Clinical trial NCT04279847: Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms
Official title: A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Myelofibrosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm Overlap Syndrome
Myeloproliferative Neoplasm
Relapsed or Refractory Primary Myelofibrosis
Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis)
ET (Essential Thrombocythemia)
Keywords: Myelofibrosis
myelodysplastic syndrome
myelodysplastic/myeloproliferative neoplasm overlap syndrome
myeloproliferative neoplasm
BET protein inhibitor
relapsed primary myelofibrosis
refractory primary myelofibrosis
secondary myelofibrosis
post-polycythemia vera myelofibrosis
post-essential thrombocythemia myelofibrosis
LIMBER
ET (essential thrombocythemia)
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2020-02-21
Enrollment: 231
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: monotherapy and ruxoltinib combination
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of INCB057643 as monotherapy or combination with ruxolitinib for participants with myelofibrosis (MF) and other myeloid neoplasms.


Eligibility criteria: Inclusion Criteria:

* Age 18 years and older at the time of signing the informed consent.
* Part 1 Monotherapy: Participants with confirmed diagnosis of relapsed or refractory MF (primary, or post-PV and post-ET), MDS, MDS/MPN, or ET who have received at least 1 prior line of therapy; are either refractory, relapsed, or intolerant to the last therapy; and there is no available therapy that would provide clinical benefit in the opinion of the investigator.

  * a. MF with measurable disease (palpable spleen and symptoms) as defined in the protocol and risk category of intermediate 2 or high according to DIPSS. MF participants must have received a JAK inhibitor(s), such as ruxolitinib.
  * b. ET participants should have disease refractory to hydroxyurea as defined by the protocol.
* Part 2 Combination with ruxolitinib.

  * a. Primary MF or secondary MFs (post-PV MF and post-ET MF), histologically or cytologically confirmed, with measurable disease (palpable spleen and symptoms) as defined in the protocol, either currently receiving ruxolitinib with suboptimal response or JAKi-naive.
  * b. Suboptimal response is defined as currently being treated with ruxolitinib monotherapy at a stable dose for ≥ 8 weeks immediately preceding the first dose of study treatment. One dose reduction due to toxicities within 8 weeks prior to Study Day 1 is permitted.
  * c. JAKi-naive is defined as those participants that have no prior use of any JAK inhibitor, including ruxolitinib, and;
  * d. Part 2 dose escalation: Risk category of intermediate-2 or high according to DIPSS.
  * e. Part 2 dose expansion: Risk category of intermediate-1, intermediate-2, or high according to DIPSS.
  * f. Part 2 dose expansion participants with chronic MF are defined as participants with bone marrow myeloblast percentage \< 5% (not applicable if dry tap or blast count deemed not reliable by the investigator) and blast count in peripheral blood \< 1% at screening and who are currently receiving ruxolitinib and having a suboptimal response.

Note: Study treatment should be delayed if peripheral blood blast count at baseline is \> 3%; treatment should only be started with medical monitor approval.

* g. Part 2 dose expansion participants with accelerated-phase MF are defined as having either a bone marrow myeloblast percentage ≥ 5% to \< 20% or a myeloblast percentage ≥ 10% in peripheral blood on 2 occasions at least 2 weeks apart, AND are currently receiving ruxolitinib and have a suboptimal response.
* h. Part 2 dose expansion participants with JAKi-naive MF are eligible to receive ruxolitinib, with peripheral blood blast count of \< 10% at the screening hematology assessment.

  * Must not be a candidate for potentially curative therapy, including hematopoietic stem cell transplantation.
  * ECOG performance status 0 to 2.
  * Life expectancy ≥ 24 weeks.
  * Willingness to avoid pregnancy or fathering children based on criteria.
* a. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after the last dose of study treatment and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed.
* b. Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed.
* c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea without any other medical reasons such as treatment with anticancer agents) are eligible.

Exclusion Criteria:

* Prior receipt of a BET inhibitor.
* Receipt of anticancer medications or investigational drugs within the protocol-defined interval before the first dose of study treatment. For Part 2 JAKi-naive, prior use of a JAK inhibitor (including ruxolitinib) and no use of experimental drug therapy for MF or any other standard drug (except hydroxyurea) used for MF or another indication within 3 months of starting study drug. For participants with suboptimal response to ruxolitinib, ruxolitinib will continue at the participants' current ongoing doses, no ruxolitinib washout is needed.
* Participants with exclusionary laboratory values at screening defined as, including, but not limited to,

  * a. Platelets. Part 1 (monotherapy dose expansion, MF): \< 75 × 109/L. Part 1 (monotherapy dose expansion, ET): \< 450 × 109/L. Part 2 (combination dose escalation and expansion): \< 75 × 109/L. Part 2 (combination dose expansion, JAKi-naïve MF): \< 100 × 109/L.
  * b. Hemoglobin: Participants unwilling to receive red blood cell transfusion to treat low hemoglobin levels are excluded.
  * c. ANC \< 0.75 × 109/L.
* inadequate renal, hepatic and coagulation functions as defined in the protocol.
* Concurrent anticancer therapy other than the therapies being tested in this study.
* Participants who have received allogeneic hematopoietic stem cell transplantation within 6 months of enrollment (unless approved by the medical monitor), or have active graft versus-host disease, or have received immunosuppressive therapy following allogeneic transplant within 2 weeks of the first dose of study treatment.
* Unless approved by the medical monitor, may not have received autologous hematopoietic stem-cell transplant within 3 months before the first dose of study treatment.
* Significant concurrent, uncontrolled medical condition, including but not limited to, significant GI disorder, history of or current clinically significant or uncontrolled cardiac disease, history or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful, and history of bleeding disorder or at a high risk of bleeding.
* Active bacterial, fungal, parasitic, or viral infection that requires therapy.
* Current use of prohibited medication as described in the protocol, including the use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half lives (whichever is longer) before the first dose of study treatment.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Primary outcomes:
measure: Number of treatment-emergent adverse events
timeFrame: Up to approximately 9 months
Secondary outcomes:
measure: Spleen Volume Response
timeFrame: Week 24
measure: Duration of a Spleen Volume Response from baseline (MF only)
timeFrame: Up to approximately 9 months
measure: Symptom Response Rate (MF or ET)
timeFrame: Week 24
measure: Anemia Response (MF only)
timeFrame: Up to approximately 9 months
measure: Duration of Anemia Response (MF only)
timeFrame: Up to approximately 9 months
measure: Changes in hemoglobin value from baseline (MF only)
timeFrame: Up to approximately 9 months
measure: Red Blood Cell (RBC) Transfusion Burden (MF only)
timeFrame: Up to approximately 9 months
measure: Overall response (ET only)
timeFrame: Up to approximately 9 months
measure: Duration of platelet count reduction or White Blood Cell (WBC) count reduction (ET only)
timeFrame: Up to approximately 9 months
measure: Bone Marrow (BM) Blast Complete Remission (MF, myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm (MPN))
timeFrame: Up to approximately 9 months
measure: BM Blast Partial Remission (MF, MDS, and MDS/MPN)
timeFrame: Up to approximately 9 months
measure: Peripheral Blast Complete Remission (MF, MDS, and MDS/MPN)
timeFrame: Up to approximately 9 months
measure: Peripheral Blast Partial Remission (MF, MDS, and MDS/MPN)
timeFrame: Up to approximately 9 months
measure: Durable Blast Complete or Partial remission (MF, MDS, and MDS/MPN)
timeFrame: Up to approximately 9 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama At Birmingham
state: Alabama
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University-Winship Cancer Institute
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of Nj
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Mineola
country: United States
facility: Nyu Langone Health - Long Island Hospital
state: New York
city: New York
country: United States
facility: Nyu Langone Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina At Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: Texas Oncology-Baylor Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: Md Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute At University of Utah
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: McGill University Jewish General Hospital
state: Quebec
city: Vancouver
country: Canada
facility: St Paul'S Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Guangzhou
country: China
facility: Nanfang Hospital_Southern Medical University
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University School of Medicine (Fahzu)
city: Zhengzhou
country: China
facility: Henan Cancer Hostipal
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Bologna
country: Italy
facility: Aou Policlinico S. Orsola-Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi (Aouc)
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori
city: Milan
country: Italy
facility: Fondazione Irccs Ca Granda Ospedale Maggiore
city: Orbassano
country: Italy
facility: Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano
city: Rome
country: Italy
facility: Azienda Policlinico Umberto 1 Universita Sapienza Di Roma
city: Verona
country: Italy
facility: Centro Ricerche Cliniche Di Verona
city: Aichi
country: Japan
facility: Fujita Health University Hospital
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Chuo
country: Japan
facility: University of Yamanashi Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto Shinto General Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Center
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrin
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de La Arrixaca
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Boston
country: United Kingdom
facility: United Lincolnshire Hospitals
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Manchester
country: United Kingdom
facility: The Christie Nhs Foundation Trust Uk
city: Oxford
country: United Kingdom
facility: University of Oxford
Study officials:
References: