A Study of Oral TP-3654 in Patients With Myelofibrosis

• ClinicalTrials.gov Identifier: NCT04176198
• Recruitment Status: Recruiting
• First Posted: November 25, 2019
• Last Update Posted: November 21, 2023
• Sponsor: Sumitomo Pharma America, Inc.
• Information provided by (Responsible Party): Sumitomo Pharma America, Inc.

Tracking Information

• First Submitted Date: November 8, 2019
• First Posted Date: November 25, 2019
• Last Update Posted Date: November 21, 2023
• Actual Study Start Date: December 16, 2019
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 21, 2021)

• Determine the incidence of dose-limiting toxicities (DLTs) at escalated doses of TP-3654 [ Time Frame: 28 days ]
  Frequency, severity, and causal relationship of study defined high grade toxicities
• Determine the incidence of treatment emergent adverse events [ Time Frame: 28 days ]
  Frequency, severity, and causal relationship of adverse events

Original Primary Outcome Measures (submitted: November 22, 2019)

• Determine the incidence of dose-limiting toxicities (DLTs) at escalated doses of TP-3654 [ Time Frame: 28 days ]
• Determine the incidence of treatment emergent adverse events [ Time Frame: 28 days ]

Current Secondary Outcome Measures (submitted: March 4, 2022)

• 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: 24 weeks ]
  Number of patients achieving objective response by IWG-MRT response criteria
• Determine proportion of patients who have ≥ 25% spleen volume reduction at week 24 [ Time Frame: 24 weeks ]
  Number of patients who have ≥ 25% spleen volume reduction compared to baseline after 24 weeks of treatment
• Determine proportion of patients who have ≥ 35% spleen volume reduction (SVR35) at week 24 [ Time Frame: 24 weeks ]
  Number of patients who have ≥ 35% spleen volume reduction compared to baseline after 24 weeks of treatment
• Determine proportion of patients with ≥ 50% improvement in total symptom score (TSS50) at week 24 [ Time Frame: 24 weeks ]
  Number of patients who have ≥ 50% total symptom score reduction by MFSAF compared to baseline after 24 weeks of treatment
• Determine the change in Patient Global Impression of Change (PGIC) at week 24 [ Time Frame: 24 weeks ]
  Change in PGIC score during treatment
• Assess the reduction in bone marrow fibrosis in repeat biopsies [ Time Frame: 12 months ]
  Change in bone marrow fibrosis during treatment compared to baseline
• Determine Overall Survival [ Time Frame: 3 years ]
  The time interval from treatment start date of death from any cause
• Determine the incidence of QT interval changes and morphology as assessed by holter electrocardiogram (ECG) monitoring [ Time Frame: 25 hours ]
  Changes in QT interval and heart rhythm
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Half-life (t½) [ Time Frame: 24 hours ]
  The estimate of time for the TP-3654 concentration or amount to be reduced by half
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Peak Plasma Concentration (Cmax) [ Time Frame: 24 hours ]
  The maximum TP-3654 concentration after administration
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Time of Maximum concentration observed (tmax) [ Time Frame: 24 hours ]
  The estimate of time to maximum TP-3654 concentration
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Area under the plasma concentration versus time curve (AUC) [ Time Frame: 24 hours ]
  The amount of drug exposure over 24 hours period after administration

Original Secondary Outcome Measures (submitted: November 22, 2019)

• Determine the incidence of QT interval changes and morphology as assessed by intensive electrocardiogram (ECG) monitoring [ Time Frame: 25 hours ]
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Half-life (t½) [ Time Frame: 24 hours ]
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Peak Plasma Concentration (Cmax) [ Time Frame: 24 hours ]
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Time of Maximum concentration observed (tmax) [ Time Frame: 24 hours ]
• Establish the pharmacokinetic (PK) parameters of TP-3654 by assessing Area under the plasma concentration versus time curve (AUC) [ Time Frame: 24 hours ]
• 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 ]

Current Other Pre-specified Outcome Measures (submitted: October 21, 2021)

Study potential pharmacodynamic (PD) markers of TP-3654 [ Time Frame: 12 months ]

Evaluate exploratory biomarkers in peripheral blood samples and bone marrow biopsy samples. Change in protein phosphorylation and inflammatory cytokines.

Original Other Pre-specified Outcome Measures (submitted: November 22, 2019)

Study potential pharmacodynamic (PD) markers of TP-3654 [ Time Frame: 12 months ]

Evaluate exploratory biomarkers in peripheral blood samples and bone marrow biopsy samples

Descriptive Information

• Brief Title: A Study of Oral TP-3654 in Patients With Myelofibrosis
• Official Title: A Phase 1/2, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 in Patients With Intermediate or High-Risk Primary or Secondary Myelofibrosis
• Brief Summary: This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of TP-3654 in patients with intermediate or high-risk primary or secondary MF.
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelofibrosis

Intervention

Drug: TP-3654

Oral PIM Inhibitor

Study Arms

Experimental: TP-3654

Intervention: Drug: TP-3654

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 14, 2023): 80
• Original Estimated Enrollment (submitted: November 22, 2019): 50
• Estimated Study Completion Date: February 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS)
• Previously treated with a JAK inhibitor 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 ≥ 25 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 MF-SAF, 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Nanci McClellan; 617-674-6800; nanci.mcclellan@oncology.sumitomo-pharma.com

Contact: Paula Minnick; paula.minnick@oncology.sumitomo-pharma.com

• Listed Location Countries: Australia, Japan, United States

Administrative Information

• NCT Number: NCT04176198
• Other Study ID Numbers: BBI-TP-3654-102
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sumitomo Pharma America, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Sumitomo Pharma America, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sumitomo Pharma America, Inc.
• Verification Date: November 2023