Trial Title:
A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS)
NCT ID:
NCT05490446
Condition:
Myelodysplastic Syndromes
Conditions: Official terms:
Preleukemia
Anemia
Myelodysplastic Syndromes
Syndrome
Conditions: Keywords:
Anemia
Lower-Risk Myelodysplastic Syndromes
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tebapivat
Description:
Tebapivat Tablet
Arm group label:
Core Period: Phase 2a - Tebapivat
Arm group label:
Core Period: Phase 2b - Tebapivat Dose Level 1
Arm group label:
Core Period: Phase 2b - Tebapivat Dose Level 2
Arm group label:
Core Period: Phase 2b - Tebapivat Dose Level 3
Other name:
AG-946
Summary:
This purpose of this study is to establish proof of concept of tebapivat in participants
with LR-MDS in Phase 2a and to evaluate the effect of tebapivat on transfusion
independence (TI) in participants with LR-MDS in phase 2b.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Phase 2a
1. At least 18 years of age at the time of providing informed consent;
2. Documented diagnosis of myelodysplastic syndromes (MDS) according to World Health
Organization (WHO) classification (Arber et al, 2016), that meets Revised
International Prognostic Scoring System (IPSS-R) classification of lower-risk
disease (risk score: ≤3.5) and <5% blasts as determined by the participant's bone
marrow biopsy/aspirate during the Screening Period;
3. Nontransfused or with low transfusion burden (LTB), based on transfusion history
from the participant's medical record, according to revised International Working
Group (IWG) 2018 criteria:
- Nontransfused (NTD): <3 red blood cell (RBC) units in the 16-week period before
administration of the first dose of study drug and no transfusions in the
8-week period before administration of the first dose of study drug, or
- LTB: 3 to 7 RBC units in the 16-week period before administration of the first
dose of study drug and <4 RBC units in the 8-week period before administration
of the first dose of study drug;
4. A hemoglobin (Hb) concentration <11.0 grams per deciliter (g/dL) during the 4-week
Screening Period;
5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2;
6. If taking iron chelation therapy, the iron chelation therapy dose must have been
stable and started ≥56 days before administration of the first dose of study drug;
7. Women of childbearing potential (WOCBP) must be abstinent of sexual activities that
may result in pregnancy as part of their usual lifestyle or agree to use a highly
effective method of contraception from the time of providing informed consent,
throughout the study, and for 28 days after the last dose of study drug; if the
highly effective method of contraception is hormonal contraception, then an
acceptable barrier method must also be used. Men with partners who are WOCBP must be
abstinent of sexual activities that may result in pregnancy as part of their usual
lifestyle or agree to use a condom from the time of providing informed consent
throughout the study and for 28 days after the last dose of study drug;
8. Written informed consent from the participant before any study-related procedures
are conducted and willing to comply with all study procedures for the duration of
the study.
Phase 2b
1. At least 18 years of age at the time of providing informed consent;
2. Documented diagnosis of MDS according to WHO classification (Arber et al, 2016),
that meets IPSS-R classification of lower-risk disease (risk score: ≤3.5) and <5%
blasts as determined by the participant's bone marrow biopsy/aspirate during the
Screening Period;
3. With LTB, or high transfusion burden (HTB), based on transfusion history from the
participant's medical record, according to revised IWG 2018 criteria:
1. LTB: 3 to 7 RBC units from at least 2 transfusion episodes in the 16-week
period before administration of the first dose of study drug AND <4 RBC units
in the 8-week period before administration of the first dose of study drug, or
2. HTB: ≥8 RBC units in the 16-week period before administration of the first dose
of study drug AND ≥4 RBC units in the 8-week period before administration of
the first dose of study drug
If a participant's transfusion burden does not fall into either the LTB or HTB
category, as defined per IWG 2018 criteria, then the transfusion burden will be
categorized based on their transfusion history in the 16-week period before
administration of the first dose of study drug.
4. Pretransfusion Hb concentration available for a minimum of 2 and at least half (50%)
of the transfusions received in the 16-week period before administration of the
first dose of study drug
5. A Hb concentration <10.0 g/dL during the 4-week Screening Period;
6. Up to 2 prior therapies including erythropoiesis-stimulating agents (ESAs) (eg,
erythropoietin [EPO], EPO + granulocyte colony-stimulating factor [G-CSF]) and/or
luspatercept;
7. ECOG Performance Status score of 0, 1, or 2;
8. If taking iron chelation therapy, the iron chelation therapy dose must have been
stable and started ≥56 days before administration of the first dose of study drug;
9. WOCBP must be abstinent of sexual activities that may result in pregnancy as part of
their usual lifestyle or agree to use a highly effective, from the time of providing
informed consent throughout the study and for 28 days after the last dose of study
drug; if the highly effective method of contraception is hormonal contraception,
then an acceptable barrier method must be used. Men with partners who are WOCBP must
be abstinent of sexual activities that may result in pregnancy as part of their
usual lifestyle or agree to use a condom from the time of providing informed consent
throughout the study and for 28 days after the last dose of study drug;
10. Written informed consent from the participant before any study-related procedures
are conducted and willing to comply with all study procedures for the duration of
the study.
Exclusion Criteria:
Phase 2a
1. Known history of acute myeloid leukemia (AML);
2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical
injury or treatment with chemotherapy and/or radiation for other diseases;
3. Prior exposure to a pyruvate kinase activator and/or disease-modifying agents for
underlying MDS:
- Immunomodulatory drugs (IMiDs) such as lenalidomide; at the Investigator's
discretion and in consultation with the Medical Monitor, participants who
received ≤1 week of treatment with IMiDs may not be excluded, provided their
last dose was ≥8 weeks before administration of the first dose of study drug
- Hypomethylating agents (HMAs); at the Investigator's discretion and in
consultation with the Medical Monitor, participants who received ≤2 doses of
HMAs may not be excluded, provided that their last dose was ≥8 weeks before
administration of the first dose of study drug
- Isocitrate dehydrogenase (IDH) inhibitors
- Immunosuppressive therapy (IST)
- Allogeneic or autologous stem cell transplant;
4. Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with
ESAs±G-CSF must have been stopped for ≥28 days before administration of the first
dose of study drug; treatment with luspatercept must have been stopped for ≥65 days
before administration of the first dose of study drug;
5. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months
before providing informed consent, including but not limited to:
- New York Heart Association Class III or IV heart failure or clinically
significant dysrhythmia
- Myocardial infarction, unstable angina pectoris, or unstable hypertension; high
risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous
thrombosis; or pulmonary or arterial embolism
- Heart rate-corrected QT interval using Fridericia's method of ≥470 milliseconds
for female participants and ≥450 milliseconds for male participants, except for
right or left bundle branch block
- Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided
heart failure, and radiographic pulmonary fibrosis >50%
- Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated;
6. History of hepatobiliary disorders, as defined by:
- Serum aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN)
(unless due to hemolysis and/or hepatic iron deposition) and alanine
aminotransferase (ALT) >2.5 × ULN (unless due to hepatic iron deposition)
- Serum bilirubin >ULN, if the elevation is associated with clinically
symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or
hepatocellular disease;
7. Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45
milliliters per minute (mL/min)/1.73 m^2;
8. Active infection requiring systemic antimicrobial therapy at the time of providing
informed consent. If antimicrobial therapy is required during the Screening Period,
screening procedures should not be performed while antimicrobial therapy is being
administered, and the last dose of antimicrobial therapy must be administered ≥7
days before administration of the first dose of study drug;
9. Major surgery within 12 weeks before administration of the first dose of study drug.
Participants must have completely recovered from any previous surgery before
administration of the first dose of study drug;
10. For any malignancy except MDS: History of malignancy (active or treated) ≤5 years
before providing informed consent for nonmelanomatous skin cancer in situ, cervical
carcinoma in situ, or breast carcinoma in situ;
11. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV
infection, or positive test for hepatitis B surface antigen (HBsAg);
12. Positive test for HIV-1 Ab or HIV-2 Ab;
13. Absolute neutrophil count (ANC) <500/microliter (μL) (0.5 × 10^9/L);
14. Platelet count ≤75,000/μL during Screening (75 × 10^9/L) platelet transfusions
within 28 days before Screening or during Screening;
15. Nonfasting triglyceride concentration >500 mg/dL;
16. Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for ≥5 days
or a time frame equivalent to 5 half-lives (whichever is longer) before
administration of the first dose of study drug;
17. Current enrollment or past participation (within 4 weeks or a time frame equivalent
to 5 half-lives of the investigational study drug before administration of the first
dose of study drug or, whichever is longer) in any other clinical study involving an
investigational treatment or device;
18. Known allergy to tebapivat or its excipients;
19. Pregnant or breastfeeding;
20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data. Also excluded are:
- Participants who are institutionalized by regulatory or court order;
- Participants with any condition(s) that could create undue influence (including
but not limited to incarceration, involuntary psychiatric confinement, and
financial or familial affiliation with the Investigator or Sponsor).
Phase 2b
1. Known history of AML;
2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical
injury or treatment with chemotherapy and/or radiation for other diseases;
3. Prior exposure to a pyruvate kinase activator, including exposure to tebapivat in
the Phase 2a part of this study, and/or disease-modifying agents for underlying MDS:
- Imetelstat; at the Investigator's discretion and in consultation with the
Medical Monitor, participants who received ≤2 doses of imetelstat may not be
excluded, provided that their last dose was ≥8 weeks before administration of
the first dose of study drug
- IMiDs such as lenalidomide; at the Investigator's discretion and in
consultation with the Medical Monitor, participants who received ≤1 week of
treatment with IMiDs may not be excluded, provided their last dose was ≥8 weeks
before administration of the first dose of study drug
- HMAs; at the Investigator's discretion and in consultation with the Medical
Monitor, participants who received ≤2 doses of HMAs may not be excluded,
provided that their last dose was ≥8 weeks before administration of the first
dose of study drug
- IDH inhibitors
- IST
- Allogeneic or autologous stem cell transplant;
4. Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with
ESAs±G-CSF must have been stopped for ≥28 days before administration of the first
dose of study drug; treatment with luspatercept must have been stopped for ≥65 days
before administration of the first dose of study drug;
5. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months
before providing informed consent, including but not limited to:
- New York Heart Association Class III or IV heart failure or clinically
significant dysrhythmia
- Myocardial infarction, unstable angina pectoris, or unstable hypertension; high
risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous
thrombosis; or pulmonary or arterial embolism
- Heart rate-corrected QT interval using Fridericia's method of ≥470 milliseconds
for female participants and ≥450 milliseconds for male participants, except for
right or left bundle branch block
- Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided
heart failure, and radiographic pulmonary fibrosis >50%
- Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated
6. History of hepatobiliary disorders, as defined by:
- Serum AST >2.5 × ULN (unless due to hemolysis and/or hepatic iron deposition)
and ALT >2.5 × ULN (unless due to hepatic iron deposition)
- Serum bilirubin >ULN, if the elevation is associated with clinically
symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or
hepatocellular disease
7. Renal dysfunction, as defined by an eGFR <45 mL/min/1.73 m^2;
8. Active infection requiring systemic antimicrobial therapy at the time of providing
informed consent. If antimicrobial therapy is required during the Screening Period,
screening procedures should not be performed while antimicrobial therapy is being
administered, and the last dose of antimicrobial therapy must be administered ≥7
days before administration of the first dose of study drug;
9. Major surgery within 12 weeks before administration of the first dose of study drug.
Participants must have completely recovered from any previous surgery before
administration of the first dose of study drug;
10. For any malignancy except MDS: History of malignancy (active or treated) ≤5 years
before providing informed consent, except for nonmelanomatous skin cancer in situ,
cervical carcinoma in situ, or breast carcinoma in situ.;
11. Positive test for HCV Ab with evidence of active HCV infection, or positive test for
HBsAg;
12. Positive test for HIV-1 Ab or HIV-2 Ab;
13. ANC <500/μL (0.5 × 10^9/L);
14. Platelet count < 75,000/μL (75 × 10^9 /L) during Screening; platelet transfusions
within 28 days before Screening or during Screening;
15. Nonfasting triglyceride concentration >500 mg/dL;
16. Receiving inhibitors of P-gp that have not been stopped for ≥5 days or a time frame
equivalent to 5 half-lives (whichever is longer) beforeadministration of the first
dose of study drug;
17. Current enrollment or past participation (within 4 weeks or a time frame equivalent
to 5 half-lives of the investigational study drug before administration of the first
dose of study drug or, whichever is longer) in any other clinical study involving an
investigational treatment or device;
18. Known allergy to tebapivat or its excipients;
19. Pregnant or breastfeeding;
20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data. Also excluded are:
- Participants who are institutionalized by regulatory or court order
- Participants with any condition(s) that could create undue influence (including
but not limited to incarceration, involuntary psychiatric confinement, and
financial or familial affiliation with the Investigator or Sponsor).
21. Known clinically significant anemia due to iron, vitamin B12, or folate
deficiencies, autoimmune or hereditary hemolytic anemia, hypothyroidism, or any type
of known clinically significant bleeding.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Innovative Clinical Research Institute Whittier
Address:
City:
Lakewood
Zip:
90805
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
David Geffen School of Medicine at UCLA
Address:
City:
Los Angeles
Zip:
90024
Country:
United States
Status:
Recruiting
Facility:
Name:
Emad Ibrahim, MD, Inc.
Address:
City:
Redlands
Zip:
92373
Country:
United States
Status:
Recruiting
Facility:
Name:
Smilow Cancer Hospital at Yale New Haven
Address:
City:
New Haven
Zip:
06510
Country:
United States
Status:
Recruiting
Facility:
Name:
Mayo Clinic Jacksonville - PPDS
Address:
City:
Jacksonville
Zip:
32224
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Edward H. Kaplan MD & Associates
Address:
City:
Skokie
Zip:
60076
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Washington University School of Medicine
Address:
City:
Saint Louis
Zip:
63110
Country:
United States
Status:
Completed
Facility:
Name:
Memorial Sloan Kettering Cancer Center
Address:
City:
Long Island City
Zip:
11101
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Duke Adult Blood and Marrow Clinic
Address:
City:
Durham
Zip:
27705
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Monash Health, Monash Medical Centre
Address:
City:
Clayton
Zip:
3168
Country:
Australia
Status:
Recruiting
Facility:
Name:
Ordensklinikum Linz GmbH Elisabethinen
Address:
City:
Linz
Zip:
4020
Country:
Austria
Status:
Completed
Facility:
Name:
Fakultni nemocnice Ostrava
Address:
City:
Ostrava
Zip:
708 52
Country:
Czechia
Status:
Completed
Facility:
Name:
Hôpital de La Conception
Address:
City:
Marseille
Zip:
13010
Country:
France
Status:
Recruiting
Facility:
Name:
CHU Angers
Address:
City:
Angers
Zip:
49933
Country:
France
Status:
Recruiting
Facility:
Name:
CHRU Lille
Address:
City:
Lille
Zip:
59037
Country:
France
Status:
Active, not recruiting
Facility:
Name:
Hôpital Saint Louis
Address:
City:
Paris
Zip:
75475
Country:
France
Status:
Recruiting
Facility:
Name:
Medizinische Hochschule Hannover
Address:
City:
Hannover
Zip:
30625
Country:
Germany
Status:
Active, not recruiting
Facility:
Name:
Universitatsklinikum Dusseldorf
Address:
City:
Düsseldorf
Zip:
40225
Country:
Germany
Status:
Active, not recruiting
Facility:
Name:
Universitatsklinikum Leipzig
Address:
City:
Leipzig
Zip:
04103
Country:
Germany
Status:
Active, not recruiting
Facility:
Name:
University Hospital of Alexandroupolis
Address:
City:
Alexandroupolis
Country:
Greece
Status:
Active, not recruiting
Facility:
Name:
Attikon University General Hospital
Address:
City:
Athens
Country:
Greece
Status:
Recruiting
Facility:
Name:
University General Hospital of Patras
Address:
City:
Patras
Country:
Greece
Status:
Active, not recruiting
Facility:
Name:
Hippokration Hospital
Address:
City:
Thessaloniki
Country:
Greece
Status:
Recruiting
Facility:
Name:
Shaare Zedek Medical Center
Address:
City:
Jerusalem
Zip:
9103102
Country:
Israel
Status:
Active, not recruiting
Facility:
Name:
Tel Aviv Sourasky Medical Center PPDS
Address:
City:
Tel Aviv
Country:
Israel
Status:
Active, not recruiting
Facility:
Name:
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Address:
City:
Milano
Country:
Italy
Status:
Recruiting
Facility:
Name:
Fondazione IRCCS Policlinico San Matteo di Pavia
Address:
City:
Pavia
Country:
Italy
Status:
Recruiting
Facility:
Name:
Istituto Clinico Humanitas
Address:
City:
Rozzano
Country:
Italy
Status:
Recruiting
Facility:
Name:
Azienda Ospedaliera Ordine Mauriziano di Torino
Address:
City:
Torino
Country:
Italy
Status:
Recruiting
Facility:
Name:
Fondazione PTV Policlinico Tor Vergata
Address:
City:
Roma
Country:
Italy
Status:
Recruiting
Facility:
Name:
Kyungpook National University Hospital
Address:
City:
Daegu
Zip:
41944
Country:
Korea, Republic of
Status:
Active, not recruiting
Facility:
Name:
Asan Medical Center - PPDS
Address:
City:
Seoul
Zip:
05505
Country:
Korea, Republic of
Status:
Active, not recruiting
Facility:
Name:
The Catholic University of Korea, Seoul St. Mary's Hospital
Address:
City:
Seoul
Country:
Korea, Republic of
Status:
Active, not recruiting
Facility:
Name:
MTZ Clinical Research Powered by PRATIA - PPDS
Address:
City:
Warszawa
Country:
Poland
Status:
Active, not recruiting
Facility:
Name:
Pratia Onkologia Katowice - PRATIA - PPDS
Address:
City:
Katowice
Country:
Poland
Status:
Active, not recruiting
Facility:
Name:
SPZOZ MiSWiA z Warminsko-Mazurskim Centrum Onkologii w Olsztynie
Address:
City:
Olsztyn
Country:
Poland
Status:
Active, not recruiting
Facility:
Name:
C.H. Regional Reina Sofia - PPDS
Address:
City:
Cordoba
Zip:
14004
Country:
Spain
Status:
Active, not recruiting
Facility:
Name:
Hospital Universitario La Paz - PPDS
Address:
City:
Madrid
Zip:
28046
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario HM Sanchinarro - CIOCC
Address:
City:
Madrid
Zip:
28050
Country:
Spain
Status:
Recruiting
Facility:
Name:
Complejo Asistencial Universitario de Salamanca - H. Clinico
Address:
City:
Salamanca
Zip:
37007
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Virgen del Rocio - PPDS
Address:
City:
Sevilla
Zip:
41013
Country:
Spain
Status:
Recruiting
Facility:
Name:
Aberdeen Royal Infirmary - PPDS
Address:
City:
Aberdeen
Zip:
AB25 2ZN
Country:
United Kingdom
Status:
Active, not recruiting
Facility:
Name:
Western General Hospital Edinburgh - PPDS
Address:
City:
Edinburgh
Zip:
EH24 2XU
Country:
United Kingdom
Status:
Active, not recruiting
Facility:
Name:
Kings College Hospital
Address:
City:
London
Zip:
SE5 9RS
Country:
United Kingdom
Status:
Recruiting
Facility:
Name:
Churchill Hospital-NHS Oxford
Address:
City:
Oxford
Zip:
OX3 7LE
Country:
United Kingdom
Status:
Recruiting
Start date:
November 7, 2022
Completion date:
November 2028
Lead sponsor:
Agency:
Agios Pharmaceuticals, Inc.
Agency class:
Industry
Source:
Agios Pharmaceuticals, Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05490446
