given alone or with azacitidine in treating patients with FLT3 gene mutated acute myeloid leukemia. TP-0903 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TP-0903 alone or with azacitidine may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine a tolerable dose of dubermatinib (TP-0903) monotherapy for
      relapsed/refractory patients with FLT3 acute myeloid leukemia (AML).

      II. To determine the maximum tolerated dose (MTD) of TP-0903 with azacitidine in untreated
      unfit patients with FLT3 AML.

      III. To determine the complete remission (CR) or complete remission with partial hematologic
      recovery (CRh) rate following induction therapy with TP-0903 in relapsed/refractory patients
      or TP-0903 with azacitidine therapy in untreated unfit patients with FLT3 AML.

      SECONDARY OBJECTIVES:

      I. To determine the toxicity profile of TP-0903 as a single agent and in combination with or
      azacitidine.

      II. To determine disease-free survival for patients achieving CR/CRh in each cohort.

      III. To determine overall survival for patients in each cohort. IV. To determine the
      proportion of patients who go to transplant.

      EXPLORATORY OBJECTIVES:

      I. To conduct pharmacokinetic studies of TP-0903 alone and in combination with azacitidine.

      II. To examine changes in circulating AXL, Gas6, FLT3 ligand, and other cytokines/chemokines
      by TP-0903.

      III. To determine the impact of TP-0903 on the inhibition of kinase signaling (AXL, FLT3,
      STAT5, AURKA), and metabolomics in AML cells.

      IV. To determine differentially expressed genes in bone marrow stromal cells and AML cells
      upon TP-0903 treatment.

      V. To examine sensitivity and resistance patterns associated with TP-0903 by genomic,
      epigenomic, and transcriptomic profiling.

      OUTLINE: This is a phase Ib, dose-escalation study of dubermatinib followed by a phase II
      study.

      (FLT3 AML WITH RELAPSED/REFRACTORY DISEASE):

      INDUCTION: Patients receive dubermatinib orally (PO) once daily (QD) on days 1-21. Treatment
      repeats every 28 days for up to 4 cycles in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE: Patients with clinical or hematologic response and not transplant eligible may
      continue dubermatinib until loss of response/clinical benefit. Patients with clinical or
      hematologic response and transplant eligible may continue dubermatinib until one week prior
      to admission.

      After completion of study treatment, patients are followed up followed every 3 months for up
      to 2 years from registration and then every 6 months for up to 5 years from registration.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dubermatinib)ExperimentalFLT3 AML WITH RELAPSED/REFRACTORY DISEASE: INDUCTION: Patients receive dubermatinib PO QD on days 1-21. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients with clinical or hematologic response and not transplant eligible may continue dubermatinib until loss of response/clinical benefit. Patients with clinical or hematologic response and transplant eligible may continue dubermatinib until one week prior to admission.
  • Azacitidine
  • Dubermatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with AML and the presence of FLT3-ITD mutation

          -  Patients with secondary AML or therapy related disease (t-AML) are eligible

          -  If the patient has co-morbid medical illness, life expectancy attributed to this must
             be greater than 6 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Total bilirubin < 2.0mg/dL unless due to Gilbert's disease

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 x institutional upper limit of normal

          -  Creatinine (Cr) clearance > 50 mL/min by Cockcroft-Gault calculation

          -  New York Heart Association (NYHA) Congestive Heart Failure (CHF) class II or better

          -  Cardiac ejection fraction >= 50%

          -  Female patients of child-bearing potential must agree to use dual methods of
             contraception and have a negative serum pregnancy test at screening, and male patients
             must use an effective barrier method of contraception if sexually active with a female
             of child-bearing potential. Acceptable methods of contraception are condoms with
             contraceptive foam, oral, implantable or injectable contraceptives, contraceptive
             patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is
             surgically sterilized or post-menopausal. For both male and female patients, effective
             methods of contraception must be used throughout the study and for three months
             following the last dose

          -  Ability to understand and willingness to sign the written informed consent document

          -  Human immunodeficiency virus (HIV) infection without history of acquired
             immunodeficiency syndrome (AIDS) and sufficiently high CD4 cells (> 400/mm^3) and low
             HIV viral loads (< 30,000 copies/ml plasma) not requiring anti-HIV therapy are
             eligible

        Exclusion Criteria:

          -  Patients with acute promyelocytic leukemia

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study. Treatment with hydoxyurea is
             permitted during cycle 1 to maintain white blood cell (WBC) < 40,000/uL

          -  Patients receiving any other investigational agents or patients that have received
             other investigational agents within 14 days of enrollment

          -  Patients with active central nervous system (CNS) malignancy

          -  Major surgery within 2 weeks before day 1

          -  Uncontrolled active infection. Patients with infection requiring parenteral
             antibiotics are eligible if the infection is controlled

          -  Patients with significantly diseased or obstructed gastrointestinal tract

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable
             angina pectoris, myocardial infarction within 6 months prior to enrollment, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities. Prior to study entry, any
             electrocardiogram (ECG) abnormality at screening has to be documented by the
             investigator as not medically relevant

          -  Patients with serious medical or psychiatric illness likely to interfere with
             participation in this clinical study

          -  Pregnant women or women who are breastfeeding are excluded from this study.
             Confirmation that the subject is not pregnant must be established by a negative serum
             beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during
             screening. Pregnancy testing is not required for post-menopausal or surgically
             sterilized women

          -  Patients with advanced malignant solid tumors

          -  Patients who are not able to swallow capsules or tablets
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of dubermatinib (TP-0903)
Time Frame:Up to 28 days
Safety Issue:
Description:Determine a tolerable dose of TP-0903 monotherapy for relapsed/refractory patients with FLT3 AML.

Secondary Outcome Measures

Measure:Disease-free survival
Time Frame:From the date of first CR/CRh until the first date of relapse/progression or death from any cause, assessed up to 5 years post registration
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method to determine disease-free survival for patients achieving complete response CR/CRh in each cohort of the study.
Measure:The Number of patients who proceed to transplant
Time Frame:Up to 5 years post registration
Safety Issue:
Description:The number of patients who got to transplant
Measure:Overall survival
Time Frame:From the treatment start date until the date of death from any cause or date last known alive, assessed up to 5 years post registration
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method.
Measure:Maximum grade of each type of adverse event
Time Frame:Up to 5 years post registration
Safety Issue:
Description:Will be recorded for each patient and summarized.
Measure:Incidence of treatment-related adverse events
Time Frame:Up to 5 years post registration
Safety Issue:
Description:Treatment-related adverse events, defined as possibly, probably or definitely related to study treatment per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be summarized separately.
Measure:Tolerability of TP-0903
Time Frame:Up to 5 years post registration
Safety Issue:
Description:Reasons for treatment discontinuation and number of TP-0903 cycles received will be summarized and used to assess tolerability.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Bhavana Bhatnagar

Last Updated

August 14, 2020