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

Eligibility: Inclusion 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
  •   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).