A Study of Oral TP-3654 in Patients With Myelofibrosis
Study Phase: Phase 1/Phase 2
Recruitment Status: Recruiting
Start Date: December 16, 2019
End Date: February 01, 2025
Tomoko Kuwabara
- 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
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Conditions:
- Primary Myelofibrosis