Ivosidenib (IVO) Monotherapy and Azacitidine (AZA) Monotherapy in Patients With Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS) With an IDH1 Mutation (PyramIDH)

A Phase 3, Multicenter, Open Label, Randomized, Non-comparative Two-arm Study of Ivosidenib (IVO) Monotherapy and Azacitidine (AZA) Monotherapy in Adult Patients With Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS) With an Isocitrate Dehydrogenase-1 (IDH1) Mutation (PyramIDH Study)

This study will enroll participants with myelodysplastic syndromes (MDS) with an Isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have not received treatment with a hypomethylating agent previously. Participants will be randomized to receive either ivosidenib (IVO) alone or azacitidine (AZA) alone. IVO will be administered daily throughout the 28-day treatment cycle and AZA will be administered for the first 7 days of each 28-day cycle. Study visits will be conducted every week during Cycle 1 (Days 1, 8, 15, and 22), and Day 1 of each cycle thereafter. After the last dose of treatment, participants will attend an safety follow-up visit and participants will be followed to assess overall survival. Study visits may include a bone marrow aspirate, physical exam, echocardiogram (ECHO), electrocardiogram (ECG), blood and urine analysis, and questionnaires.

Study Overview

• Status: Not yet recruiting
• Conditions: Myelodysplastic Syndromes (MDS); Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS)
• Intervention / Treatment: Drug: Ivosidenib; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department; Phone Number: +33 1 55 72 60 00; Email: scientificinformation@servier.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of HMA naive IDH1 R132 mutated MDS defined according to 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:
• Have cytopenias related to MDS, defined as: <100 platelets/microliter, or absolute neutrophil count (ANC) <1000/mm3, or hemoglobin <10g/dL AND
• Have a blast count between 5-19% AND
• Be eligible for HMA therapy (very low risk participants are to be excluded)
• Locally or centrally confirmed IDH1 R132 C/G/H/L/S mutation

Exclusion Criteria:

• 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.
• >20% blasts by morphology or immunohistochemistry on screening bone marrow aspirate/biopsy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ivosidenib monotherapy	Drug: Ivosidenib; Two 250 mg tablets, totaling 500 mg, administered orally once daily until disease relapse or progression, unacceptable toxicity, confirmed pregnancy, undergoing HSCT, death, withdrawal of consent, lost to follow-up, or Sponsor ending the study, whichever occurs first.
Experimental: Azacitidine monotherapy	Drug: Azacitidine; Azacitidine 75mg/m^2/day administered by subcutaneous (SC) or intravenous (IV) injection for 1 week (7 days) of each 4-week (28 day) treatment cycle until disease relapse or progression, unacceptable toxicity, confirmed pregnancy, undergoing HSCT, death, withdrawal of consent, lost to follow-up, or Sponsor ending the study, whichever occurs first.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants achieving CR and PR at 4 months	Complete remission (CR) or Partial remission (PR) as per International Working Group (IWG) 2006 criteria	Through 4 months after starting treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response (OR) rate per IWG 2023 criteria	Defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI)	Through the end of the study (approximately 4 years)
Event-free survival (EFS)	Defined as the date of randomization to the date of first documented confirmed relapse /progression /death, whichever occurs first	Through the end of the study (approximately 4 years)
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.	Through the end of the study (approximately 4 years)
Duration of CR and PR	Among participants who achieved CR+PR per IWG 2006 criteria	Through the end of the study (approximately 4 years)
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	Through the end of the study (approximately 4 years)
Acute myeloid leukemia (AML) transformation rate		Through the end of the study (approximately 4 years)
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.	Through the end of the study (approximately 4 years)
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.	Through the end of the study (approximately 4 years)
Transfusion independence rate		Through the end of the study (approximately 4 years)
Change from baseline in Quality of life (QOL) based on the QUALMS score	Quality of Life in Myelodysplasia Scale (QUALMS) scores range from 0 to 100, with a higher score representing a better QOL.	Through the Event Free Survival Follow up (approximately 4 years)
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.	Through the Event Free Survival Follow up (approximately 4 years)
Number of participants who proceed to hematopoietic stem cell transplantation (HSCT)		Through the end of the study (approximately 4 years)
Ivosidenib plasma concentrations	For participants receiving ivosidenib monotherapy	Through Cycle 22 (each cycle is 28 days)
2-HG plasma concentrations	For participants receiving ivosidenib monotherapy	Through Cycle 22 (each cycle is 28 days)
Number of participants achieving CR and PR at 6 months as per IWG 2006 criteria		Through 6 months after starting treatment
Number of participants achieving CR and PR at 6 months as per IWG 2023 criteria		Through 6 months after starting treatment
Number of participants achieving CR and PR at 4 months as per IWG 2023 criteria		Through 4 months after starting treatment
Number of adverse events (AEs) and serious adverse events (SAEs)		Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment)

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: Servier Bio-Innovation LLC

Study record dates

Study Major Dates

• Study Start (Estimated): December 30, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: June 14, 2024
• First Submitted That Met QC Criteria: June 14, 2024
• First Posted (Actual): June 20, 2024

Study Record Updates

• Last Update Posted (Actual): June 20, 2024
• Last Update Submitted That Met QC Criteria: June 14, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Ivosidenib
• Other Study ID Numbers: S095031-178; 2023-510155-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data. Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (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 for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorization in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No