A Study of Oral TP-3654 in Patients With Myelofibrosis

Myelofibrosis Clinical Trial

Official title:

A Phase 1/2, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 in Patients With Intermediate or High-Risk Primary or Secondary Myelofibrosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04176198
• Other study ID #: BBI-TP-3654-102
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 16, 2019
• Est. completion date: April 30, 2030

Study information

• Verified date: May 2024
• Source: Sumitomo Pharma America, Inc.
• Contact: Reyna Bishop
• Phone: 617-674-6800
• Email: reyna.bishop[@]us.sumitomo-pharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of TP-3654 in patients with intermediate or high-risk primary or secondary MF.

Description:

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: April 30, 2030
• Est. primary completion date: April 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Patients must meet all of the following inclusion criteria to be eligible:

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.

• 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 splenic length = 5 cm below the costal margin by palpation or 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 measureable with each score of = 3 or a total average score of = 10 per MFSAF, v4.0.

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 TP-3654, 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 splenic length = 5 cm below the costal margin by palpation or 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

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 splenic length = 5 cm below the costal margin by palpation or 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:

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 2 weeks before the first dose of either study drug.

• 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 TP-3654, 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).

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: 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 TP-3654, 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 2 weeks prior to Cycle 1 Day 1

• 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

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 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 TP-3654, 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 2 weeks prior to Cycle 1 Day 1

• 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

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

Drug:
• TP-3654
Oral PIM Inhibitor
• Ruxolitinib
Oral JAK inhibitor
• Momelotinib
Oral JAK inhibitor

Locations

Country	Name	City	State
Australia	Icon Cancer Centre (Ashford Cancer Centre Research)	Adelaide
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Eastern Health Box Hill Hospital	Box Hill	Victoria
Belgium	ZNA Cadix	Antwerp
Belgium	ZNA Middelheim	Antwerp
Belgium	University Hospitals Leuven	Leuven	Vlaams-Brabant
France	Centre Hospitalier Universitaire D'Amiens	Amiens
France	Hospitalier Universitaire (CHU) de Nice - Hopital de l'Archet	Nice
France	Hospital Saint Louis	Paris
France	Institut Gustave Roussy	Villejuif
Italy	IRCCS Azienda Ospedaliero -Universitaria Di Bologna - Dipartimento Malattie Oncologiche ed Ematologiche - UO Ematologia	Bologna
Italy	IRCCS istituto Romagnolo per lo studio dei tumori "Dino Amadori"	Meldola
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milan
Italy	Azienda Ospedaliera Universitaria Citta' Della Salute E della Scienza di Torino	Torino
Japan	Aichi Medical University Hospital	Aichi
Japan	National Cancer Center Hospital East	Chiba
Japan	Kyushu University Hospital	Fukuoka
Japan	University of Miyazaki Hospital	Miyazaki
Japan	Okayama University Hospital	Okayama
Japan	Osaka University Hospital	Osaka
Japan	Saitama Medical Center	Saitama
Japan	Tohoku University Hospital	Sendai
Japan	Shizuoka Cancer Center	Shizuoka
Japan	Juntendo University Hospital	Tokyo
United Kingdom	United Lincolnshire Hospitals NHS Trust - Pilgrim Hospital	Lincoln
United Kingdom	University College London Hospital's NHS foundation Trust	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Alabama	Birmingham	Alabama
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	Blood Cancer Center	Denver	Colorado
United States	City of Hope	Duarte	California
United States	Duke Cancer Institute	Durham	North Carolina
United States	University of Florida Health Shands Cancer Hospital	Gainesville	Florida
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Southern California	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Tri-Star Centennial Medical Center	Nashville	Tennessee
United States	Vanderbilt University	Nashville	Tennessee
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical Center	New York	New York
United States	Hoag Family Cancer Institute	Newport Beach	California
United States	Washington University of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of Washington - Fred Hutchinson Cancer Center	Seattle	Washington
United States	The University of Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Sumitomo Pharma America, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  France,  Italy,  Japan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Study potential pharmacodynamic (PD) markers of TP-3654	Evaluate exploratory biomarkers, including change in protein phosphorylation and inflammatory cytokines, in peripheral blood samples and bone marrow biopsy samples.	12 months
Other	Number of patients with reduction in bone marrow fibrosis		Every 24 weeks to end of study
Other	TP-3654 monotherapy: Changes in platelet count over time in patients with baseline platelet count < 100		From start of treatment to end of study
Other	TP-3654 combination arms: Assess the increase in hemoglobin =1.5 or = 2 g/dL from baseline		From start of treatment to end of study
Other	TP-3654 combination arms: Assess red blood cell transfusion independence status or any requirement change		From start of treatment to end of study
Other	Establish overall survival	The time interval from treatment start date of death from any cause	From start of treatment to end of study
Primary	Determine the incidence of dose-limiting toxicities (DLTs)	Number of participants with DLTs	28 days
Primary	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
Primary	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	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	Determine the incidence of QT interval changes	Changes in QT interval and heart rhythm	25 hours
Secondary	Establish the half-life (t½) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The estimate of time for the TP-3654 concentration or amount to be reduced by half	24 hours
Secondary	Establish the Peak Plasma Concentration (Cmax) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The maximum TP-3654 concentration after administration	24 hours
Secondary	Establish the Time of Maximum concentration observed (tmax) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The time to reach maximum TP-3654 concentration	24 hours
Secondary	Establish the Area under the plasma concentration versus time curve (AUC) of TP-3654 monotherapy, in combination with ruxolitinib, and in combination with momelotinib	The amount of drug exposure over 24 hours period after administration	24 hours