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

Myelodysplastic Syndromes (MDS) Clinical Trial

— PyramIDH  

Official 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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06465953
• Other study ID #: S095031-178
• Secondary ID: 2023-510155-37
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: December 30, 2024
• Est. completion date: December 1, 2028

Study information

• Verified date: June 2024
• Source: Servier
• Contact: Institut de Recherches Internationales Servier (I.R.I.S.), Clini
• Phone: +33 1 55 72 60 00
• Email: scientificinformation[@]servier.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 48
• Est. completion date: December 1, 2028
• Est. primary completion date: November 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Myelodysplastic Syndromes (MDS)
• Preleukemia
• Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	Servier Bio-Innovation LLC

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	Duration of CR and PR	Among participants who achieved CR+PR per IWG 2006 criteria	Through the end of the study (approximately 4 years)
Secondary	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)
Secondary	Acute myeloid leukemia (AML) transformation rate		Through the end of the study (approximately 4 years)
Secondary	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)
Secondary	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)
Secondary	Transfusion independence rate		Through the end of the study (approximately 4 years)
Secondary	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)
Secondary	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)
Secondary	Number of participants who proceed to hematopoietic stem cell transplantation (HSCT)		Through the end of the study (approximately 4 years)
Secondary	Ivosidenib plasma concentrations	For participants receiving ivosidenib monotherapy	Through Cycle 22 (each cycle is 28 days)
Secondary	2-HG plasma concentrations	For participants receiving ivosidenib monotherapy	Through Cycle 22 (each cycle is 28 days)
Secondary	Number of participants achieving CR and PR at 6 months as per IWG 2006 criteria		Through 6 months after starting treatment
Secondary	Number of participants achieving CR and PR at 6 months as per IWG 2023 criteria		Through 6 months after starting treatment
Secondary	Number of participants achieving CR and PR at 4 months as per IWG 2023 criteria		Through 4 months after starting treatment
Secondary	Number of adverse events (AEs) and serious adverse events (SAEs)		Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment)