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

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

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.

Condition or disease Intervention/treatment Phase
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) Drug: INCB057643 Drug: Ruxolitinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 216 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: monotherapy and ruxoltinib combination
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms
Actual Study Start Date : February 23, 2021
Estimated Primary Completion Date : November 30, 2024
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Part 1 : INCB057643 Monotherapy
INCB057643 dose escalation and dose expansion
Drug: INCB057643
INCB057643 dose escalation and dose expansion.

Experimental: Part 2 : INCB057643 Combination with Ruxolitinib
Combination arm in dose escalation and dose expansion
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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04279847


Contacts
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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

Locations
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Sponsors and Collaborators
Incyte Corporation
Additional Information:
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Responsible Party: Incyte Corporation
ClinicalTrials.gov Identifier: NCT04279847    
Other Study ID Numbers: INCB 57643-103
2023-506145-38-00 ( Registry Identifier: EU CT Number )
First Posted: February 21, 2020    Key Record Dates
Last Update Posted: June 21, 2024
Last Verified: June 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Access to patient level data is not available for this study

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Incyte Corporation:
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)
Additional relevant MeSH terms:
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Neoplasms
Preleukemia
Polycythemia Vera
Myelodysplastic Syndromes
Primary Myelofibrosis
Myeloproliferative Disorders
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myelodysplastic-Myeloproliferative Diseases
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
INCB057643
Antineoplastic Agents