a study of oral nuvisertib (tp-3654) in patients with myelofibrosis

Conditions: Myelofibrosis

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.

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.

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