Protocol No.: OCR35242
Sponsor Protocol No.: BBI-TP-3654-102
Protocol Title.: A Study of Oral TP-3654 in Patients With Myelofibrosis
Principal Investigator: Brown, Randall
Objective: 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.
Description: This study will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive ruxolitinib or fedratinib.
Phase: Phase I
Age Group: Adult
Age: 18 Years - N/A
Detailed Eligibility: 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 bone marrow fibrosis, as confirmed by bone marrow biopsy within 12 weeks prior to Screening Fulfill the following laboratory parameters: - Platelet count ≥ 50 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 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, 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 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 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).