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

Trial ID: 2022-502597-16-00
Protocol: BBI-TP-3654-102
Sponsor: Sumitomo Pharma America Inc.

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Diseases & Conditions

Myelofibrosis

Objectives

The primary objective of this study is to identify the recommended Phase 2 dose (**RP2D**) of **Nuvisertib** monotherapy and in combination with **Momelotinib** in patients with intermediate or high-risk primary or secondary **myelofibrosis**. This is crucial for determining the optimal dosing regimen that balances efficacy and safety, thereby guiding future clinical development and therapeutic use.

Secondary objectives include:

Assessing any preliminary clinical activity of Nuvisertib monotherapy and in combination with Momelotinib.
Determining the cardiac safety of Nuvisertib.
Establishing the pharmacokinetic profile of orally administered Nuvisertib monotherapy and in combination with Momelotinib at steady state.

Participants

The clinical trial involves a total of **204 participants** diagnosed with **Intermediate or High-risk Primary or Secondary Myelofibrosis**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific clinical laboratory parameters and previous treatment history with JAK inhibitors. The trial includes individuals with adequate renal and hepatic function, as well as those with a life expectancy of at least six months. Participants are required to have a confirmed pathological diagnosis of myelofibrosis and must be capable of providing informed consent. The study population is characterized by a range of health statuses, including those with splenomegaly and specific symptom scores as per the Myelofibrosis Symptom Assessment Form (MFSAF v4.0). Lifestyle considerations such as the ability to swallow orally administered medication and the use of contraception are also noted. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational treatment's safety and efficacy across a diverse group of participants.

Plans and Procedures

The clinical trial is a **Phase 1/2, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study** designed to evaluate the effects of oral **Nuvisertib** (TP-3654) in patients with intermediate or high-risk primary or secondary **myelofibrosis**. The trial aims to identify the recommended Phase 2 dose (RP2D) of Nuvisertib monotherapy and in combination with **Momelotinib**. The study will assess the overall safety and preliminary clinical activity of these treatments. The trial is expected to conclude by April 30, 2030, with recruitment having commenced on June 15, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific clinical and laboratory criteria. The trial includes multiple follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment. The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, with conditions for early termination including significant adverse events or withdrawal of consent.

Key elements of the research methodology include a dose-escalation approach to determine the maximum tolerated dose and a dose-expansion phase to further evaluate efficacy and safety. The trial is not randomized or double-blind, as it is an open-label study. Participants will be monitored for dose-limiting toxicities, adverse events, and changes in spleen volume and symptom scores. The study will also assess pharmacokinetic parameters such as Cmax, tmax, AUC, and t½. The trial's primary endpoints focus on safety and efficacy, while secondary endpoints include symptom score responses and patient-reported outcomes.

Treatment

The clinical trial involves the administration of **Nuvisertib**, an experimental medication, in the form of a **capsule**. Nuvisertib, also known by its sponsor product code TP-3654, is a chemical compound with the active substance name **Nuvisertib**. The pharmaceutical form is a capsule, and it is administered orally. The dosage for Nuvisertib is specified as 120 mg capsules, and the administration frequency is determined by the study protocol. The compound is developed by Sumitomo Pharma America Inc. and is not a paediatric formulation. The trial aims to identify the recommended Phase 2 dose and assess the safety and preliminary clinical activity of Nuvisertib monotherapy in patients with intermediate or high-risk primary or secondary **myelofibrosis**.

In addition to Nuvisertib, the trial also includes the administration of **Momelotinib Dihydrochloride Monohydrate** in combination with Nuvisertib. Momelotinib is provided in the form of a **tablet** and is also administered orally. The sponsor product code for Momelotinib is GSK3070785, and it is developed by GlaxoSmithKline Research & Development Limited. This compound is designated as an orphan drug, with the designation number EU/3/11/887. The trial seeks to determine the recommended Phase 2 dose and evaluate the safety and preliminary clinical activity of the combination therapy of Nuvisertib and Momelotinib in the specified patient population.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study does not include any non-experimental treatments such as standard-of-care therapy or placebo. The trial is structured to assess both the monotherapy and combination therapy arms, with specific objectives for each phase of the study.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of **dose-limiting toxicity (DLT)** at escalated doses of Nuvisertib, both as monotherapy and in combination with Momelotinib, during Phase 1. Additionally, adverse events (AEs) characterized by type, frequency, severity, seriousness, and relationship to study drugs will be monitored. In Phase 2, the primary endpoint will focus on the spleen volume response, specifically a ≥35% spleen volume reduction (SVR35) at any time.

Secondary endpoints will further assess efficacy through various measures. These include spleen volume response with a ≥25% reduction (SVR25) at any time and the duration of this response. Total symptom score response will be evaluated using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0, with a ≥50% improvement in total symptom score (TSS50) at Week 24, along with the duration of TSS50 over time and absolute TSS change from baseline at Week 24. Patient Global Impression of Change (PGIC) will be assessed at Week 24 and at any time. Response evaluation will be conducted per the revised IWG-MRT criteria, including complete remission (CR), partial remission (PR), clinical improvement (CI), stable disease (SD), and progressive disease (PD). Pharmacokinetic (PK) parameters of Nuvisertib and Momelotinib, such as Cmax, tmax, AUC, and t½, will also be analyzed as data permits.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Arm 1: Adult (≥18 years of age).
Arm 1: Previously treated with an approved JAK inhibitor(s) and is intolerant, resistant, refractory or has lost response to an approved the JAK inhibitor(s), or is ineligible to be treated with an approved JAK inhibitor as determined by the Investigator in accordance with the local product labels. Note: “Intolerant” is considered as requiring a transfusion of ≥ 4 units of red blood cells in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma for ruxolitinib and fedratinib; Grade ≥2 peripheral neuropathy for momelotinib.
Arm 1: Fulfills the following laboratory parameters: a. Platelet count ≥ 25 × 10^9 /L without the assistance of growth factors or platelet transfusions; b. Absolute neutrophil count (ANC) ≥ 1 × 10^9 /L without the assistance of granulocyte growth factors.
Arm 1: Peripheral blood blast count < 5%.
Arm 1: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
Arm 1: Life expectancy ≥ 6 months.
Arm 1: 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 (using Cockcroft-Gault formula).
Arm 1: Adequate hepatic function: ALT and AST ≤ 3 × ULN, (ALT and AST ≤ 5 × ULN, if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN; and coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 × ULN permitted if on chronic anticoagulant therapy).
Arm 3: 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.
Arm 3: Fulfills the following clinical laboratory parameters: a. Anemic, defined as Hb <10 g/dL; b. Platelet count ≥ 50 × 109 /L (without the assistance of growth factors or platelet transfusions); c. ANC ≥ 1 × 10^9 /L without the assistance of granulocyte growth factors; d. Peripheral blood blast count < 5% at screening; e. 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); f. 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; g. Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 × ULN permitted if on chronic anticoagulant therapy).
Arm 3: Splenomegaly, defined as spleen volume of ≥ 450 cm3 by MRI/CT scan within 2 weeks prior to Cycle 1 Day 1.
Arm 1: Capable of providing signed informed consent as described in Section 10.1.3 of the study protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Arm 3: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0.
Arm 3: ECOG performance status ≤ 1.
Arm 3: Life expectancy ≥ 6 months.
Arm 3: Non-fertile or agree to use an adequate method of contraception.
Arm 3: Capable of providing signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Arm 3: Able to swallow orally administered medication.
Arm 1: Non-fertile or agrees to use an adequate method of contraception.
Arm 1: Splenomegaly, defined as spleen volume of ≥ 450 cm3 by magnetic resonance Imaging (MRI) or computerized tomography (CT) scan, within 2 weeks prior to Cycle 1 Day 1.
Arm 1: Dose Escalation: at least 2 symptoms measurable (score ≥ 1) using the MFSAF v4.0. Dose Expansion: at least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0.
Arm 1: Able to swallow orally administered medication.
Arm 3: Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF as per WHO diagnostic criteria (Section 10.2.4), and intermediate or high-risk primary or secondary MF based on the DIPSS.
Arm 1: Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera (PV)-MF/post-ET-MF as per World Health Organization (WHO) diagnostic criteria, and intermediate or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS).
Arm 3: Adult (≥18 years of age).

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Exclusion Criteria

Arm 1: 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: 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.
Arm 1: Systemic steroid therapy (>10 mg/day prednisone or equivalent) within 1 week prior to the first dose of study treatment (Note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).
Arm 1: Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.
Arm 1: Major surgery within 4 weeks prior to first dose of either study drug and/or have not recovered adequately from complications of any surgical intervention prior to first dose.
Arm 1: Pregnant (as evidenced by a positive serum or urine pregnancy test) or is breastfeeding.
Arm 3: 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; - Prior treatment with 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.
Arm 3: 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.
Arm 3: Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1.
Arm 3: Known allergic reactions or sensitivity to Nuvisertib, momelotinib, or any structurally similar drug, or to any component of the formulations of either study intervention.
Arm 3: Splenic irradiation within 6 months prior to screening or prior splenectomy.
Arm 3: 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.
Arm 1: 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 regimen.
Arm 1: Splenic irradiation within 6 months prior to screening or prior splenectomy.
Arm 1: 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 graft versus host disease (GVHD) are eligible.
Arm 1: Eligible for allogeneic bone marrow or stem cell transplantation. Note: Patients who are willing to undergo transplantation, or for whom a suitable donor is not available are considered transplant ineligible.
Arm 1: Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1.
Arm 1: Unresolved Grade ≥ 2 non-hematological toxicity related to prior treatment (however, stable Grade 2 exceptions may be permitted if discussed in advance with the Sponsor).
Arm 1: History of symptomatic congestive heart failure or myocardial infarction, or uncontrolled arrhythmia within the 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.
Arm 1: Corrected QT interval (using Fridericia's correction formula; QTcF) of > 470.
Arm 3: 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.
Arm 3: Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately from complications of any surgical intervention prior to first dose.
Arm 3: Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 14 days prior to Cycle 1 Day 1.
Arm 1: 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.
Arm 3: Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required).
Arm 3: 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.
Arm 3: Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment (stable Grade 2 conditions may be permitted in consultation with the Sponsor).
Arm 3: Presence of Grade ≥ 2 peripheral neuropathy.
Arm 3: 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.
Arm 3: Corrected QTcF of > 470 msec.
Arm 3: 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.
Arm 3: History of a medical condition or GI tract surgery that could impair absorption or could result in short bowel syndrome with diarrhea.
Arm 3: Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.
Arm 3: Pregnant (as evidenced by a positive serum or urine pregnancy test) or is breastfeeding.
Arm 1: Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 14 days prior to Cycle 1 Day 1.
Arm 1: Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required).
Arm 1: Currently receiving any other investigational agent.
Arm 1: Exhibited allergic reactions or sensitivity to Nuvisertib, or any structurally similar compound, biological agent, or to any component of the formulation.
Arm 1: Medical condition or gastrointestinal (GI) tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Yet Recruiting	15 Jun 2023	2
Belgium	Recruiting	15 Jun 2023	7
Bulgaria	Not Yet Recruiting	15 Jun 2023	2
Czechia	Not Yet Recruiting	15 Jun 2023	2
Denmark	Not Yet Recruiting	15 Jun 2023	2
France	Recruiting	15 Jun 2023	6
Germany	Recruiting	15 Jun 2023	2
Hungary	Not Yet Recruiting	15 Jun 2023	2
Italy	Recruiting	15 Jun 2023	25
The Netherlands	Not Yet Recruiting	15 Jun 2023	—