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A Study of Oral TP-3654 in Patients With Myelofibrosis

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. Identifier: NCT04176198
Recruitment Status : Recruiting
First Posted : November 25, 2019
Last Update Posted : June 15, 2021
Information provided by (Responsible Party):
Sumitomo Dainippon Pharma Oncology, Inc

Brief Summary:
This study is a Phase 1, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of TP-3654 in patients with intermediate-2 and high-risk primary or secondary MF.

Condition or disease Intervention/treatment Phase
Intermediate-2 Myelofibrosis High-Risk Primary Myelofibrosis High-Risk Secondary Myelofibrosis Drug: TP-3654 Phase 1

Detailed Description:
This study will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive ruxolitinib or fedratinib.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 in Patients With Intermediate-2 and High-Risk Primary or Secondary Myelofibrosis
Actual Study Start Date : December 16, 2019
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : July 2024

Arm Intervention/treatment
Experimental: TP-3654 Drug: TP-3654
Oral PIM Inhibitor

Primary Outcome Measures :
  1. Determine the incidence of dose-limiting toxicities (DLTs) at escalated doses of TP-3654 [ Time Frame: 28 days ]
  2. Determine the incidence of treatment emergent adverse events [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Determine the incidence of QT interval changes and morphology as assessed by holter electrocardiogram (ECG) monitoring [ Time Frame: 25 hours ]
  2. Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Half-life (t½) [ Time Frame: 24 hours ]
  3. Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Peak Plasma Concentration (Cmax) [ Time Frame: 24 hours ]
  4. Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Time of Maximum concentration observed (tmax) [ Time Frame: 24 hours ]
  5. Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Area under the plasma concentration versus time curve (AUC) [ Time Frame: 24 hours ]
  6. Assess patients for any evidence of Preliminary activity by proportion of patients with responses in complete remission, partial remission, clinical improvement, progressive disease and stable disease [ Time Frame: 12 months ]

Other Outcome Measures:
  1. Study potential pharmacodynamic (PD) markers of TP-3654 [ Time Frame: 12 months ]
    Evaluate exploratory biomarkers in peripheral blood samples and bone marrow biopsy samples

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

Patients must meet all of the following inclusion criteria to be eligible:

  • Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF as per WHO diagnostic criteria and intermediate-2 or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS)
  • Previously treated with a JAKi and failed on a JAK inhibitor or are ineligible to be treated with Ruxolitinib or Fedratinib at the discretion of the investigator
  • Grade ≥ 2 bone marrow fibrosis, as confirmed by bone marrow biopsy within 12 weeks prior to Screening

Fulfill the following laboratory parameters:

  • Platelet count ≥ 50 X 10^9 /L, without the assistance of growth factors or platelet transfusions
  • Absolute Neutrophil Count (ANC) ≥ 1 x 10^9/L without the assistance of granulocyte growth factors
  • Peripheral blood blast count < 10%
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • Life expectancy ≥ 3 months
  • Adequate renal function, as determined by clinical laboratory tests (serum creatinine ≤ 1.5 x upper limit of normal (ULN), and calculated creatinine clearance ≥ 30 mL/min) (Cockcroft-Gault)
  • Adequate hepatic function (ALT/AST ≤ 3 x ULN, total bilirubin ≤ 1.5 x ULN; or ALT/AST ≤ 5 x ULN, direct bilirubin ≤ 2 x ULN if due to myelofibrosis), and coagulation ([PT and PTT] ≤ 1.5 x ULN)
  • Agree to provide bone marrow biopsies during the study: at baseline or within 12 weeks prior to enrollment, and every 6 months during treatment.
  • Splenomegaly during the screening period as demonstrated by splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan
  • Show at least 2 symptoms measurable (score ≥ 1) using the MFSAF, v4.0.

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

  • Received previous systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, ESA, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.
  • Major surgery within 2 weeks before the first dose of either study drug.
  • Splenic irradiation within 6 months prior to Screening or prior splenectomy.
  • AML, MDS, or peripheral blasts ≥ 10%.
  • Prior autologous or allogeneic stem cell transplant at any time.
  • Eligible for allogeneic bone marrow or stem cell transplantation within 3 months following enrollment.
  • Experiencing electrolyte abnormalities of NCI CTCAE Grade ≥ 2 unless they can be corrected during screening and are deemed not clinically significant by the Investigator.
  • History of congestive heart failure, myocardial infarction within the past 6 months prior to Cycle 1/Day 1; left ventricular ejection fraction < 45% by echocardiogram or MUGA, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1/Day 1.
  • Corrected QT interval (using Fridericia's correction formula) of > 450 msec in men and > 470 msec in women.
  • Central nervous system (CNS) cancer or metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (eg, unstable vertebral metastases).
  • Other invasive malignancies within the last 3 years, except non-melanoma skin cancer, and localized cured prostate and cervical cancer
  • Experienced portal hypertension or any of its complications.
  • Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 14 days.
  • Known bleeding diathesis or signs of uncontrolled active bleeding (hematuria, GI bleeding) other than self-limited causes of benign etiology that have been adequately investigated at the discretion of the Investigator.
  • Requiring anticoagulation with aspirin > 81mg daily, unfractionated heparin, low molecular weight heparin (LMWH), direct anti-thrombin inhibitors, or vitamin K antagonists (eg, warfarin).
  • Severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of < 90% breathing room air).
  • Medical condition or 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.
  • Used hydroxyurea or anagrelide within 24 hours prior to the first dose.
  • Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 7 days prior to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).

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 identifier (NCT number): NCT04176198

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Contact: Tegan Nguyen 617-674-8745

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United States, Florida
University of Florida Health Shands Cancer Hospital Recruiting
Gainesville, Florida, United States, 32608
Contact: Wendy Sheehan    352-273-9148   
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center Not yet recruiting
Hackensack, New Jersey, United States, 07601
Contact: Michelle Borza    551-966-8017   
United States, New York
Roswell Park Comprehensive Cancer Center Recruiting
Buffalo, New York, United States, 14263
Contact: Krista Belko    716-845-3373   
United States, North Carolina
Duke Cancer Institute Recruiting
Durham, North Carolina, United States, 27710
Contact: Sally West    919-684-0113   
United States, Ohio
University Hospitals Cleveland Medical Center Active, not recruiting
Cleveland, Ohio, United States, 44106
United States, Texas
NEXT Oncology Active, not recruiting
San Antonio, Texas, United States, 78229
United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22903
Contact: Ioannis Vassalos    434-924-9496   
Sponsors and Collaborators
Sumitomo Dainippon Pharma Oncology, Inc
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Responsible Party: Sumitomo Dainippon Pharma Oncology, Inc Identifier: NCT04176198    
Other Study ID Numbers: BBI-TP-3654-102
First Posted: November 25, 2019    Key Record Dates
Last Update Posted: June 15, 2021
Last Verified: June 2021

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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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Neoplasm Metastasis
Primary Myelofibrosis
Neoplastic Processes
Pathologic Processes
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases