This study is assessing how safe and tolerable a new drug (called TP-3654) is in people with intermediate or high-risk primary or secondary myelofibrosisA 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

Exclusion

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).