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

• ClinicalTrials.gov Identifier: NCT04279847
• Recruitment Status: Recruiting
• First Posted: February 21, 2020
• Last Update Posted: January 12, 2024
• Sponsor: Incyte Corporation
• Information provided by (Responsible Party): Incyte Corporation

Tracking Information

• First Submitted Date: February 18, 2020
• First Posted Date: February 21, 2020
• Last Update Posted Date: January 12, 2024
• Actual Study Start Date: February 23, 2021
• Estimated Primary Completion Date: November 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 3, 2021)

Number of treatment-emergent adverse events [ Time Frame: Up to approximately 9 months ]

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.

Original Primary Outcome Measures (submitted: February 20, 2020)

Number of treatment-emergent adverse events [ Time Frame: Up to approximately 9 months ]

Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug.

Current Secondary Outcome Measures (submitted: January 10, 2024)

• Spleen Volume Response [ Time Frame: Week 24 ]
  Defined as achieving a protocol defined reduction at Week 24 relative to baseline as measured by MRI or CT scan.
• Duration of a Spleen Volume Response from baseline (MF only) [ Time Frame: Up to approximately 9 months ]
  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.
• Symptom Response Rate (MF or ET) [ Time Frame: Week 24 ]
  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.
• Anemia Response (MF only) [ Time Frame: Up to approximately 9 months ]
  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.
• Duration of Anemia Response (MF only) [ Time Frame: Up to approximately 9 months ]
  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.
• Changes in hemoglobin value from baseline (MF only) [ Time Frame: Up to approximately 9 months ]
  Defined as the mean change from baseline in the hemoglobin value over 12-week treatment periods.
• Red Blood Cell (RBC) Transfusion Burden (MF only) [ Time Frame: Up to approximately 9 months ]
  Defined as the average number of RBC units per participant-month through Weeks 12, 24, and 48.
• Overall response (ET only) [ Time Frame: Up to approximately 9 months ]
  Defined as proportion of participants with complete response or partial response and hematological improvement/response as per definition for ET.
• Duration of platelet count reduction or White Blood Cell (WBC) count reduction (ET only) [ Time Frame: Up to approximately 9 months ]
  Defined as platelet count reduction or WBC count reduction lasting ≥ 12 weeks.
• Bone Marrow (BM) Blast Complete Remission (MF, myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm (MPN)) [ Time Frame: Up to approximately 9 months ]
  Defined as BM blasts achieving the protocol defined criteria.
• BM Blast Partial Remission (MF, MDS, and MDS/MPN) [ Time Frame: Up to approximately 9 months ]
  Defined as BM blasts achieving the protocol defined criteria.
• Peripheral Blast Complete Remission (MF, MDS, and MDS/MPN) [ Time Frame: Up to approximately 9 months ]
  Defined as peripheral blasts achieving the protocol defined criteria.
• Peripheral Blast Partial Remission (MF, MDS, and MDS/MPN) [ Time Frame: Up to approximately 9 months ]
  Defined as peripheral blast achieving the protocol defined criteria.
• Durable Blast Complete or Partial remission (MF, MDS, and MDS/MPN) [ Time Frame: Up to approximately 9 months ]
  Defined as achieving the protocol defined criteria.

Original Secondary Outcome Measures (submitted: February 20, 2020)

• Rate of anemia response [ Time Frame: Up to approximately 9 months ]
  Anemia response defined by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) Consensus Report
• Red blood cell (RBC) transfusion independence rate [ Time Frame: Up to approximately 9 months ]
  Assessed by need for transfusion support
• Rate of converting from RBC transfusion dependence to independence [ Time Frame: Up to approximately 9 months ]
  Assessed by need for transfusion support
• RBC transfusion frequency per participant [ Time Frame: Up to approximately 9 months ]
  Assessed by need for transfusion support
• RBC transfusion frequency per month [ Time Frame: Up to approximately 9 months ]
  Assessed by need for transfusion support
• Hemoglobin improvement [ Time Frame: Up to approximately 9 months ]
  Defined as hemoglobin level increase ≥ 1.5 g/dL or hemoglobin level ≥ 8.5 g/dL)
• Best spleen volume percentage change from baseline [ Time Frame: 12 weeks ]
  Measured by imaging
• Percent of participants with spleen volume reduction of 35% or more [ Time Frame: Up to approximately 9 months ]
  Assessed by imaging measurements and calculating the differences from image to image
• Rate of spleen response by imaging [ Time Frame: 24 weeks ]
  Defined by IWG-MRT and ELN Consensus Report
• Time from spleen response to progressive disease [ Time Frame: Up to approximately 9 months ]
  Based on splenomegaly as defined by IWG-MRT and ELN Consensus Report
• Percent of participants achieving 50% or more improvement in total symptom score [ Time Frame: Up to approximately 9 months ]
  Based on the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score questionnaire.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

monotherapy and ruxoltinib combination

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• 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)

Intervention

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

Study Arms

• Experimental: Part 1 : INCB057643 Monotherapy
  INCB057643 dose escalation and dose expansion
  Intervention: Drug: INCB057643
• Experimental: Part 2 : INCB057643 Combination with Ruxolitinib
  Combination arm in dose escalation and dose expansion
  Interventions:

  • Drug: INCB057643
  • Drug: Ruxolitinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 10, 2024): 216
• Original Estimated Enrollment (submitted: February 20, 2020): 15
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: November 30, 2024 (Final data collection date for primary outcome measure)

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% 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Incyte Corporation Call Center (US); 1.855.463.3463; medinfo@incyte.com

Contact: Incyte Corporation Call Center (ex-US); 1.855.463.3463; globalmedinfo@incyte.com

• Listed Location Countries: Canada, Finland, Italy, Japan, Spain, United Kingdom, United States
• Removed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT04279847
• Other Study ID Numbers: INCB 57643-103; 2023-506145-38-00 ( Registry Identifier: EU CT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Access to patient level data is not available for this study

• Current Responsible Party: Incyte Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Incyte Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Incyte Corporation
• Verification Date: January 2024