A study to evaluate KER-050 as a monotherapy or in combination with Ruxolitinib in Myelofibrosis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

22 Apr 2022 → ongoing

Decision date (initial)

2024-09-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2023-507468-38-00

EudraCT number

2021-003227-15

WHO UTN

U1111-1294-3670

ClinicalTrials.gov

NCT05037760

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Efficacy, Safety, Others

Part 1 Dose Escalation:
• Safety: To evaluate the safety and tolerability of ascending doses of elritercept monotherapy in participants with primary myelofibrosis (PMF), postessential thrombocythemia myelofibrosis (post-ET MF), and postpolycythemia vera myelofibrosis (post-PV MF) who have anemia
• Safety: To evaluate the safety and tolerability of ascending doses of elritercept in combination with ruxolitinib in participants with PMF, post-ET MF, and post-PV MF who have anemia
• To determine the recommended Phase 2 dose (RP2D(s)) for Part 2

Part 2 Dose Expansion:
• Safety: To further evaluate the safety and tolerability of the dose(s) selected in Part 1

Long Term Extension:
• Safety: To evaluate the long-term safety and tolerability of elritercept administered with or without ruxolitinib in participants in the Long-Term Extension (LTE)

Secondary objectives 5

1. Safety: To evaluate the effect of elritercept administered with or without ruxolitinib on progression to acute myeloid leukemia (AML) or accelerated myelofibrosis (MF)
2. Efficacy: To evaluate the effect of elritercept administered with or without ruxolitinib on anemia in participants with PMF/post-ET MF/post-PV MF
3. Efficacy: To evaluate the effect of elritercept administered with or without ruxolitinib on MF disease manifestations and symptoms in participants with PMF/post-ET MF/post-PV MF
4. Pharmacokinetics: To evaluate the pharmacokinetics (PK) of elritercept administered with or without ruxolitinib in participants with PMF/post-ET MF/post-PV MF
5. Pharmacodynamics: To evaluate the effect of elritercept administered with or without ruxolitinib on erythropoiesis in participants with PMF/post-ET MF/post-PV MF

Conditions and MedDRA coding

Myelofibrosis

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003239-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female ≥18 years of age, at the time of signing informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
3. Life expectancy ≥12 months per Investigator assessment
4. 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 (IWGMRT) criteria (see Appendix 4).
5. Anemia, defined as: a. 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 b. Having ≥3 evaluable Hgb measurements at <10.0 g/dL including ≥1 evaluable Hgb measurement assessed 8 to 13 weeks prior to C1D1. with or without receiving RBC transfusions to be evaluated for anemia criterion “b.”, partecipants receiving RBC transusion must meet the below parameters: i. 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. ii. 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.
6. Arm-specific criteria: Arm 1A and 2A: - a. Previously treated with JAK inhibitor(s) and, per the Investigator, discontinued due to one of the following reasons: i. Relapsed disease following treatment with JAK inhibitor(s) ii. Refractory to treatment with JAK inhibitor(s) iii. Intolerance to treatment with JAK inhibitor(s) iv. Participant no longer met risk/benefit ratio to continue JAK inhibitor(s) OR v. Participant with prognostic score of intermediate-1 or higher Dynamic International Prognostic Scoring System (DIPSS) and is ineligible for JAK inhibitor(s) in the opinion of the Investigator b.Participants previously treated with JAK inhibitor(s) must have discontinued JAK inhibitor therapy ≥8 weeks before C1D1
7. Arms 1B and 2B: a.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. b.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 i.The participant's cytopenias are limiting the participant's ruxolitinib dose intensity ii.The participant's disease is symptomatic and warrants additional therapy
8. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception as described in the protocol.

Exclusion criteria 21

1. 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: a. New York Heart Association Class 3 or 4 heart failure b. QTcF (QT interval corrected by Fridericia's formula) >500 msec on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements) c. Uncontrolled clinically significant arrhythmia (participants with ratecontrolled atrial fibrillation are not excluded) d. 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 and/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. 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.
8. History of solid organ or hematological transplantation.
9. 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.
10. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.
11. NCI CTCAE Grade ≥2 bleeding events within the 3 months prior to C1D1.
12. 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.
13. Prior treatment with luspatercept, sotatercept, or other commercially available or investigational transforming growth factor (TGF)-β inhibitors (all arms).
14. Treatment within 28 days prior to C1D1 with: a. Erythropoiesis-stimulating agent b. Granulocyte colony-stimulating factor c. Granulocyte-macrophage colony-stimulating factor d. Thrombopoietin agonists e. Immunomodulator imide drugs (e.g., thalidomide, pomalidomide, lenalidomide) f. Interferon g. Hydroxyurea h. Steroids at doses exceeding corticosteroid equivalent of 10 mg/day prednisone
15. Newly initiated iron chelation therapy within the 8 weeks prior to C1D1. Stable doses of iron chelators are allowed if prescribed per label.
16. Vitamin B12 or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
17. 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.
18. 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.
19. 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.
20. Peripheral blood blast percentage ≥10%
21. Estimated glomerular filtration rate <30 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease Epidemiology Collaboration equation)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1 Dose Escalation: •Safety and tolerability as determined by the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs), severe AEs, and serious AEs (SAEs)
2. Part 2 Dose Expansion: •Safety and tolerability as determined by the incidence of AEs, including severe AEs and SAEs
3. Long-Term Extension: •Safety and tolerability as determined by the incidence of AEs, including severe AEs and SAEs over time

Secondary endpoints 10

1. Proportion of participants with progression to AML
2. Proportion of participants with progression to accelerated MF
3. Subgroup of participants with anemia requiring red blood cell (RBC) transfusions (See Table 3 in Protocol KER050-MF-301 v 6.0).
4. Subgroup of transfusion-independent participants (and, when appropriate, the subgroup of participants with anemia requiring RBC transfusions who are deemed not evaluable for assessment of transfusion independence) (See Table 3 Protocol KER050-MF-301 v 6.0).
5. Proportion of participants with improvement in the MF-SAF (v4.0)-TSS of ≥50% from baseline at Week 24
6. Proportion of participants with decrease in spleen volume of ≥35% from baseline as measured by computed tomography/magnetic resonance imaging (CT/MRI) at Week 24 (excluding participants’ status post splenectomy or splenic irradiation)
7. Plasma concentrations of elritercept
8. Maximum observed serum concentration (Cmax), time to maximum observed concentration (Tmax), and area under the concentration-time curve from time 0 to the time of last quantifiable concentration (AUC0-last; Cycle 1 only)
9. Minimum observed serum concentration (Cmin) and accumulation rate (Rac)
10. Change from baseline of red cell parameters, including reticulocyte count, Hgb, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocyte cell Hgb by visit

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Leopold Sellner

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 11

Locations

3 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 48 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications