A Phase 3, multicenter, open label, randomized, non-comparative two-arm study of ivosidenib monotherapy (IVO) and azacitidine monotherapy (AZA) in adult patients with hypomethylating agent (HMA) naive myelodysplastic syndromes (MDS) with an IDH1 mutation (PyramIDH study).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

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

8 May 2025 → ongoing

Decision date (initial)

2024-12-05

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ADIR France · Laboratorios Servier, S.L

External identifiers

EU CT number

2023-510155-37-00

ClinicalTrials.gov

NCT06465953

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacoeconomic, Efficacy, Others, Safety, Pharmacodynamic, Pharmacokinetic

To assess the efficacy of IVO monotherapy in participants with HMA naive MDS with an IDH1m

Secondary objectives 4

1. To assess the efficacy of IVO monotherapy in participants with HMA naive MDS with an IDH1m.
2. To assess the efficacy of IVO monotherapy in participants with HMA naive MDS based on QOL and health economic outcome measures
3. To evaluate the PK and PD of ivosidenib administered as monotherapy
4. To assess the safety and tolerability of IVO in participants with HMA naive MDS

Conditions and MedDRA coding

Hypomethylating agent (HMA) naive myelodysplastic syndromes Myelodysplastic Symdrome (MDS)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Servier’s Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. Researchers can ask for a study protocol, patient-level and/or study-level clinical study data including clinical study reports. They can ask for all interventional CTs in patients: - Submitted for new medicines and new indications approved after 1 January 2014 in the EEA or the US. -Where Servier or an affiliate are the MAH. The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered within this scope. In addition, Servier’s data sharing policy includes all interventional CTs in patients: - sponsored by Servier, - with a first patient enrolled as of 1 January 2004 onwards, - for a New Chemical Entity or a New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any MA approval.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Diagnosis of HMA naive IDH1 R132 mutated MDS defined according to World Health Organization (WHO) criteria (5th edition): - Moderate high, high and very high-risk MDS per IPSS-M score will be eligible regardless of blood counts and with blast counts 0-19%. - Low and moderate low-risk MDS per IPSS-M score must: o Have cytopenias related to MDS, defined as: <100 platelets/μL, or absolute neutrophil count (ANC) <1000/mm3, or Hgb <10g/dL AND o Have a blast count between 5-19% AND o Be eligible for HMA therapy (very low risk participants are to be excluded).
2. Locally or centrally confirmed IDH1 R132 C/G/H/L/S mutation.

Exclusion criteria 2

1. Received prior anticancer/disease modifying treatment for MDS (including HMA’s, cytotoxic chemotherapy, investigational agents, bcl-2 inhibitor based-regimens, hematopoietic stem cell transplant (HSCT), IDH1 inhibitors). For LR-MDS patients, prior treatment with growth factors, luspatercept, lenalidomide, and imetelstat are allowed.
2. > 20% blasts by morphology or immunohistochemistry on screening bone marrow aspirate.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete remission (CR) + Partial remission (PR) by 4 months as per IWG 2006 criteria.

Secondary endpoints 18

1. Overall Response (OR) rate per IWG 2023 criteria defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI).
2. Event-free survival (EFS) defined as the date of randomization to the date of first documented confirmed relapse/progression/death, whichever occurs first.
3. Overall Survival (OS) defined as the time from randomization to the date of death due to any cause. Participants who are alive at the analysis cutoff date will be censored at the date they were last known to be alive.
4. Duration of CR and PR among participants who achieve CR + PR per IWG 2006 criteria.
5. Time to CR and PR defined as time from the date of the randomization to the date of CR+PR, among participants who achieve CR+PR based on IWG 2006 Response Criteria.
6. Acute myeloid leukemia (AML) transformation rate
7. Time to transfusion independence (TTTI) defined as time from date of randomization to date transfusion independence (TI) is first observed (Day 1 of a ≥ 56 days period without a transfusion), among participants who are baseline transfusion dependent and have achieved post-baseline TI. In the event a participant had more than one ≥ 56-day period, which met TI criteria, the earliest period will be used in analysis.
8. Duration of transfusion independence (DOTI) among participants who have achieved post-baseline TI, DOTI will be calculated as the time from the date TI is first observed (Day 1 of a ≥ 56-day period without a transfusion) until the day before the participants had a subsequent transfusion.
9. Transfusion independence rate
10. Quality of Life in Myelodysplasia Scale (QUALMS) scores range from 0 to 100, with a higher score representing a better QOL.
11. Change from baseline in health economic outcomes measures based on EQ-5D-5L score. Health economic outcomes measures as assessed by the 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) scores range from 5 to 25 with a higher number representing a worse health status.
12. Number of participants who proceed to hematopoietic stem cell transplantation (HSCT).
13. Ivosidenib plasma concentration and 2-HG plasma concentrations for participants receiving Ivosidenib monotherapy.
14. Number of participants achieving CR and PR by 6 months as per IWG 2006 criteria.
15. Number of participants achieving CR and PR by 6 months as per IWG 2023 criteria.
16. Number of participants achieving CR and PR by 4 months as per IWG 2023 criteria.
17. Number of adverse events (AEs) and serious adverse events (SAEs).
18. Health economic outcomes measures as assessed by the 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) scores range from 5 to 25 with a higher number representing a worse health status.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 10

Locations

5 EU/EEA countries · 28 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 46 files

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

Application history

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