Clinical trial NCT04176198: A Study of Oral Nuvisertib (TP-3654) in Patients With Myelofibrosis
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myelofibrosis
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2019-11-25
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility 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

Primary outcomes:
measure: Determine the incidence of dose-limiting toxicities (DLTs)
timeFrame: 28 days
measure: Determine the incidence of treatment emergent adverse events
timeFrame: From start of treatment to end of study
measure: Assess patients for any evidence of preliminary activity by determining the number of patients with ≥ 35% spleen volume reduction (SVR35)
timeFrame: From start of treatment to end of study
Secondary outcomes:
measure: Number of participants achieving objective response by IWG-MRT response criteria
timeFrame: From start of treatment to end of study
measure: Number of participants who have ≥ 25% spleen volume reduction
timeFrame: Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks therafter during treatment.
measure: Number of participants with ≥ 50% improvement in total symptom score (TSS50) at week 24
timeFrame: 24 weeks
measure: Determine the change in Patient Global Impression of Change (PGIC) at week 24 through end of study.
timeFrame: After 24 weeks of treatment to end of study
measure: Determine the incidence of QT interval changes
timeFrame: 25 hours
measure: Establish the half-life (t½) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
timeFrame: 24 hours
measure: Establish the Area under the plasma concentration versus time curve (AUC) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
timeFrame: 24 hours
measure: Establish the Peak Plasma Concentration (Cmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
timeFrame: 24 hours
measure: Establish the Time of Maximum concentration observed (tmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib
timeFrame: 24 hours
Other outcomes:
measure: Number of patients with reduction in bone marrow fibrosis
timeFrame: Every 24 weeks to end of study
measure: Study potential pharmacodynamic (PD) markers of nuvisertib
timeFrame: 12 months
measure: Nuvisertib monotherapy: Changes in platelet count over time in patients with baseline platelet count < 100 x 10^9/L
timeFrame: From start of treatment to end of study
measure: Nuvisertib combination arms: Assess the increase in hemoglobin ≥1.5 or ≥ 2 g/dL from baseline
timeFrame: From start of treatment to end of study
measure: Nuvisertib combination arms: Assess red blood cell transfusion independence status or any requirement change
timeFrame: From start of treatment to end of study
measure: Establish overall survival
timeFrame: From start of treatment to end of study
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Newport Beach
country: United States
facility: Hoag Family Cancer Institute
state: California
city: Denver
country: United States
facility: Blood Cancer Center
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health Shands Cancer Hospital
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University of Medicine
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Cancer Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Tri-Star Centennial Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Seattle
country: United States
facility: University of Washington - Fred Hutchinson Cancer Center
state: Washington
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Eastern Health Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash University
state: Victoria
city: Melbourne
country: Australia
facility: Peter McCallum Center
state: Victoria
city: Richmond
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Adelaide
country: Australia
facility: Icon Cancer Centre (Ashford Cancer Centre Research)
city: Leuven
country: Belgium
facility: University Hospitals Leuven
state: Vlaams-Brabant
city: Antwerp
country: Belgium
facility: ZNA Cadix
city: Antwerp
country: Belgium
facility: ZNA Middelheim
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Liege
country: Belgium
facility: CHU de Liege
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital Hematology/Oncology Research
state: British Columbia
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Amiens
country: France
facility: Centre Hospitalier Universitaire D'Amiens
city: Angers
country: France
facility: CHU Angers
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Nice
country: France
facility: Hospitalier Universitaire (CHU) de Nice - Hopital de l'Archet
city: Nimes
country: France
facility: Institut de cancerologie du Gard
city: Nimes
country: France
facility: Institut de cancerologie du Gard
city: Paris
country: France
facility: Hospital Saint Louis
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Alessandria
country: Italy
facility: Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo
city: Aviano
country: Italy
facility: Istituto Nazionale Tumori, IRCCS Centro di Riferimento Oncologico di Aviano
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero -Universitaria Di Bologna - Dipartimento Malattie Oncologiche ed Ematologiche - UO Ematologia
city: Brescia
country: Italy
facility: ASST - Spedali Civili di Brescia
city: Meldola
country: Italy
facility: IRCCS istituto Romagnolo per lo studio dei tumori "Dino Amadori"
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: Università degli Studi di Milano-Bicocca
city: Torino
country: Italy
facility: Azienda Ospedaliera Universitaria Citta' Della Salute E della Scienza di Torino
city: Aichi
country: Japan
facility: Aichi Medical University Hospital
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Hokkaido
country: Japan
facility: Hokkaido University Hospital
city: Miyazaki
country: Japan
facility: University of Miyazaki Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: The University of Osaka Hospital
city: Saitama
country: Japan
facility: Saitama Medical Center
city: Sendai
country: Japan
facility: Tohoku University Hospital
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tsu
country: Japan
facility: Mie University Hospital
city: Lincoln
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust - Pilgrim Hospital
city: London
country: United Kingdom
facility: University College London Hospital's NHS foundation Trust
Study officials:
References: