A Study of Oral TP-3654 in Patients With Myelofibrosis

Study Overview
=================
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.

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

Conditions
-----------------
Myelofibrosis

Intervention / Treatment
-----------------
* Drug: TP-3654


Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TP-3654<br> | Drug: TP-3654<br>* Oral PIM Inhibitor<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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