study of the efficacy of treatment with AG-221 in patients with myelodysplastic syndrome and mutation IDH2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Groupe Francophone Des Myelodysplasies

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

6 Feb 2019 → ongoing

Decision date (initial)

2024-12-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Celgene/Bristol Myers Squibb (BMS)

External identifiers

EU CT number

2024-513858-29-01

EudraCT number

2018-001693-25

ClinicalTrials.gov

NCT03503409

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Cohorts A and B : To determine the response rate (CR+PR+ stable disease with HI according to IWG 2006 criteria) of the administration of AG221 in each group (A and B) of patients.
Cohort C : To determine the safety and tolerability of AG-221: We will use CTCAE Version 5 for evaluation of non-hematological toxicities

Secondary objectives 7

1. To determine the response rate (CR+PR+ + stable disease with HI according to IWG 2006 criteria) of the administration of AG221 in each group of patients with IDH2 mutation (Cohort C)
2. To determine the response duration, time to IPSS progression, and loss of RBC transfusion independence in responders
3. To determine the rate and interval to AML evolution
4. To determine overall survival
5. To identify prognostic and predictive factors of response, including IPSS-R, IPSS-karyotype and somatic mutations
6. To assess the evolution of IDH2 VAF on therapy
7. Safety

Conditions and MedDRA coding

myelodysplastic syndrome with IDH2 mutated

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Myelodysplastic syndrome according to WHO classification including non-proliferative AML up to 29% of BM blast
2. Age ≥ 18 years
3. Belonging to one of the following categories: 1. higher risk MDS (IPSS int-2, high) without response to azacitidine (CR,PR, stable disease with HI) after at least 6 cycles , or relapsing after a response but without overt progression (defined by at least doubling of marrow blasts, compared to pre azacitidine bone marrow, or AML progression beyond 30% blasts) 2. Untreated higher risk MDS (IPSS int-2, high) without life threatening cytopenia including ANC <500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom 3. Lower risk MDS with resistance or loss of response to a previous treatment with epoetin alpha/ beta (>=60000 U/w) or Darbopoetin (>=250 ug/w) given for at least 12 weeks and RBC transfusion requirement at least 2 U/8 weeks in the previous 16 weeks
4. Presence of IDH2 mutation in either blood or marrow prior to start of therapy
5. Normal renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance (Modification of diet in renal disease) (MDRD) ≥ 50 mL/min
6. France: Normal liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal / Germany: Normal liver function, defined by total bilirubin < 2.0 mg/dl (exception permitted in patients with Gilbert’s Syndrome) and transaminases less than 1.5 times the upper limit of normal
7. Adequate cardiac ejection fraction (>40%)
8. Patient is not known to be refractory to platelet transfusions
9. Written informed consent
10. Patient must understand and voluntarily sign consent form
11. Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
12. ECOG performance status 0-2 at the time of screening
13. Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles. • France: Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 120 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices. • Germany: Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent,during the study and for 365 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal) - progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system ( IUS) - bilateral tubal occlusion - vasectomised partner -sexual abstinence
14. Male patients must : - Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment. - Agree to learn about the procedures for preservation of sperm before starting treatment

Exclusion criteria 13

1. Severe infection or any other uncontrolled severe condition
2. Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months
3. Less than 14 days since prior treatment with growth factors (EPO, G-CSF).
4. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicity from any previous therapy
5. Subject has a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study
6. Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast
7. Patient already enrolled in another therapeutic trial of an investigational drug
8. France: Known HIV infection or active hepatitis B or C. / Germany: HIV infection or active hepatitis B or C (test prior to inclusion required)
9. Women who are or could become pregnant or who are currently breastfeeding
10. Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
11. Patient eligible for allogeneic stem cell transplantation
12. Known allergies to AG-221 or any of its excipients
13. No affiliation to a health insurance system

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall hematological response at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006) for cohort A and B; SAFETY FOR COHORT C

Secondary endpoints 8

1. Response duration and Time response
2. Time to IPSS and IPSS-R progression
3. Rate and time to AML evolution
4. Overall survival
5. Cytogenetic and molecular response
6. Prognostic factors of response, including IPSS-R, IPSS-karyotype and somatic mutations
7. Evolution of IDH2 VAF on therapy
8. Adverse events and toxicity as measured by NCI CTCAE 5

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Groupe Francophone Des Myelodysplasies

Sponsor organisation

Groupe Francophone Des Myelodysplasies

Address

Opital St Louis Hemato Seniors T4, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Lionel ADES

Public contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Lionel ADES

Locations

2 EU/EEA countries · 23 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 11 files

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

Application history

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