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)

Overview

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Number of participants achieving CR and PR by 4 months [Time frame: Through 4 months after starting treatment]

Secondary outcome measures (12)

• Overall Response (OR) rate per IWG 2023 criteria [Time frame: Through the end of the study (approximately 4 years)]
• Event-free survival (EFS) [Time frame: Through the end of the study (approximately 4 years)]
• Overall Survival (OS) [Time frame: Through the end of the study (approximately 4 years)]
• Duration of CR and PR [Time frame: Through the end of the study (approximately 4 years)]
• Time to CR and PR [Time frame: Through the end of the study (approximately 4 years)]
• Acute myeloid leukemia (AML) transformation rate [Time frame: Through the end of the study (approximately 4 years)]
• Time to transfusion independence (TTTI) [Time frame: Through the end of the study (approximately 4 years)]
• Duration of transfusion independence (DOTI) [Time frame: Through the end of the study (approximately 4 years)]
• Transfusion independence rate [Time frame: Through the end of the study (approximately 4 years)]
• 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)]
• 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)]
• Number of participants who proceed to hematopoietic stem cell transplantation (HSCT) [Time frame: Through the end of the study (approximately 4 years)]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 9 centers

• Presbyterian / St. Luke'S Medical Center — Denver
• University of Chicago, Duchossois Center for Advanced Medicine (DCAM) — Chicago
• Massachusetts General Hospital — Boston
• MSKCC — New York
• Unc Lineberger Comprehensive Cancer Center — Chapel Hill
• Ohio State University Comprehensive Cancer Center — Columbus
• Oncology Associates of Oregon — Eugene
• University of Texas UT Southwestern Comprehensive Cancer Center — Dallas
• … and 1 more center

Brazil · 8 centers

• Liga Paranaense de Combate ao Câncer - Hospital Erasto Gaertner — Curitiba
• Centro de Pesquisa Clínica - Hospital Nove de Julho — São Paulo
• Real E Benemérita Associação Portuguesa de São Paulo — São Paulo
• Hospital das Clínicas da Faculdade de Medicina da USP — São Paulo
• Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein — São Paulo
• Casa de Saúde Santa Marcelina — São Paulo
• Centro de Pesquisas Clínicas da Fundação Doutor Amaral Carvalho — São Paulo
• Instituto Nacional do Câncer — São Paulo

Italy · 7 centers

• Azienda Ospedaliero Universitaria Delle Marche — Ancona
• Istituto Di Ematologia "Lorenzo E Ariosto Seragnoli" - Policlinico Di S. Orsola — Bologna
• Azienda Ospedaliero-Universitaria Careggi — Florence
• Humanitas Research Hospital (Istituto Clinico Humanitas) — Milan
• Fondazione I.R.C.C.S. Policlinico San Matteo — Pavia
• Dipartimento Di Biomedicina E Prevenzione - Universita Degli Studi Di Roma "Tor Vergata" — Roma
• Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino - Presidio — Torino

Spain · 7 centers

• Institut Catala D' Oncologia — Badalona
• H. Valle de Hebron — Barcelona
• Clinica Universitaria de Navarra (Madrid) — Madrid
• Clinica Universitaria de Navarra (Pamplona) — Pamplona
• Hospital Clinico Universitario de Salamanca — Salamanca
• Hospital Universitario Virgen de La Macarena — Seville
• H. Universitario La Fe — Valencia

Australia · 6 centers

• Royal Adelaide Hospital — Adelaide
• Monash Health — Clayton
• Northern Health — Epping
• Liverpool Hospital — Liverpool
• Sir Charles Gairdner Hospital — Nedlands
• Calvary Mater Newcastle — Waratah

France · 6 centers

• Chu Nantes-Hotel Dieu — Nantes
• Chu de Nice - Hôpital L'Archet 1 — Nice
• Hopital Saint Louis — Paris
• Chu Bordeaux, Hopital Du Haut Leveque — Pessac
• Institut Universitaire Du Cancer Toulouse-Oncopole — Toulouse
• Chu Brabois — Vandœuvre-lès-Nancy

Japan · 6 centers

• University of Fukui Hospital — Yoshida-gun
• Kyushu University Hospital — Higashi-ku, Fukuoka-city, Fukuoka
• Japanese Red Cross Society Himeji Hospital — Himeji-city, Hyogo
• Tokai University Hospital — Isehara-city, Kanagawa
• Japanese Red Cross Musashino Hospital — Musashino-city, Tokyo
• Kitasato University Hospital — Sagamihara

United Kingdom · 6 centers

• Western General Hospital — Edinburgh
• St James' University Hospital — Leeds
• University College London Hospital — London
• Kings College Hospital — London
• Churchill Hospital — Oxford
• Torbay Hospital — Torquay

Germany · 5 centers

• Universitatsklinikum Dresden Carl Gustav Carus — Dresden
• Marien Hospital Duesseldorf — Düsseldorf
• Universitaetsmedizin Goettingen (Umg) — Göttingen
• Universitaetsklinikum Leipzig — Leipzig
• Tum Klinikum Rechts Der Isar — Munich

Netherlands · 2 centers

• Umc Amsterdam - Vumc — Amsterdam
• Umc Groningen — Groningen

Identifiers

NCT: NCT06465953 · S095031-178 · 2023-510155-37

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗