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.
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 MF23, as confirmed by bone marrow biopsy within 12 weeks prior to Screening
Fulfill the following laboratory parameters:
- Platelet count > 50 X 109 /L, without the assistance of growth factors or platelet
- Absolute Neutrophil Count (ANC) ≥ 1 x 109/L without the assistance of granulocyte
- Hemoglobin ≥ 8 g/dL
- 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 ≥60 mL/min)
- Adequate hepatic function (ALT/AST < 2.5 x ULN, bilirubin < 1.5 x ULN), and
coagulation ([PT and PTT] < 1.5 x ULN)
- Agree to provide 3 bone marrow biopsies during the study: at baseline or within 12
weeks prior to enrollment, and every 6 months post-treatment.
- Splenomegaly during the screening period as demonstrated by splenic length ≥ 5 cm 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, and alpha-interferon) or any experimental therapy
within 14 days or 5 half-lives, whichever is shorter, before the first dose of study
- 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. 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
- 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.