Overview

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.

Eligibility

Patients must meet all of the following inclusion criteria to be eligible:

TP-3654 Monotherapy Arm:

• Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ETMF 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 JAK inhibitor(s) and is intolerant, resistant, refractory or has lost response to the JAK inhibitor(s) or is ineligible to be treated with JAK inhibitor.
• 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 < 5%
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  • Life expectancy ≥ 6 months
  • Adequate renal function, as determined by clinical laboratory tests (serum creatinine ≤ 1.5 x upper limit of normal (ULN), or calculated creatinine clearance ≥ 30 mL/min) (Cockcroft-Gault)
  • Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN
  • Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy)
  • Splenomegaly defined as 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, within 2 weeks prior to Cycle 1 Day 1.
  • Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF, v4.0.
  • Dose expansion: At least 2 symptoms measureable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF, v4.0.

TP-3654 + Ruxolitinib Arm:

• Confirmed pathological diagnosis of 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 DIPSS
• Has been on ruxolitinib treatment for ≥ 6 months, and on a stable dose of ruxolitinib (5 to 25 mg BID) for ≥ 8 weeks prior to the first dose of TP-3654, but has either lost response or had a suboptimal or plateau in response
• Fulfills the following laboratory parameters:
  • Platelet count ≥ 50 × 10^9/L (without the assistance of growth factors or platelet transfusions)
  • ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors
  • Peripheral blood blast count < 5% at screening
  • Adequate renal function, as determined by clinical laboratory tests: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula)
  • Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN
  • Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy)
  • Splenomegaly, defined as splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by MRI/CT scan, within 2 weeks prior to Cycle 1 Day 1
  • At least 2 symptoms measurable with each score ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0
  • ECOG performance status ≤ 1
  • Life expectancy ≥ 6 months

TP-3654 + Momelotinib Arm

• Confirmed pathological diagnosis of 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 DIPSS
• Previously treated with an approved JAK inhibitor (except momelotinib) for PMF or Post-PV/ET MF for ≥ 12 weeks, or ≥ 4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥ 4 units of red blood cells in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma
• Fulfills the following laboratory parameters:
• Anemic, defined as Hb <10 g/dL or requiring RBC transfusion at baseline
• Platelet count ≥ 50 × 109/L (without the assistance of growth factors or platelet transfusions)
• ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors
• Peripheral blood blast count < 5% at screening
• Adequate renal function, as determined by clinical laboratory tests: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula)
  • Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if there is liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN
  • Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 × ULN permitted if on chronic anticoagulant therapy)
  • Splenomegaly, defined as splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by MRI/CT scan within 2 weeks prior to Cycle 1 Day 1
  • At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0
  • ECOG performance status ≤ 1
  • Life expectancy ≥ 6 months

        Patients meeting any one of these exclusion criteria will be prohibited from participating
        in this study:
        TP-3654 Monotherapy Arm:
          -  Received previous systemic antineoplastic therapy or any experimental therapy within 2
             weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1.
          -  Major surgery within 2 weeks before the first dose of either study drug.
          -  Splenic irradiation within 6 months prior to Screening or prior splenectomy.
          -  Prior allogeneic stem cell transplant within the last 6 months.
          -  Eligible for allogeneic bone marrow or stem cell transplantation.
          -  Unresolved Grade ≥ 2 non-hematological toxicity related to prior treatment
          -  History of symptomatic congestive heart failure, or myocardial infarction, or
             uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; left ventricular
             ejection fraction (LVEF)< 45% by echocardiogram within 4 weeks prior to Cycle 1 Day 1.
          -  Corrected QT interval (using Fridericia's correction formula) of > 480 msec.
          -  Prior or concurrent malignancy whose natural history or treatment would have a
             significant potential to interfere with the safety or efficacy assessments of the
             investigational regime.
          -  Known history of chronic liver disease, e.g. portal hypertension or any of its
             complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin
             deficiency, Wilson's disease, etc.
          -  Experienced portal hypertension or any of its complications.
          -  Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
             antimicrobial within 1 week prior to Cycle 1 Day 1.
          -  Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B
             and C are required)
          -  Exhibited allergic reactions or sensitivity to TP-3654, or any structurally similar
             compound, biological agent, or to any component of the formulation.
          -  Medical condition or gastrointestinal (GI) tract surgery that could impair absorption
             or result in short bowel syndrome with diarrhea.
          -  Used hydroxyurea or anagrelide within 24 hours prior to the first dose.
          -  Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior
             to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic
             steroids are not prohibited).
        TP-3654 + Ruxolitinib Arm:
          -  Received previous systemic antineoplastic therapy (other than ruxolitinib) or any
             other experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior
             to Cycle 1 Day 1 (Note: Hydroxyurea or anagrelide are allowed up to 24 hours prior to
             Cycle 1 Day 1).
          -  Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1
             week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids
             are not prohibited)
          -  Currently receiving treatment with a prohibited medication that cannot be discontinued
             at least 1 week prior to Cycle 1 Day 1 (Section 6.9.1)
          -  Known allergic reactions or sensitivity to TP-3654, any structurally similar drug, or
             to any component of the formulation
          -  Splenic irradiation within 6 months prior to Screening or prior splenectomy
          -  Prior allogeneic stem cell transplant within the last 6 months (Note: Patients who
             have relapsed after 6 months post-transplant and do not have active GVHD are
             eligible).
          -  Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who
             are not willing to undergo transplantation or for whom a suitable donor is not
             available are considered as transplant ineligible._
          -  Major surgery within 2 weeks prior to Cycle 1 Day 1
          -  Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral
             antimicrobial within 1 week prior to Cycle 1 Day 1
          -  Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B
             and C are required)
          -  Known history of chronic liver disease (eg, portal hypertension or any of its
             complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin
             deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline
             imaging may require additional testing, as needed).
          -  Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment
             (stable Grade 2 conditions may be permitted in consultation with the Sponsor)
          -  History of myocardial infarction or symptomatic congestive heart failure or
             uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; LVEF < 45% by
             echocardiogram within 4 weeks prior to Cycle 1 Day 1
          -  Corrected QTcF of > 480 msec
          -  Prior or concurrent malignancy whose natural history or treatment has a significant
             potential to interfere with the safety or efficacy assessment of the study
             intervention
          -  History of a medical condition or GI tract surgery that could impair absorption or
             could result in short bowel syndrome with diarrhea
          -  Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
             or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding
        TP-3654 + Momelotinib Arm:
          -  Received previous systemic antineoplastic therapy or any experimental therapy within 2
             weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (Notes: Prior
             treatment with momelotinib is not allowed, in patients with ongoing JAK inhibitor
             therapy, ie, ruxolitinib, at screening, JAK inhibitor therapy must be tapered over a
             period of at least 1 week. Patients on a low dose of ruxolitinib (eg, 5 mg QD) may
             have a reduced taper period or no taper, hydroxyurea or anagrelide are allowed up to
             24 hours prior to Cycle 1 Day 1).
          -  Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1
             week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids
             are not prohibited).
          -  Currently receiving treatment with a prohibited medication that cannot be discontinued
             at least 1 week prior to Cycle 1 Day 1
          -  Known allergic reactions or sensitivity to TP-3654, momelotinib, or any structurally
             similar drug, or to any component of the formulations of either study intervention
          -  Splenic irradiation within 6 months prior to screening or prior splenectomy
          -  Prior allogenic stem cell transplant within the last 6 months (Note: Patients who have
             relapsed after 6 months post-transplant and do not have active GVHD are eligible).
          -  Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who
             are not willing to undergo transplantation or for whom a suitable donor is not
             available are considered as transplant ineligible).
          -  Major surgery within 2 weeks prior to Cycle 1 Day 1
          -  Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral
             antimicrobial within 1 week prior to Cycle 1 Day 1
          -  Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B
             and C are required)
          -  Known history of chronic liver disease (eg, portal hypertension or any of its
             complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin
             deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline
             imaging may require additional testing, as needed)
          -  Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment
             (stable Grade 2 conditions may be permitted in consultation with the Sponsor)
          -  Presence of Grade ≥ 2 peripheral neuropathy
          -  History of myocardial infarction or symptomatic congestive heart failure or
             uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; LVEF < 45% by
             echocardiogram within 4 weeks prior to Cycle 1 Day 1
          -  Corrected QTcF of > 480 msec
          -  Prior or concurrent malignancy whose natural history or treatment has a significant
             potential to interfere with the safety or efficacy assessment of the study
             intervention
          -  History of a medical condition or GI tract surgery that could impair absorption or
             could result in short bowel syndrome with diarrhea
          -  Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
             or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding