Oral Decitabine Plus Ivosidenib as First Line for Older/Unfit Adult AML Patients (DECISIVO)

A Phase II, Multicentre, Open Label Clinical Trial Evaluating the Efficacy and Safety of Oral Decitabine Plus Ivosidenib in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia Older Than 60 Years Old and/or Who Are Ineligible for Standard Induction Chemotherapy

The goal of this clinical trial is to learn if the combination of oral decitabine plus ivosidenib works to treat naïve adult patients with acute myeloid leukemia (AML) with IDH1 R132 mutation older than 60 years old or those who are older than 18 years old with defined comorbidities that make them not suitable for standard induction therapy. The main objectives of this clinical trial are:

• Asses the Complete Remission (CR) and Complete Remission with incomplete marrow recovery (CRi) rates of this treatment.
• Determine the incidence and severity of all adverse events (AEs).

All participants will receive oral ivosidenib and oral decitabine in treatment cycles of 28 days until disease progression, lack of clinical benefit or the end of the study. Patients who achieve CR/CRi will be elegible to receive allogeneic stem cell transplantation.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia With Gene Mutations
• Intervention / Treatment: Drug: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET; Drug: Ivosidenib Oral Tablet; Drug: Hydroxyurea; Drug: Cytarabine; Procedure: Allogeneic stem cell transplantation

Detailed Description

A total of 50 participants will be assigned to the single treatment arm which will have treatment cycles of 28 days with Ivosidenib 500 mg/orally on Days 1-28 plus oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) on days 1-5.

Hydroxiurea or maximum 1 gram/sqm of cytarabine is allowed to control hyperleukocytosis during the screening period as well as during the first two cycles of induction.

Participants will continue their study treatment until documented disease progression per Investigator assessment, unacceptable toxicity, withdrawal of consent, the subject meets other protocol criteria for discontinuation or study completion (whichever occurs first).

Participants who are considered eligible for an allogeneic stem cell transplant after achieving CR/CRi will perform a pre-transplant visit into the study, collecting MRD stats and characteristics of transplant. They will be allowed to resume ivosidenib after day +60 of transplant. The post-transplant schedule can be administered for up to 2 years. If they do not resume ivosidenib they will perform end of trial visit (and if this is not possible the pre-transplant visit will be considered as en of trial visit).

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pau Montesinos; Phone Number: +34 96 1244925; Email: montesinos_pau@gva.es
• Study Contact Backup: Name: Juan José Lahuerta; Email: jjlahuerta@telefonica.net

Study Locations

• Spain
  • Albacete, Spain, 02006
    • Complejo Hospitalario de Albacete
  • Alicante, Spain
    • Hospital General Universitario Dr. Balmis
  • Burgos, Spain, 09006
    • Hospital Universitario de Burgos
  • Cáceres, Spain
    • Hospital San Pedro Alcántara
  • Córdoba, Spain, 14004
    • Complejo Hospitalario Regional Reina Sofía
  • Las Palmas, Spain
    • Hospital Universitario de Gran Canaria Doctor Negrin
  • Las Palmas de Gran Canaria, Spain
    • Hospital Universitario de Canarias
  • Lugo, Spain
    • Hospital Universitario Lucus Augusti
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain
    • H. 12 de Octubre
  • Madrid, Spain
    • Hospital Univeristario Ramón y Cajal
  • Málaga, Spain
    • Hospital Virgen de la Victoria
  • Seville, Spain
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain
    • Hospital Universitari i Politècnic La Fe
  • Valencia, Spain
    • H. Dr. Peset

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Morphological diagnosis of AML (WHO criteria 2022)
2. Newly diagnosed AML.
3. IDH1 R132 mutations (centrally assessed by PCR and NGS). A patient will be allowed to be included with local result after approval of the medical monitor.
4. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2 if ≥ 60 years of age, or 0 to 3 if ≥ 18 to 60 years.

5. Age ≥ 18 years with comorbidities contraindicating intensive chemotherapy; or age ≥ 60 years.

   • ≥ 60 years of age;

   • or ≥ 18 to 60 with at least one of the following co-morbidities:

     • ECOG Performance Status of 2 or 3;
     • Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable angina;
     • DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive;
     • Creatinine clearance ≥ 25 mL/min to < 50 ml/min
     • Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
     • Non active/controlled prior neoplastic disease
     • Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the PETHEMA medical monitor before study enrolment (e.g, prior MDS or MPS, high-risk cytogenetics)
6. Patients <70 years, with favorable risk AML according to ELN will be included only if they are not candidates to standard treatment with intensive chemotherapy.
7. Adequate renal function as demonstrated by a creatinine clearance ≥ 25 mL/min (calculated by the Cockcroft Gault formula).
8. Adequate liver function as demonstrated by: aspartate aminotransferase (AST) ≤ 5.0 × ULN, alanine aminotransferase (ALT) ≤ 5.0 × ULN, bilirubin ≤ 2.5 × ULN (unless considered to be due to leukemic disease, in which case it should be approved by the PETHEMA medical monitor).
9. Subject has a white blood cell count < 30 × 109/L (Hydroxyurea is permitted to meet this criterion)
10. Female subjects must be either postmenopausal OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control. Female subjects of childbearing potential must have negative results for pregnancy tests performed along the study (screening and every three cycles). A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
11. Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception.
12. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

Exclusion Criteria:

1. Subject has history of myeloproliferative neoplasm [MPN] with BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
2. Prior therapy for AML (except hydroxiurea).
3. Genetic diagnosis of acute promyelocytic leukemia.
4. Subject is known to be positive for HIV (HIV testing is not required.)
5. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required).
6. Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients that in the opinion of the investigator would adversely affect his/her participating in this study.
7. Any severe uncontrolled systemic infection.
8. Subject has a history of other malignancies within 1 year prior to study entry which is not controlled and/or requiring active therapy which may compromise the administration of IVO and oral decitabine.
9. Creatinine clearance <25 mL/min (calculated by the Cockcroft-Gault formula).
10. Inadequate liver function as demonstrated by AST or ALT > 5.0 × ULN, or bilirubin > 2.5 × ULN (unless considered to be due to leukemic disease, in which case it should be approved by the PETHEMA medical monitor)
11. Subject has a white blood cell count > 30 × 109/L that is not controlled using hydrea or 1 gr/sqm/day per 1 day of cytarabine.
12. Contraindications for IVO or oral decitabine according to the SmPC.
13. Patient has a heart rate-corrected QT interval using Fridericia's method QT for corrected heart rate (QTcF) ≥450 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (e.g., hypokalemia, family history of long QT interval syndrome). Patients with prolonged QTcF interval in the setting of bundle branch block may participate in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Decitabine+Ivosidenib; Participants will receive treatment cycles of 28 days with Ivosidenib 500 mg/orally on Days 1-28 plus oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) on days 1-5. Hydroxiurea or maximum 1 gram/sqm of cytarabine is allowed to control hyperleukocytosis during the screening period as well as during the first two cycles of induction. Participants who achieve CR/CRi can be submitted to allogeneic stem cell transplant and will be allowed to resume ivosidenib after day +60 of transplant. The post-transplant schedule can be administered for up to 2 years.

Drug: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET; Oral Decitabine (Decitabine/Cedazuridine 35 Mg-100 Mg) will be administerd on Days 1-5 of each treatment cycle; Drug: Ivosidenib Oral Tablet; Ivosidenib 500 mg/orally on Days 1-28 of each treatment cycle; Drug: Hydroxyurea; 0.5-6 gram/day orally during the screening period and the two first treatment cycles if hyperleukocytosis at diagnosis; Drug: Cytarabine; Maximum 1 gram/sqm/day during the screening period and the two first treatment cycles if hyperleukocytosis at diagnosis; Procedure: Allogeneic stem cell transplantation; Only for those participants achieving CR/CRi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of CR/CRi	To assess the rates of Complete Remission (CR) and Complete Remission with incomplete marrow recovery (CRi) of participants treated with Ivosidenib plus Decitabine	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate CR/CRi compared to historical cohort	To evaluate the CR (Complete Remission)/CRi (Complete Remission with incomplete marrow recovery) rates after 2, 3 and 6 cycles of Ivosidenib and oral Decitabine, and compare with a matched historical cohort.	3 years
OS compared to historical cohort	To assess OS (overall survival, measured as the number of days from the date of enrollment to the date of death, whatever the cause of death) and compare the median between Ivosidenib with oral Decitabine and a matched historical cohort.	3 years
EFS compared to historical cohort	To evaluate EFS (event-free survival, defined as the number of days from enrollment until the date of progressive disease, relapse from CR or CRi, failure to achieve CR or CRi, or death from any cause) and compare with a matched historical control cohort	3 years
Hematologic and non-hematologic toxicity and AE	Toxicity and adverse events (AE) will be recorded and evaluated to determine treatment safety. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.019.	3 years
Quality of CR	The quality of the Complete Remission (CR) will measured by the study of minimal residual disease percentages in the bone marrow using multiparametric flow cytometry and Next Generation Sequencing	3 years
Early mortality	To evaluate the mortality rate during the first 60 days of treatment	3 years

Collaborators and Investigators

• Sponsor: PETHEMA Foundation
• Investigators: Study Chair: Pau Montesinos, Hospital Universitari i Politèncic La Fe

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: March 27, 2026
• First Submitted That Met QC Criteria: March 27, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: AML; Decitabine; Ivosidenib; older adult; allogeneic stem cell transplant; unfit; IDH1 R132 mutation
• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Amides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Arabinonucleosides; Azacitidine; Urea; Decitabine; Cytarabine; Hydroxyurea; ivosidenib; cedazuridine
• Other Study ID Numbers: DECISIVO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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