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

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.
 
ClinicalTrials.gov Identifier: NCT04518345
Recruitment Status : Recruiting
First Posted : August 19, 2020
Last Update Posted : January 20, 2022
Sponsor:
Collaborator:
Sumitomo Pharma Oncology, Inc.
Information provided by (Responsible Party):
Uma Borate, Ohio State University Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Drug: Azacitidine Drug: Dubermatinib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of TP-0903 in Patients With Acute Myeloid Leukemia and FLT3 Mutations
Actual Study Start Date : November 5, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Experimental: Treatment (dubermatinib)

FLT3 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.

Drug: Azacitidine
Given IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Dubermatinib
Given PO
Other Names:
  • TP 0903
  • TP-0903
  • TP0903




Primary Outcome Measures :
  1. Maximum tolerated dose of dubermatinib (TP-0903) [ Time Frame: Up to 28 days ]
    Determine a tolerable dose of TP-0903 monotherapy for relapsed/refractory patients with FLT3 AML.

  2. Composite complete response (CR) rate [ Time Frame: Up to 5 years post registration ]
    Will calculate the composite CR rate (complete remission [CR]/complete remission with incomplete count recovery [CRh) defined according to the 2017 European LeukemiaNet Acute Myeloid Leukemia recommendation.

  3. Composite CR rate with partial hematologic recovery (CRh) rate [ Time Frame: through study completion, an average of 1 year ]
    Will calculate the composite CR rate (CR/CRh), defined according to the International Working Group criteria and assessed at the end of induction.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. The Number of patients who proceed to transplant [ Time Frame: Up to 5 years post registration ]
    The number of patients who got to transplant

  3. 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 ]
    Will be summarized by the Kaplan-Meier method.

  4. Maximum grade of each type of adverse event [ Time Frame: Up to 5 years post registration ]
    Will be recorded for each patient and summarized.

  5. Incidence of treatment-related adverse events [ Time Frame: Up to 5 years post registration ]
    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.

  6. Tolerability of TP-0903 [ Time Frame: Up to 5 years post registration ]
    Reasons for treatment discontinuation and number of TP-0903 cycles received will be summarized and used to assess tolerability.


Other Outcome Measures:
  1. Peak Plasma Concentration (Cmax) pharmacokinetics (PK) [ Time Frame: Up to 5 years post registration ]
    Initial analysis of plasma PK data will include standard compartmental and noncompartmental methods. Descriptive statistics including means, standard deviations, and frequencies will be computed for all variables. Relationships between continuous variables will be performed using standard linear correlation and linear regression. Relationships between PK parameters such as maximum concentration with response will be performed using standard t-tests or Wilcoxon rank sum tests and illustrated using boxplots or other graphical displays.

  2. Area under the plasma concentration (AUC) pharmacokinetics (PK) [ Time Frame: Up to 5 years post registration ]
    Initial analysis of plasma PK data will include standard compartmental and noncompartmental methods. Descriptive statistics including means, standard deviations, and frequencies will be computed for all variables. Relationships between continuous variables will be performed using standard linear correlation and linear regression. Relationships between PK parameters such as area under curve with response will be performed using standard t-tests or Wilcoxon rank sum tests and illustrated using boxplots or other graphical displays.

  3. Changes in cytokines/chemokines [ Time Frame: Up to 5 years post registration ]
    Differences in cytokines/chemokines will be evaluated using paired t-tests or Wilcoxon signed rank tests. Values will be log transformed as appropriate to reflect biologic plausibility. Cytokines/chemokines to be measured include: AXL, GAS6, FLT3 ligand, GM-CSF, IL-6, IL-8, RANTES, MIP-1α, MCP-1, sCD40L, EGF, VEGF

  4. Effect of TP-0903 on inhibition of phospho-protein expression Effect of TP-0903 on inhibition of phospho-protein expression Effect of TP-0903 on inhibition of phospho-protein expression Impact of TP-0903 on kinase signaling [ Time Frame: Up to 5 years post registration ]
    Percent inhibition of phospho-protein expression in AML cells. Phospho-proteins to be measured include: phospho-FLT3, phospho-STAT5, phospho-AURKA/B, phosho-AXL

  5. Patterns of sensitivity and resistance [ Time Frame: Up to 5 years post registration ]
    Mutational status in AML cells will be determined in samples at baseline and during treatment. Mutations in genes with single nucleotide changes and indels at variant allele frequency (VAF) >0.1 will be reported. Mutations with decreasing VAF represent sensitivity, and increasing VAF represent resistance.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 ≥40%
  • 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

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): NCT04518345


Contacts
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Contact: Ohio State University Comprehensive Cancer Center 800-293-5066 OSUCCCClinicaltrials@osumc.edu
Contact: Stacey Dillion Stacey.Dillion@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Uma Borate, MD    614-293-6050      
Principal Investigator: Uma Borate, MD         
Sponsors and Collaborators
Uma Borate
Sumitomo Pharma Oncology, Inc.
Investigators
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Principal Investigator: Uma Borate, MD Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Uma Borate, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04518345    
Other Study ID Numbers: OSU-19229
NCI-2020-04292 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: August 19, 2020    Key Record Dates
Last Update Posted: January 20, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors