A Study of Oral TP-3654 in Patients With Myelofibrosis

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-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 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