Clinical trial NCT05037760: Study to Evaluate KER-050 as a Monotherapy or in Combination With Ruxolitinib in Myelofibrosis
Official title: A Phase 2 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of KER-050 as Monotherapy or in Combination With Ruxolitinib in Participants With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Myelofibrosis
Keywords: Thrombocytopenia
Anemia
Red blood cells
Bone marrow
Lead sponsor: Keros Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2021-09-08
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a Phase 2, multicenter, open-label study to evaluate the safety and efficacy of KER-050 as monotherapy or in combination with ruxolitinib in participants with Myelofibrosis.

Detailed description: KER-050 is an investigational therapeutic protein designed to increase red blood cell and platelet production by inhibiting the signaling of a subset of the transforming growth factor beta (TGF-ß) family of proteins to promote hematopoiesis. It is being developed for the treatment of low blood cell counts, or cytopenias including anemia and thrombocytopenia in patients with Myelodysplastic Syndrome (MDS) and Myelofibrosis (MF)

Eligibility criteria: Inclusion Criteria:

1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.
2. In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
3. Male or female ≥18 years of age, at the time of signing informed consent.
4. Eastern Cooperative Oncology Group (ECOG) performance score ≤2 (see Appendix 2).
5. Life expectancy ≥12 months per Investigator assessment.
6. Confirmed diagnosis of PMF (prefibrotic or overtly fibrotic) according to the 2016 World Health Organization (WHO) criteria (see Appendix 3), post-PV MF, or post-ET MF according to the 2008 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria (see Appendix 4).
7. Anemia, defined as:

   1. Having received ≥6 units of RBC transfusion for Hgb ≤8.5 g/dL in the 12 weeks prior to the planned C1D1, including ≥1 unit of RBC transfusion in the 28 days prior to C1D1; or
   2. Having ≥3 evaluable Hgb measurements at \<10.0 g/dL including ≥1 evaluable Hgb measurement assessed 8 to 13 weeks prior to C1D1. Participants receiving RBC transfusions but not meeting criterion "a." may enroll under criterion "b." following the below parameters:

      * All pre-transfusion Hgb values (defined as a Hgb assessed within the 3 days prior to a transfusion) should be recorded, and ≥1 pre-transfusion Hgb value is required.
      * Hgb values collected within the 28 days following a transfusion will not be considered evaluable unless qualifying as a pre-transfusion Hgb; in cases where multiple transfusions are given in succession due to poor Hgb response, only the first pre-transfusion Hgb will be considered evaluable.
8. Arm-specific criteria:

   Arms 1A and 2A:
   1. Previously treated with JAK inhibitor(s) and, per the Investigator, discontinued due to one of the following reasons:

      * Relapsed disease following treatment with JAK inhibitor(s)
      * Refractory to treatment with JAK inhibitor(s)
      * Intolerance to treatment with JAK inhibitor(s)
      * Participant no longer met risk/benefit ratio to continue JAK inhibitor(s) OR
      * Participant with prognostic score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS; see Appendix 7) and is ineligible for JAK inhibitor(s) in the opinion of the Investigator
   2. Participants previously treated with JAK inhibitor(s) must have discontinued JAK inhibitor therapy ≥8 weeks before C1D1

   Arms 1B and 2B:
   1. Has been receiving ruxolitinib prescribed for a diagnosis of PMF (prefibrotic or overtly fibrotic), post-PV MF, or post-ET MF for ≥8 weeks prior to C1D1 and on a stable dose for ≥4 weeks prior to C1D1. In Arm 2B only, at least 10 participants should have been on ruxolitinib for \<6 months prior to C1D1.
   2. Meets ≥1 of the following criteria in the opinion of the Investigator:

      * Current ruxolitinib treatment is considered to be providing insufficient control of the disease
      * The participant's cytopenias are limiting the participant's ruxolitinib dose intensity
      * The participant's disease is symptomatic and warrants additional therapy

   Arm 2C (Brazil only):
   1. No prior treatment with JAK inhibitor(s) and no access to JAK inhibitor therapy as determined by the Investigator
   2. Platelet count ≥ 50 × 109/L
   3. Spleen volume ≥ 450 cm3 as assessed by CT or MRI collected during the pretreatment period
   4. MF-SAF-TSS meeting at least one of the following criteria during the pretreatment period:

      * 2 symptoms with average score ≥ 3
      * Average total score ≥ 10
9. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception as described in the protocol.

Exclusion Criteria:

Medical History:

1. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
2. Presence of the following cardiac conditions:

   1. New York Heart Association Class 3 or 4 heart failure
   2. QTcF (QT interval corrected by Fridericia's formula) \>500 msec on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements)
   3. Uncontrolled clinically significant arrhythmia (participants with rate-controlled atrial fibrillation are not excluded)
   4. Acute myocardial infarction or unstable angina pectoris ≤6 months prior to C1D1
3. Body mass index (BMI) ≥40 kg/m2.
4. Presence of uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite adequate treatment.
5. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
6. History of stroke, deep venous thrombosis, or arterial embolism within 6 months prior to C1D1.
7. Major surgery within 28 days prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1 in the opinion of the Investigator.
8. Known positive for HIV, active infectious hepatitis B with positive viral load (hepatitis B virus \[HBV\] DNA), or active infectious hepatitis C with positive viral load (hepatitis C virus \[HCV\] RNA). Participants without a known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
9. Any malignancy other than PMF, post-ET MF, or post-PV MF that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or biologic therapy, within 1 year prior to C1D1. In situ cancers, squamous cell and basal cell carcinomas, and monoclonal gammopathy of unclear significance are allowed at the discretion of the Investigator.
10. History of solid organ or hematological transplantation.
11. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational drug, or ruxolitinib for participants enrolling in Arm 1B or 2B.
12. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.
13. History of intracranial hemorrhage (any grade).
14. NCI CTCAE Grade ≥2 bleeding events within the 3 months prior to C1D1.
15. Receipt of an RBC or platelet transfusion for any reason(s) or combination of reasons other than underlying MF within the 12 weeks prior to C1D1. If a participant requires a transfusion for an unanticipated reason during the Pretreatment Period, a prolonged screening period may be considered after discussion with the Medical Monitor.

    Treatment History:
16. Prior treatment with luspatercept, sotatercept, or other commercially available or investigational TGF-β inhibitors (all arms).
17. Treatment within 28 days prior to C1D1 with:

    1. ESA
    2. Granulocyte colony-stimulating factor (G-CSF)
    3. Granulocyte-macrophage colony-stimulating factor (GM-CSF)
    4. TPO agonists
    5. IMiDs (e.g., thalidomide, pomalidomide, lenalidomide)
    6. Interferon
    7. Hydroxyurea
    8. Steroids at doses exceeding corticosteroid equivalent of 10 mg/day prednisone
18. Newly initiated iron chelation therapy within the 8 weeks prior to C1D1. Stable doses of iron chelators are allowed if prescribed per label.
19. Vitamin B12 and/or folate therapy initiated within 28 days prior to C1D1. Participants on stable replacement doses for ≥8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
20. Treatment with another investigational drug or device or approved therapy for the treatment of MF or anemia in MF ≤28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
21. For Arms 1B and 2B (participants receiving ruxolitinib), initiation of treatment with strong cytochrome P450 (CYP)3A4 inhibitors within 2 weeks prior to C1D1. Participants receiving CYP3A4 inhibitors/inducers as concomitant therapy with ruxolitinib in accordance with ruxolitinib local prescribing information may continue to receive such therapies in this study.

    Laboratory Exclusions (during screening):
22. Bone marrow aspirate blast percentage \>5%

    a. In the event of a non-evaluable pretreatment bone marrow aspirate expected to be due to marrow fibrosis, participants may be enrolled without bone marrow aspirate blast percentage data if all other eligibility criteria are met. Historical bone marrow data may be requested to support confirmation of diagnosis.
23. Peripheral blood blast percentage ≥10%
24. Platelet count \<25 × 109/L or \>450 × 109/L
25. Persistent Hgb \<7 g/dL despite RBC transfusions
26. Transferrin saturation \<15%
27. Ferritin \<50 ng/mL
28. Folate \<4.5 nmol/L (\<2.0 pg/L)
29. Vitamin B12 \<148 pmol/L (\<200 pg/mL)
30. Estimated glomerular filtration rate \<40 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease Epidemiology Collaboration equation)
31. AST or ALT \>2.5 × ULN
32. Total bilirubin \>1.5 × ULN
33. INR \>1.2 × ULN, unless participant is receiving anticoagulation, in which instance the INR must fall within the participant's designated therapeutic range.

    Miscellaneous:
34. Pregnant or lactating females.
35. Any other condition not specifically noted above that, in the opinion of the Investigator or Sponsor, would preclude the participant from participating in the study.
36. Participants who are investigational site staff members directly involved in the conduct of the study and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Keros or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

Primary outcomes:
measure: Incidence of adverse events (Safety and Tolerability)
timeFrame: 52 Weeks
Secondary outcomes:
measure: Evaluate the effect of KER-050 on progression to AML or accelerated MF
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on progression to AML or accelerated MF
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on anemia
timeFrame: 24 weeks
measure: Evaluate the effect of KER-050 on anemia
timeFrame: 24 weeks
measure: Evaluate the effect of KER-050 on anemia
timeFrame: 24 weeks
measure: Evaluate the effect of KER-050 on anemia
timeFrame: 24 weeks
measure: Evaluate the effect of KER-050 on MF disease manifestations and symptoms
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on MF disease manifestations and symptoms
timeFrame: 52 weeks
measure: Evaluate the PK profile of KER-050
timeFrame: 52 weeks
measure: Evaluate the PK profile of KER-050
timeFrame: 52 weeks
measure: Evaluate the PK profile of KER-050
timeFrame: 52 weeks
measure: Evaluate the PK profile of KER-050
timeFrame: Through Cycle 1 (each cycle is 28 days)
measure: Evaluate the PK profile of KER-050
timeFrame: 52 weeks
measure: Evaluate the PK profile of KER-050
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on erythropoiesis
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on erythropoiesis
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on erythropoiesis
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on erythropoiesis
timeFrame: 52 weeks
measure: Evaluate the effect of KER-050 on erythropoiesis
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Concord
country: Australia
facility: Concord Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Woodville South
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital Melbourne
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Wendouree
country: Australia
facility: Ballarat Oncology & Hematology Service
state: Victoria
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: IMV Pesquisa Cardiologica Sociedade Simples
city: São Paulo
country: Brazil
facility: Albert Einstein Sociedade Beneficente Israelita Brasiliera
city: São Paulo
country: Brazil
facility: Hospital Beneficencia Portuguesa de Sao Paulo
city: São Paulo
country: Brazil
facility: Hospital das Clínicas FMUSP: HC
city: São Paulo
country: Brazil
facility: Instituto de Ensino e Pesquisas Sao Lucas
city: Amiens
country: France
facility: CHU Amiens - Hopital Sud
city: Brest
country: France
facility: Hôpital Morvan
city: Cesson-Sévigné
country: France
facility: Hopital Prive Sevigne
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Nîmes
country: France
facility: Institut de Cancerologie du Gard
city: Orléans
country: France
facility: Hopital de la Source - CHR Orleans
city: Bari
country: Italy
facility: Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Milano
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Umberto I
city: Roma
country: Italy
facility: Policlinico Universitario Fondazione Agostino Gemelli
city: Varese
country: Italy
facility: Azienda Socio Sanitaria Territoriale Sette Laghi
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital, The Catholic University of Korea
city: Seoul
country: Korea, Republic of
facility: Soonchunhyang University Seoul Hospital
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia Badalona - Hospital Universitari Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital QuironSalud de Zaragoza
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Leeds
country: United Kingdom
facility: St. James Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
Study officials:
References: