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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
19/09/2024

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:
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 - TP-3654
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Momelotinib

Experimental: Arm 1: TP-3654 -

Experimental: Arm 2: TP-3654 added on to ruxolitinib -

Experimental: Arm 3: TP-3654 in combination with momelotinib -


Treatment: Drugs: TP-3654
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 TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [6] 0 0
24 hours
Secondary outcome [7] 0 0
Establish the Peak Plasma Concentration (Cmax) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [7] 0 0
24 hours
Secondary outcome [8] 0 0
Establish the Time of Maximum concentration observed (tmax) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib
Timepoint [8] 0 0
24 hours
Secondary outcome [9] 0 0
Establish the Area under the plasma concentration versus time curve (AUC) of TP-3654 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 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.

Nuvisertib (TP-3654) + Ruxolitinib Arm:

* 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

Nuvisertib (TP-3654) + Momelotinib Arm

* 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

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.
* 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).

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)
* 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

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 and 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).
* Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1
* 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 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)
* 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 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
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
Icon Cancer Centre (Ashford Cancer Centre Research) - Adelaide
Recruitment postcode(s) [1] 0 0
- Adelaide
Recruitment postcode(s) [2] 0 0
- Box Hill
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
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Michigan
Country [9] 0 0
United States of America
State/province [9] 0 0
Missouri
Country [10] 0 0
United States of America
State/province [10] 0 0
New Jersey
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
North Carolina
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Tennessee
Country [15] 0 0
United States of America
State/province [15] 0 0
Texas
Country [16] 0 0
United States of America
State/province [16] 0 0
Utah
Country [17] 0 0
United States of America
State/province [17] 0 0
Virginia
Country [18] 0 0
United States of America
State/province [18] 0 0
Washington
Country [19] 0 0
Belgium
State/province [19] 0 0
Vlaams-Brabant
Country [20] 0 0
Belgium
State/province [20] 0 0
Antwerp
Country [21] 0 0
France
State/province [21] 0 0
Amiens
Country [22] 0 0
France
State/province [22] 0 0
Nice
Country [23] 0 0
France
State/province [23] 0 0
Paris
Country [24] 0 0
France
State/province [24] 0 0
Villejuif
Country [25] 0 0
Italy
State/province [25] 0 0
Bologna
Country [26] 0 0
Italy
State/province [26] 0 0
Meldola
Country [27] 0 0
Italy
State/province [27] 0 0
Milan
Country [28] 0 0
Italy
State/province [28] 0 0
Torino
Country [29] 0 0
Japan
State/province [29] 0 0
Aichi
Country [30] 0 0
Japan
State/province [30] 0 0
Chiba
Country [31] 0 0
Japan
State/province [31] 0 0
Fukuoka
Country [32] 0 0
Japan
State/province [32] 0 0
Miyazaki
Country [33] 0 0
Japan
State/province [33] 0 0
Okayama
Country [34] 0 0
Japan
State/province [34] 0 0
Osaka
Country [35] 0 0
Japan
State/province [35] 0 0
Saitama
Country [36] 0 0
Japan
State/province [36] 0 0
Sendai
Country [37] 0 0
Japan
State/province [37] 0 0
Shizuoka
Country [38] 0 0
Japan
State/province [38] 0 0
Tokyo
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Lincoln
Country [40] 0 0
United Kingdom
State/province [40] 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
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.
Trial website
https://clinicaltrials.gov/study/NCT04176198
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04176198