Brief Summary
This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of nuvisertib (TP-3654) in patients with intermediate or high-risk primary or secondary MF.
Brief Title
A Study of Oral Nuvisertib (TP-3654) in Patients With Myelofibrosis
Detailed Description
Arm 1 will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive treatment with a JAK inhibitor.
Arm 2 will enroll patients who are on a stable dose of ruxolitinib, but who have either lost response or had a suboptimal or plateau in response.
Arm 3 will enroll patients who have been previously treated on JAK inhibitor (except momelotinib) that was complicated by anemia, thrombocytopenia or hematoma.
Arm 2 will enroll patients who are on a stable dose of ruxolitinib, but who have either lost response or had a suboptimal or plateau in response.
Arm 3 will enroll patients who have been previously treated on JAK inhibitor (except momelotinib) that was complicated by anemia, thrombocytopenia or hematoma.
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
617-674-6800
Central Contact Email
reyna.bishop@us.sumitomo-pharma.com
Central Contact Role
Contact
Central Contact Email
jordan.simpson@us.sumitomo-pharma.com
Completion Date
Completion Date Type
Estimated
Conditions
Myelofibrosis
Eligibility Criteria
Patients must meet all of the following inclusion criteria to be eligible:
Nuvisertib (TP-3654) Monotherapy Arm:
* Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Platelet count ≥ 25 x 10\^9 /L, without assistance of growth factors or platelet transfusions
* ANC ≥ 1 x 10\^9/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5%
* ECOG performance status ≤ 1
* Life expectancy ≥ 6 months
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (spleen volume of ≥ 450 cm3 by MRI or CT scan) within 2 weeks prior to Cycle 1 Day 1.
* Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF
* Dose expansion: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF
Nuvisertib (TP-3654) + Ruxolitinib Arm:
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF and intermediate or high-risk primary or secondary MF
* 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 nuvisertib, but has either lost response or had a suboptimal or plateau in response
* Fulfills the following clinical laboratory parameters:
* Platelet count ≥ 50 × 10\^9/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Nuvisertib (TP-3654) + Momelotinib Arm
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Anemic, defined as Hb \<10 g/dL or requiring RBC transfusion at baseline
* Platelet count ≥ 50 × 109/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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:
Nuvisertib (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. Hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).
* Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or not recovered adequately from from surgery prior to first dose.
* 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 \> 480msec.
* Prior or concurrent malignancy that could interfere with 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.
* 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 nuvisertib, or similar compound.
* Medical condition or GI tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.
* 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).
* Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.
* Pregnant or breastfeeding
* Currently receiving any other investigational agent.
Nuvisertib (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: Prior treatment with nuvisertib is not allowed. 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)
* Known allergic reactions or sensitivity to nuvisertib, or similar compound.
* 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 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately prior to first dose.
* 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 that could 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
* Pregnant or breastfeeding
Nuvisertib (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 or nuvisertib 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).
* Known allergic reactions or sensitivity to nuvisertib, 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 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately from surgery prior to first dose.
* 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 that could 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
* Pregnant or breastfeeding
Nuvisertib (TP-3654) Monotherapy Arm:
* Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Platelet count ≥ 25 x 10\^9 /L, without assistance of growth factors or platelet transfusions
* ANC ≥ 1 x 10\^9/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5%
* ECOG performance status ≤ 1
* Life expectancy ≥ 6 months
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (spleen volume of ≥ 450 cm3 by MRI or CT scan) within 2 weeks prior to Cycle 1 Day 1.
* Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF
* Dose expansion: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF
Nuvisertib (TP-3654) + Ruxolitinib Arm:
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF and intermediate or high-risk primary or secondary MF
* 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 nuvisertib, but has either lost response or had a suboptimal or plateau in response
* Fulfills the following clinical laboratory parameters:
* Platelet count ≥ 50 × 10\^9/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Nuvisertib (TP-3654) + Momelotinib Arm
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Anemic, defined as Hb \<10 g/dL or requiring RBC transfusion at baseline
* Platelet count ≥ 50 × 109/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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:
Nuvisertib (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. Hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).
* Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or not recovered adequately from from surgery prior to first dose.
* 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 \> 480msec.
* Prior or concurrent malignancy that could interfere with 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.
* 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 nuvisertib, or similar compound.
* Medical condition or GI tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.
* 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).
* Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.
* Pregnant or breastfeeding
* Currently receiving any other investigational agent.
Nuvisertib (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: Prior treatment with nuvisertib is not allowed. 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)
* Known allergic reactions or sensitivity to nuvisertib, or similar compound.
* 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 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately prior to first dose.
* 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 that could 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
* Pregnant or breastfeeding
Nuvisertib (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 or nuvisertib 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).
* Known allergic reactions or sensitivity to nuvisertib, 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 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately from surgery prior to first dose.
* 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 that could 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
* Pregnant or breastfeeding
Inclusion Criteria
inclusion criteria to be eligible:
Nuvisertib (TP-3654) Monotherapy Arm:
* Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Platelet count ≥ 25 x 10\^9 /L, without assistance of growth factors or platelet transfusions
* ANC ≥ 1 x 10\^9/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5%
* ECOG performance status ≤ 1
* Life expectancy ≥ 6 months
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (spleen volume of ≥ 450 cm3 by MRI or CT scan) within 2 weeks prior to Cycle 1 Day 1.
* Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF
* Dose expansion: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF
Nuvisertib (TP-3654) + Ruxolitinib Arm:
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF and intermediate or high-risk primary or secondary MF
* 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 nuvisertib, but has either lost response or had a suboptimal or plateau in response
* Fulfills the following clinical laboratory parameters:
* Platelet count ≥ 50 × 10\^9/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Nuvisertib (TP-3654) + Momelotinib Arm
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Anemic, defined as Hb \<10 g/dL or requiring RBC transfusion at baseline
* Platelet count ≥ 50 × 109/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Nuvisertib (TP-3654) Monotherapy Arm:
* Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Platelet count ≥ 25 x 10\^9 /L, without assistance of growth factors or platelet transfusions
* ANC ≥ 1 x 10\^9/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5%
* ECOG performance status ≤ 1
* Life expectancy ≥ 6 months
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (spleen volume of ≥ 450 cm3 by MRI or CT scan) within 2 weeks prior to Cycle 1 Day 1.
* Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF
* Dose expansion: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF
Nuvisertib (TP-3654) + Ruxolitinib Arm:
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF and intermediate or high-risk primary or secondary MF
* 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 nuvisertib, but has either lost response or had a suboptimal or plateau in response
* Fulfills the following clinical laboratory parameters:
* Platelet count ≥ 50 × 10\^9/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Nuvisertib (TP-3654) + Momelotinib Arm
* Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF and intermediate or high-risk primary or secondary MF
* 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 clinical laboratory parameters:
* Anemic, defined as Hb \<10 g/dL or requiring RBC transfusion at baseline
* Platelet count ≥ 50 × 109/L (without assistance of growth factors or platelet transfusions)
* ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
* Peripheral blood blast count \< 5% at screening
* Adequate renal function
* Adequate hepatic function
* Adequate coagulation function
* Splenomegaly (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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04176198
Org Class
Industry
Org Full Name
Sumitomo Pharma America, Inc.
Org Study Id
BBI-TP-3654-102
Overall Status
Recruiting
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase 1/2, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral Nuvisertib (TP-3654) in Patients With Intermediate or High-Risk Primary or Secondary Myelofibrosis
Primary Outcomes
Outcome Description
Number of participants with DLTs
Outcome Measure
Determine the incidence of dose-limiting toxicities (DLTs)
Outcome Time Frame
28 days
Outcome Description
Number of participants with Treatment Emergent Adverse Events and Serious Adverse Events
Outcome Measure
Determine the incidence of treatment emergent adverse events
Outcome Time Frame
From start of treatment to end of study
Outcome Description
Number of participants with ≥ 35% spleen volume reduction (SVR35)
Outcome Measure
Assess patients for any evidence of preliminary activity by determining the number of patients with ≥ 35% spleen volume reduction (SVR35)
Outcome Time Frame
From start of treatment to end of study
Secondary Outcomes
Outcome Description
Number of participants achieving complete remission, partial remission, clinical improvement, progressive disease and stable disease.
Outcome Time Frame
From start of treatment to end of study
Outcome Measure
Number of participants achieving objective response by IWG-MRT response criteria
Outcome Description
Number of participants who have ≥ 25% spleen volume reduction compared to baseline
Outcome Time Frame
Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks therafter during treatment.
Outcome Measure
Number of participants who have ≥ 25% spleen volume reduction
Outcome Description
Number of participants who have ≥ 50% total symptom score reduction by MFSAF compared to baseline after 24 weeks of treatment.
Outcome Time Frame
24 weeks
Outcome Measure
Number of participants with ≥ 50% improvement in total symptom score (TSS50) at week 24
Outcome Description
Change in PGIC score
Outcome Time Frame
After 24 weeks of treatment to end of study
Outcome Measure
Determine the change in Patient Global Impression of Change (PGIC) at week 24 through end of study.
Outcome Description
Changes in QT interval and heart rhythm
Outcome Time Frame
25 hours
Outcome Measure
Determine the incidence of QT interval changes
Outcome Description
The estimate of time for the nuvisertib concentration or amount to be reduced by half
Outcome Time Frame
24 hours
Outcome Measure
Establish the half-life (t½) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Outcome Description
The amount of drug exposure over 24 hours period after administration
Outcome Time Frame
24 hours
Outcome Measure
Establish the Area under the plasma concentration versus time curve (AUC) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Outcome Description
The maximum nuvisertib concentration after administration
Outcome Time Frame
24 hours
Outcome Measure
Establish the Peak Plasma Concentration (Cmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Outcome Description
The time to reach maximum nuvisertib concentration
Outcome Time Frame
24 hours
Outcome Measure
Establish the Time of Maximum concentration observed (tmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Swati Goel
Investigator Email
swgoel@montefiore.org
Investigator Phone
718-920-6310 / 718-920-4137