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Oral Nuvisertib for Patients with Myelofibrosis

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

PHASE1; PHASE2 · Sumitomo Pharma America, Inc. · NCT04176198

This study is testing a new oral medication called nuvisertib to see if it can help people with myelofibrosis who haven't had success with other treatments.

Quick facts

PhasePHASE1; PHASE2
Study typeInterventional
Enrollment240 (estimated)
Ages18 Years and up
SexAll
SponsorSumitomo Pharma America, Inc. (industry)
Drugs / interventionsRuxolitinib, Momelotinib, prednisone
Locations84 sites (Birmingham, Alabama and 83 other locations)
Trial IDNCT04176198 on ClinicalTrials.gov

What this trial studies

This is a Phase 1/2, multicenter, open-label trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of nuvisertib (TP-3654) in patients with intermediate or high-risk myelofibrosis. The study consists of three arms: one for patients who have failed JAK inhibitor treatment, another for those on stable ruxolitinib doses with inadequate response, and a third for patients with complications from previous JAK inhibitor treatments. Participants will be monitored for their response to the treatment and any adverse effects.

Who should consider this trial

Good fit: Ideal candidates include patients with intermediate or high-risk myelofibrosis who have previously been treated with JAK inhibitors and have either failed treatment or are ineligible for further JAK inhibitor therapy.

Not a fit: Patients who have not been previously treated with JAK inhibitors or those with low-risk myelofibrosis may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with myelofibrosis who have not responded to existing JAK inhibitors.

How similar studies have performed: Other studies have shown promise with similar approaches targeting myelofibrosis, but this specific treatment is novel.

Eligibility criteria

Show full inclusion / exclusion 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

Where this trial is running

Birmingham, Alabama and 83 other locations

+34 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.

View on ClinicalTrials.gov →

Conditions: Myelofibrosis

Last reviewed 2026-05-15 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.