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

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.

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).

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.