Clinical trial NCT05568225: A Study of Etavopivat for the Treatment of Anemia in Patients With Myelodysplastic Syndromes (MDS)
Official title: A Phase 2 Open-Label Study to Evaluate Etavopivat for the Treatment of Anemia in Patients With Myelodysplastic Syndromes (MDS)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Very Low Risk, Low Risk, or Intermediate Risk MDS Per IPSS-R
Keywords: Anemia
Myelodysplastic Syndromes
MDS
Pyruvate Kinase
Activator
Transfusion dependent
FT-4202
Etavopivat
IPSS-R very low risk
IPSS-R low risk
IPSS-R intermediate risk
ESA refractory
ESA intolerant
Luspatercept refractory
Luspatercept intolerant
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2022-10-05
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and efficacy of etavopivat (FT-4202) for the treatment of anemia in adult patients with very low risk, low risk, or intermediate risk MDS.


Eligibility criteria: INCLUSION CRITERIA:

1. Patient has provided documented informed consent; the informed consent form (ICF) must be reviewed and signed by each patient prior to any study-related assessments/procedures being conducted.
2. Age ≥ 18 years at time of first dose.
3. Patients, if female and of childbearing potential, must agree to use acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and who if male are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug.
4. Documented diagnosis of idiopathic/de novo MDS according to World Health Organization (WHO) classification that meets the IPSS-R classification of very low, low, or intermediate risk disease, and:

   * \< 5% blasts in bone marrow based on local pathology review
   * \< Intermediate risk cytogenetic abnormalities per IPSS-R
5. Anemia defined as:

   * Non-transfusion dependent (NTD): Subjects with mean Hb concentration \< 10.0 g/dL of 2 measurements (1 performed within 3 days prior to Day 1 and the other performed 7 to 28 days prior to Day 1, not influenced by RBC transfusion within 7 days of measurement) and \< 3 RBC transfusions for anemia in the prior 16 weeks before Day 1 of etavopivat dosing

   OR
   * Transfusion dependent (TD): Subjects having received ≥ 3 units of RBCs for the treatment of anemia within 16 weeks prior to Day 1
6. Serum erythropoietin level \> 200 U/L, OR, if ≤ 200 U/L, subject is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents, or erythropoiesis-stimulating agents are contraindicated or unavailable.
7. ECOG performance status of ≤ 2
8. Subject is non-responsive, refractory, or intolerant to luspatercept, or luspatercept is contraindicated or not indicated.
9. No alternative treatment options are available and/or appropriate for the subject, at the discretion of the investigator.
10. Patient is willing and able to adhere to the study visit schedule and other protocol requirements

EXCLUSION CRITERIA:

\[MDS History\]

1. MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality
2. Therapy-associated MDS (eg. t-MDS) that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases
3. Known history of acute myeloid leukemia (AML)

   \[Medical Conditions\]
4. Female who is breast feeding or pregnant
5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
6. Absolute neutrophil count \< 500/µL (0.5 x 10\^9/L)
7. Platelet count \< 50,000/µL (50 x 10\^9/L) without transfusion support within 2 weeks
8. Hepatic dysfunction characterized by:

   * Alanine aminotransferase (ALT) \> 5.0 × upper limit of normal (ULN)
   * Total bilirubin \> 3.0 × ULN
   * History of cirrhosis
9. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory \< 30 mL/min/1.73 m\^2 ) or on chronic dialysis.
10. Patients with clinically significant and active bacterial, fungal, parasitic, or viral infection.

    * Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay Screening/ enrollment until active therapy has been completed.
    * Patients with acute viral infections without available therapies (eg, coronavirus disease 2019 \[COVID-19\]) should delay Screening/ enrollment until the acute infection has resolved.

    Note: Infection prophylaxis is allowed.
11. Known human immunodeficiency virus (HIV) positivity
12. Active infection with hepatitis B virus (hepatitis B surface antigen \[HepBsAg\] and hepatitis B core antibody \[HepBcAb\] positive)
13. Active hepatitis C infection
14. History of malignancy, other than MDS, within the past 2 years prior to treatment Day 1 requiring systemic chemotherapy and/or radiation.

    * Patients with malignancy considered surgically cured are eligible (eg, non-melanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast)
    * Patients with incidental histologic findings of prostate cancer (T1a or T1b) are eligible
15. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:

    * Unstable angina pectoris or myocardial infarction or elective coronary intervention
    * Heart disease, heart failure as classified by the New York Heart Association classification 3 or higher, or significant arrhythmia requiring treatment,
    * Pulmonary fibrosis or pulmonary hypertension which are clinically significant ie, ≥ Grade 3 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (or higher)
16. Uncontrolled hypertension, defined as repeated elevation of diastolic blood pressure ≥ 100 mmHg despite adequate treatment
17. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).

    \[Prior/Concomitant Therapy\]
18. Prior treatment with azacitidine (injectable or oral) or decitabine
19. Use of erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of starting study treatment or anticipated need for such agents during the study.
20. Prior use of luspatercept:

    * NTD patients must not have received luspatercept within 30 days prior to Day 1 treatment
    * TD patients must not have received luspatercept within 16 weeks prior to Day 1 treatment
21. Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP)3A4/5 (see Appendix F) within 2 weeks of starting study treatment or anticipated need for such agents during the study.
22. Prior allogeneic or autologous stem cell transplant
23. Initiation of a new chelation therapy within 3 months before the first dose of study treatment.

    \[Prior/Concurrent Clinical Study Experience\]
24. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device).

    \[Other Exclusions\]
25. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent.

Primary outcomes:
measure: The hematologic improvement based on an erythroid response (HI -E) ≥ 8 weeks duration in patients with MDS after 16 weeks of etavopivat treatment
timeFrame: 16 weeks
Secondary outcomes:
measure: The HI-E ≥ 8 weeks duration in this population of patients after 24 and 48 weeks of etavopivat treatment
timeFrame: 24 and 48 weeks
measure: The HI-E ≥ 16 weeks duration in this population of patients after 24 and 48 weeks of etavopivat treatment
timeFrame: 24 and 48 weeks
measure: Incidence of AEs, serious adverse events (SAEs), and AEs related to etavopivat
timeFrame: 4(first 6 participants), 16, 24, and 48 weeks
measure: Number of premature discontinuations, dose interruptions, and dose reductions
timeFrame: 4(first 6 participants), 16, 24, and 48 weeks
measure: Overall response rate for MDS
timeFrame: 16, 24, and 48 weeks.
measure: Duration of response
timeFrame: 16, 24, and 48 weeks.
measure: Percentage of participants who achieved RBC transfusion independence in participants with LTB or HTB at study entry
timeFrame: 16, 24, and 48 weeks.
measure: Change from baseline in RBC units transfused in patients with NTD, LTB or HTB at study entry
timeFrame: 16, 24, and 48 weeks.
measure: Participants who achieved a hematologic improvement in neutrophil
timeFrame: 16, 24, and 48 weeks.
measure: Participants who achieved a hematologic improvement in platelet response
timeFrame: 16, 24, and 48 weeks.
measure: Change from baseline in mean serum ferritin
timeFrame: 16, 24, and 48 weeks.
measure: Change from baseline in mean daily dose of iron chelation therapy
timeFrame: 16, 24, and 48 weeks.
measure: Overall survival
timeFrame: 16, 24, and 48 weeks.
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Hospital and Clinics
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology
state: Florida
city: Plainsboro
country: United States
facility: Cedars-Sinai Medical Center
state: New Jersey
city: Plainsboro
country: United States
facility: Northwell Health
state: New Jersey
city: Plainsboro
country: United States
facility: Northwestern Memorial Hospital
state: New Jersey
city: Plainsboro
country: United States
facility: The Ohio State University Medical Center
state: New Jersey
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Vancouver
country: Canada
facility: University of British Columbia - St. Paul's Hospital
state: British Columbia
city: Route De Saint-Antoine
country: France
facility: Nice University Hospital - Hôpital de l'Archet
state: Nice
city: Paris La Défense
country: France
facility: Master centre for France
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Centre Hospitalier Universitaire de Bordeaux-Hopital Haut Leveque-1
city: Heidelberg
country: Germany
facility: Universitoetsklinikum Heidelberg
city: Mainz
country: Germany
facility: Charite Universitätsmedizin Berlin
city: Mainz
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik
city: Münster
country: Germany
facility: Universitaetsklinikum Muenster
city: Münster
country: Germany
facility: Universitoetsklinikum Halle (Saale)
Study officials:
affiliation: Novo Nordisk A/S
name: Clinical Transparency (dept. 2834), MD
role: STUDY_DIRECTOR
References: