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NCT Number: NCT06465953

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

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.

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Key information

Conditions

Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS) Bone Marrow Diseases Hematologic Diseases Hemic and Lymphatic Diseases Myelodysplastic Syndromes Myelodysplastic Syndromes (MDS)

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Royal Adelaide Hospital, Adelaide, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Ivosidenib

Drug

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.

Azacitidine

Drug

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.

Primary outcomes

  1. Number of participants achieving CR and PR by 4 months

    Time frame: Through 4 months after starting treatment

    Complete remission (CR) or Partial remission (PR) as per International Working Group (IWG) 2006 criteria

Secondary outcomes

  1. Overall Response (OR) rate per IWG 2023 criteria

    Time frame: Through the end of the study (approximately 4 years)

    Defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI)

  2. Event-free survival (EFS)

    Time frame: Through the end of the study (approximately 4 years)

    Defined as the date of randomization to the date of first documented confirmed relapse /progression /death, whichever occurs first

  3. Overall Survival (OS)

    Time frame: Through the end of the study (approximately 4 years)

    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

    Time frame: Through the end of the study (approximately 4 years)

    Among participants who achieved CR+PR per IWG 2006 criteria

  5. Time to CR and PR

    Time frame: Through the end of the study (approximately 4 years)

    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

    Time frame: Through the end of the study (approximately 4 years)

  7. Time to transfusion independence (TTTI)

    Time frame: Through the end of the study (approximately 4 years)

    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)

    Time frame: Through the end of the study (approximately 4 years)

    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

    Time frame: Through the end of the study (approximately 4 years)

  10. Change from baseline in Quality of life (QOL) based on the QUALMS score

    Time frame: Through the Event Free Survival Follow up (approximately 4 years)

    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

    Time frame: Through the Event Free Survival Follow up (approximately 4 years)

    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)

    Time frame: Through the end of the study (approximately 4 years)

  13. Ivosidenib plasma concentrations

    Time frame: Through Cycle 22 (each cycle is 28 days)

    For participants receiving ivosidenib monotherapy

  14. 2-HG plasma concentrations

    Time frame: Through Cycle 22 (each cycle is 28 days)

    For participants receiving ivosidenib monotherapy

  15. Number of participants achieving CR and PR by 6 months as per IWG 2006 criteria

    Time frame: Through 6 months after starting treatment

  16. Number of participants achieving CR and PR by 6 months as per IWG 2023 criteria

    Time frame: Through 6 months after starting treatment

  17. Number of participants achieving CR and PR by 4 months as per IWG 2023 criteria

    Time frame: Through 4 months after starting treatment

  18. Number of adverse events (AEs) and serious adverse events (SAEs)

    Time frame: Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment)

Study contacts

Contact information is provided by the study sponsor or research team.

Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department

CONTACT

[email protected]

+33 1 55 72 60 00

Sponsors and collaborators

Lead sponsor

Institut de Recherches Internationales Servier

Other

Collaborators

  • Servier Bio-Innovation LLC

Registry information

Official study title

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)

Acronym: PyramIDH

Important dates

Study start
2024
Primary completion
2027
Study completion
2028
First posted
Jun 20, 2024
Registry last updated
May 11, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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