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

PHASE1PHASE2RECRUITING

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.

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Study details:

Arm 1 will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive treament 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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF as per WHO diagnostic criteria and intermediate or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS)

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 as determined by the investigator in accordance with the local product labels.

Fulfill the following laboratory parameters: * Platelet count ≥ 25 X 10^9 /L, without the assistance of growth factors or platelet transfusions * Absolute Neutrophil Count (ANC) ≥ 1 x 10^9/L without the assistance of granulocyte growth factors * Peripheral blood blast count < 5% * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 * Life expectancy ≥ 6 months * 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) (Cockcroft-Gault) * Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN * Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy) * 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. * Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF, 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.

Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF as per WHO diagnostic criteria, and intermediate or high-risk primary or secondary MF based on the DIPSS

Has been 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 laboratory parameters: * Platelet count ≥ 50 × 10^9/L (without the assistance of growth factors or platelet transfusions) * ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors * Peripheral blood blast count < 5% at screening * 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) * Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN * Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy) * Splenomegaly defined as 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

Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF as per WHO diagnostic criteria, and intermediate or high-risk primary or secondary MF based on the DIPSS

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 laboratory parameters: * Anemic, defined as Hb <10 g/dL or requiring RBC transfusion at baseline * Platelet count ≥ 50 × 109/L (without the assistance of growth factors or platelet transfusions) * ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors * Peripheral blood blast count < 5% at screening * 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) * 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 * Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 × ULN permitted if on chronic anticoagulant therapy) * Splenomegaly defined as 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

Exclusion criteria

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.

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.

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 (using Fridericia's correction formula) of > 480 msec.

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 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.

Experienced portal hypertension or any of its complications.

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 any structurally similar compound, biological agent, or to any component of the formulation.

Medical condition or gastrointestinal (GI) tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.

Used hydroxyurea or anagrelide within 24 hours prior to the first dose.

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).

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)

Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1 (Section 6.9.1)

Known allergic reactions or sensitivity to nuvisertib, any structurally similar drug, or to any component of the formulation

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 from complications of any surgical intervention 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 whose natural history or treatment has a significant potential to 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

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2019-12-16

Primary completion: 2027-04-30

Study completion finish: 2030-04-30

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT04176198

Intervention or treatment

DRUG: Nusivertib

DRUG: Ruxolitinib

DRUG: Momelotinib

Conditions

• Myelofibrosis

Condition: Myelofibrosis
DRUG: Nusivertib and other drugs
Adelaide, South Australia, Australia and more
Sponsor: Sumitomo Pharma America, Inc.

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

Find a site

Closest Location:

Royal Adelaide Hospital

Research sites nearby

Select from list below to view details:

Royal Adelaide Hospital
Adelaide, South Australia, Australia
Eastern Health Box Hill Hospital
Box Hill, Victoria, Australia
Monash University
Clayton, Victoria, Australia
Icon Cancer Centre (Ashford Cancer Centre Research)
Adelaide, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm 1: nuvisertib (TP-3654) Not Specified	DRUG: Nusivertib Oral PIM Inhibitor
EXPERIMENTAL: Arm 2: nuvisertib (TP-3654) added on to ruxolitinib Not Specified	DRUG: Nusivertib Oral PIM Inhibitor
EXPERIMENTAL: Arm 3: nuvisertib (TP-3654) in combination with momelotinib Not Specified	DRUG: Nusivertib Oral PIM Inhibitor

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Determine the incidence of dose-limiting toxicities (DLTs)	Number of participants with DLTs	28 days
Determine the incidence of treatment emergent adverse events	Number of participants with Treatment Emergent Adverse Events and Serious Adverse Events	From start of treatment to end of study
Assess patients for any evidence of preliminary activity by determining the number of patients with ≥ 35% spleen volume reduction (SVR35)	Number of participants with ≥ 35% spleen volume reduction (SVR35)	From start of treatment to end of study

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Number of participants achieving objective response by IWG-MRT response criteria	Number of participants achieving complete remission, partial remission, clinical improvement, progressive disease and stable disease.	From start of treatment to end of study
Number of participants who have ≥ 25% spleen volume reduction	Number of participants who have ≥ 25% spleen volume reduction compared to baseline	Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks therafter during treatment.
Number of participants with ≥ 50% improvement in total symptom score (TSS50) at week 24	Number of participants who have ≥ 50% total symptom score reduction by MFSAF compared to baseline after 24 weeks of treatment.	24 weeks
Determine the change in Patient Global Impression of Change (PGIC) at week 24 through end of study.	Change in PGIC score	After 24 weeks of treatment to end of study
Determine the incidence of QT interval changes	Changes in QT interval and heart rhythm	25 hours
Establish the half-life (t½) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The estimate of time for the nuvisertib concentration or amount to be reduced by half	24 hours
Establish the Area under the plasma concentration versus time curve (AUC) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The amount of drug exposure over 24 hours period after administration	24 hours
Establish the Peak Plasma Concentration (Cmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The maximum nuvisertib concentration after administration	24 hours
Establish the Time of Maximum concentration observed (tmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The time to reach maximum nuvisertib concentration	24 hours

Frequently Asked Questions

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You may be eligible to participate in this trial based on your search.Apply for study

Are you running this trial? If you're a clinic or sponsor, you can claim this study.Claim this trial

References

Clinical Trials Gov: A Study of Oral Nuvisertib (TP-3654) in Patients with Myelofibrosis