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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04176198




Registration number
NCT04176198
Ethics application status
Date submitted
8/11/2019
Date registered
25/11/2019
Date last updated
4/06/2025

Titles & IDs
Public title
A Study of Oral Nuvisertib (TP-3654) in Patients With Myelofibrosis
Scientific title
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
Secondary ID [1] 0 0
BBI-TP-3654-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Nusivertib
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Momelotinib

Experimental: Arm 1: nuvisertib (TP-3654) -

Experimental: Arm 2: nuvisertib (TP-3654) added on to ruxolitinib -

Experimental: Arm 3: nuvisertib (TP-3654) in combination with momelotinib -


Treatment: Drugs: Nusivertib
Oral PIM Inhibitor

Treatment: Drugs: Ruxolitinib
Oral JAK inhibitor

Treatment: Drugs: Momelotinib
Oral JAK inhibitor
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Determine the incidence of dose-limiting toxicities (DLTs)
Timepoint [1] 0 0
28 days
Primary outcome [2] 0 0
Determine the incidence of treatment emergent adverse events
Timepoint [2] 0 0
From start of treatment to end of study
Primary outcome [3] 0 0
Assess patients for any evidence of preliminary activity by determining the number of patients with = 35% spleen volume reduction (SVR35)
Timepoint [3] 0 0
From start of treatment to end of study
Secondary outcome [1] 0 0
Number of participants achieving objective response by IWG-MRT response criteria
Timepoint [1] 0 0
From start of treatment to end of study
Secondary outcome [2] 0 0
Number of participants who have = 25% spleen volume reduction
Timepoint [2] 0 0
Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks therafter during treatment.
Secondary outcome [3] 0 0
Number of participants with = 50% improvement in total symptom score (TSS50) at week 24
Timepoint [3] 0 0
24 weeks
Secondary outcome [4] 0 0
Determine the change in Patient Global Impression of Change (PGIC) at week 24 through end of study.
Timepoint [4] 0 0
After 24 weeks of treatment to end of study
Secondary outcome [5] 0 0
Determine the incidence of QT interval changes
Timepoint [5] 0 0
25 hours
Secondary outcome [6] 0 0
Establish the half-life (t½) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [6] 0 0
24 hours
Secondary outcome [7] 0 0
Establish the Area under the plasma concentration versus time curve (AUC) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [7] 0 0
24 hours
Secondary outcome [8] 0 0
Establish the Peak Plasma Concentration (Cmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [8] 0 0
24 hours
Secondary outcome [9] 0 0
Establish the Time of Maximum concentration observed (tmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [9] 0 0
24 hours

Eligibility
Key inclusion 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/12/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/04/2030
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Eastern Health Box Hill Hospital - Box Hill
Recruitment hospital [3] 0 0
Monash University - Clayton
Recruitment hospital [4] 0 0
Peter McCallum Center - Melbourne
Recruitment hospital [5] 0 0
Epworth Healthcare - Richmond
Recruitment hospital [6] 0 0
Icon Cancer Centre (Ashford Cancer Centre Research) - Adelaide
Recruitment postcode(s) [1] 0 0
- Adelaide
Recruitment postcode(s) [2] 0 0
- Box Hill
Recruitment postcode(s) [3] 0 0
- Clayton
Recruitment postcode(s) [4] 0 0
- Melbourne
Recruitment postcode(s) [5] 0 0
- Richmond
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
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United States of America
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Colorado
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United States of America
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Connecticut
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United States of America
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Florida
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United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Maryland
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United States of America
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Massachusetts
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United States of America
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Michigan
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United States of America
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Minnesota
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United States of America
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Missouri
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United States of America
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New Jersey
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United States of America
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New York
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United States of America
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North Carolina
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United States of America
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Ohio
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South Carolina
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Tennessee
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Texas
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Utah
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Virginia
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United States of America
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Washington
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Belgium
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Vlaams-Brabant
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Belgium
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Antwerp
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Belgium
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Gent
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Belgium
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Liege
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Canada
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Alberta
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Canada
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British Columbia
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Canada
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Ontario
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Canada
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Quebec
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France
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Amiens
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France
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Angers
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France
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Lyon
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France
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Nice
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France
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Nimes
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France
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Paris
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France
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Villejuif
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Italy
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Alessandria
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Italy
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Aviano
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Italy
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Bologna
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Italy
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Brescia
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Italy
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Meldola
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Italy
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Milan
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Italy
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Torino
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Fukuoka
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Japan
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Hokkaido
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Japan
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Miyazaki
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Japan
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Okayama
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Japan
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Osaka
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Japan
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Saitama
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Japan
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Sendai
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Japan
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Shizuoka
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Japan
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Tokyo
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Japan
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Tsu
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United Kingdom
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Lincoln
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United Kingdom
State/province [59] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Sumitomo Pharma America, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reyna Bishop
Address 0 0
Country 0 0
Phone 0 0
617-674-6800
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT04176198