Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

Myelodysplastic Syndrome Clinical Trial

— LIMBER  

Official title:

A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04279847
• Other study ID #: INCB 57643-103
• Secondary ID: 2023-506145-38-0
• Status: Recruiting
• Phase: Phase 1
• Start date: February 23, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: June 2024
• Source: Incyte Corporation
• Contact: Incyte Corporation Call Center (US)
• Phone: 1.855.463.3463
• Email: medinfo[@]incyte.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 216
• Est. completion date: December 31, 2024
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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% and no blasts detected/not persistent blast count in peripheral blood at screening or baseline, AND who are currently receiving ruxolitinib and having suboptimal response.

• 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. Hydroxyurea must be discontinued 3 weeks prior to starting study treatment. 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.

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelofibrosis
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms
• Polycythemia
• Polycythemia Vera
• Preleukemia
• Primary Myelofibrosis
• Relapsed or Refractory Primary Myelofibrosis
• Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis)
• Syndrome
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• INCB057643
INCB057643 dose escalation and dose expansion.
• Ruxolitinib
Ruxolitinib will be administered twice a day using the dose described for each Cohort in the protocol for Part 2.

Locations

Country	Name	City	State
Canada	McGill University Jewish General Hospital	Montreal	Quebec
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Canada	St Paul'S Hospital	Vancouver
Finland	Helsinki University Central Hospital	Helsinki
Italy	Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi	Bologna
Italy	Azienda Ospedaliero-Universitaria Careggi (Aouc)	Firenze
Italy	Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori	Meldola
Italy	Fondazione Irccs Ca Granda Ospedale Maggiore	Milan
Italy	Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano	Orbassano
Italy	Azienda Policlinico Umberto 1 Universita Sapienza Di Roma	Rome
Italy	Azienda Ospedaliera Universitaria Integrata Di Verona - Centro Ricerche Cliniche Dr Verona	Verona
Japan	Fujita Health University Hospital	Aichi
Japan	Chiba University Hospital	Chiba
Japan	National Cancer Center Hospital East	Chiba
Japan	University of Yamanashi Hospital	Chuo
Japan	Kyushu University Hospital	Fukuoka
Japan	Kumamoto Shinto General Hospital	Kumamoto
Netherlands	Radboud University Nijmegen Medical Center	Nijmegen
Spain	Germans Trias I Pujol	Badalona
Spain	Hospital Universitario Insular de Gran Canaria	Las Palmas
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Virgen de La Arrixaca	Murcia
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
United Kingdom	Lincoln County Hospital	Boston
United Kingdom	United Lincolnshire Hospitals	Boston
United Kingdom	The Christie Nhs Foundation Trust Uk	Manchester
United Kingdom	University of Oxford	Oxford
United States	Emory University-Winship Cancer Institute	Atlanta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	University of Alabama At Birmingham	Birmingham	Alabama
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina At Chapel Hill	Chapel Hill	North Carolina
United States	University of Cincinnati Cancer Institute	Cincinnati	Ohio
United States	Ohio State University	Columbus	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Md Anderson Cancer Center	Houston	Texas
United States	University of Iowa Hospital and Clinics	Iowa City	Iowa
United States	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Rutgers Cancer Institute of Nj	New Brunswick	New Jersey
United States	Nyu Langone Laura and Isaac Perlmutter Cancer Center	New York	New York
United States	Weill Medical College of Cornell University	New York	New York
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute At University of Utah	Salt Lake City	Utah
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Incyte Corporation

Countries where clinical trial is conducted

United States,  Canada,  Finland,  Italy,  Japan,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of treatment-emergent adverse events	Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with ruxolitinib.	Up to approximately 9 months
Secondary	Spleen Volume Response	Defined as achieving a protocol defined reduction at Week 24 relative to baseline as measured by MRI or CT scan.	Week 24
Secondary	Duration of a Spleen Volume Response from baseline (MF only)	Defined as the interval between the first spleen volume response and the date of the first measurement that no longer achieves the protocol defined criteria.	Up to approximately 9 months
Secondary	Symptom Response Rate (MF or ET)	Defined as the proportion of participants who achieve a protocol defined reduction in Total Symptomatic Score (TSS) relative to baseline as measured by the MPN-symptom assessment form (SAF) TSS.	Week 24
Secondary	Anemia Response (MF only)	A hemoglobin increase of 1.5 g/dL relative to baseline for any "rolling" 12-week period during the study treatment period, if transfusion independent (TI) at baseline or Achieving TI for any "rolling" 12-week period during the study treatment period, if transfusion dependent (TD) at baseline.	Up to approximately 9 months
Secondary	Duration of Anemia Response (MF only)	The interval from the first onset of anemia response to the earliest date of loss of anemia response that persists for at least 4 weeks or death from any cause for the TI participants at baseline or duration of RBC-TI period for participants achieving RBC-TI for at least 12 consecutive weeks during the study treatment period for the TD participants at baseline.	Up to approximately 9 months
Secondary	Changes in hemoglobin value from baseline (MF only)	Defined as the mean change from baseline in the hemoglobin value over 12-week treatment periods.	Up to approximately 9 months
Secondary	Red Blood Cell (RBC) Transfusion Burden (MF only)	Defined as the average number of RBC units per participant-month through Weeks 12, 24, and 48.	Up to approximately 9 months
Secondary	Overall response (ET only)	Defined as proportion of participants with complete response or partial response and hematological improvement/response as per definition for ET.	Up to approximately 9 months
Secondary	Duration of platelet count reduction or White Blood Cell (WBC) count reduction (ET only)	Defined as platelet count reduction or WBC count reduction lasting = 12 weeks.	Up to approximately 9 months
Secondary	Bone Marrow (BM) Blast Complete Remission (MF, myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm (MPN))	Defined as BM blasts achieving the protocol defined criteria.	Up to approximately 9 months
Secondary	BM Blast Partial Remission (MF, MDS, and MDS/MPN)	Defined as BM blasts achieving the protocol defined criteria.	Up to approximately 9 months
Secondary	Peripheral Blast Complete Remission (MF, MDS, and MDS/MPN)	Defined as peripheral blasts achieving the protocol defined criteria.	Up to approximately 9 months
Secondary	Peripheral Blast Partial Remission (MF, MDS, and MDS/MPN)	Defined as peripheral blast achieving the protocol defined criteria.	Up to approximately 9 months
Secondary	Durable Blast Complete or Partial remission (MF, MDS, and MDS/MPN)	Defined as achieving the protocol defined criteria.	Up to approximately 9 months

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