Clinical trial NCT06465953: Ivosidenib (IVO) Monotherapy and Azacitidine (AZA) Monotherapy in Patients With Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS) With an IDH1 Mutation
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS)
Myelodysplastic Syndromes (MDS)
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: Servier Bio-Innovation LLC
First posted: 2024-06-20
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of participants achieving CR and PR at 4 months
timeFrame: Through 4 months after starting treatment
Secondary outcomes:
measure: Overall Response (OR) rate per IWG 2023 criteria
timeFrame: Through the end of the study (approximately 4 years)
measure: Event-free survival (EFS)
timeFrame: Through the end of the study (approximately 4 years)
measure: Overall Survival (OS)
timeFrame: Through the end of the study (approximately 4 years)
measure: Duration of CR and PR
timeFrame: Through the end of the study (approximately 4 years)
measure: Time to CR and PR
timeFrame: Through the end of the study (approximately 4 years)
measure: Acute myeloid leukemia (AML) transformation rate
timeFrame: Through the end of the study (approximately 4 years)
measure: Time to transfusion independence (TTTI)
timeFrame: Through the end of the study (approximately 4 years)
measure: Duration of transfusion independence (DOTI)
timeFrame: Through the end of the study (approximately 4 years)
measure: Transfusion independence rate
timeFrame: Through the end of the study (approximately 4 years)
measure: Change from baseline in Quality of life (QOL) based on the QUALMS score
timeFrame: Through the Event Free Survival Follow up (approximately 4 years)
measure: Change from baseline in health economic outcomes measures based on EQ-5D-5L score
timeFrame: Through the Event Free Survival Follow up (approximately 4 years)
measure: Number of participants who proceed to hematopoietic stem cell transplantation (HSCT)
timeFrame: Through the end of the study (approximately 4 years)
measure: Ivosidenib plasma concentrations
timeFrame: Through Cycle 22 (each cycle is 28 days)
measure: 2-HG plasma concentrations
timeFrame: Through Cycle 22 (each cycle is 28 days)
measure: Number of participants achieving CR and PR at 6 months as per IWG 2006 criteria
timeFrame: Through 6 months after starting treatment
measure: Number of participants achieving CR and PR at 6 months as per IWG 2023 criteria
timeFrame: Through 6 months after starting treatment
measure: Number of participants achieving CR and PR at 4 months as per IWG 2023 criteria
timeFrame: Through 4 months after starting treatment
measure: Number of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago, Duchossois Center for Advanced Medicine (DCAM)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: MSKCC
state: New York
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Dallas
country: United States
facility: University of Texas UT Southwestern Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Centre
state: Texas
city: Clayton
country: Australia
facility: Monash Health
city: Epping
country: Australia
facility: Northern Health
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
city: Yoshida-gun
country: Japan
facility: University of Fukui Hospital
state: Eiheiji-cho 670-8540 Himeji
city: Higashi-ku, Fukuoka-city, Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Himeji-city, Hyogo
country: Japan
facility: Japanese Red Cross Society Himeji Hospital
city: Isehara-city, Kanagawa
country: Japan
facility: Tokai University Hospital
city: Musashino-city, Tokyo
country: Japan
facility: Japanese Red Cross Musashino Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Leeds
country: United Kingdom
facility: St James' University Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Torquay
country: United Kingdom
facility: Torbay Hospital
Study officials:
References: