A Study of Oral Nuvisertib (TP-3654) in Patients With Myelofibrosis

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