A Phase 3b study to learn more about the safety and tolerability of ivosidenib in combination with azacitidine in adult patients newly diagnosed with IDH1m acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Servier Affaires Medicales

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Jun 2023 → ongoing

Decision date (initial)

2023-05-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Servier Affaires Medicales

External identifiers

EU CT number

2022-501709-11-00

ClinicalTrials.gov

NCT05907057

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacoeconomic, Efficacy, Pharmacogenomic

To assess the safety and tolerability of treatment with ivosidenib + azacitidine

Secondary objectives 4

1. To assess efficacy of ivosidenib + azacitidine according to local clinical practice
2. To assess the impact of treatment on health-related quality of life (QoL)
3. To assess the impact of treatment on healthcare resource utilization (HCRU) and costs
4. To assess IDH1m diagnostic pathway

Conditions and MedDRA coding

Isocitrate deshydrogenase1 mutation-positive (IDH1m) acute myeloid leukemia (AML)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Has previously untreated AML, defined according to the 2022 ELN Recommendations for AML or the International Consensus Classification of myeloid neoplasms and acute leukemia
2. Be ≥18 years of age and meet at least one of the following criteria defining ineligibility for IC: a. ≥75 years old b. ECOG PS =2 c. Any comorbidity that the Investigator judges to be incompatible with IC, including: i. Severe cardiac disorder ii. Severe pulmonary disorder iii. Creatinine clearance <45 mL/minute iv. Bilirubin >1.5 times upper limit of normal v. Any other comorbidity that the Investigator judges to be incompatible with IC as documented before study enrolment.
3. Has documented R132 IDH1m based on local biomolecular profiling method
4. Has an ECOG ≤2.
5. Has adequate hepatic function as evidenced by Child-Pugh class A or B
6. Has adequate renal function, as described in the protocol
7. Willing to voluntarily provide written, signed, and dated informed consent.

Exclusion criteria 13

1. Has received any prior treatment for AML with the exception of hydroxyurea or leukapheresis for white count control
2. Has extramedullary disease alone (i.e., no detectable bone marrow and no detectable peripheral blood AML)
3. Has previously received treatment for an antecedent hematologic disorder, including investigational agents, may not be enrolled until a washout period of ≥5 half-lives of the investigational or standard of care agent have elapsed since the last dose of that agent (Note: previous treatment with HMA for MDS or MDS/MPN is allowed)
4. Has received prior treatment with an IDH1 inhibitor
5. Has a known hypersensitivity to any of the components of ivosidenib or azacitidine
6. Is a woman who is pregnant or breastfeeding
7. Is taking known strong cytochrome P450 (CYP) 3A4 inducers, known moderate or strong inhibitors or known sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9 or CYP2C19 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications or unless the patient can be properly monitored during the study
8. Is taking P‑glycoprotein (P-gp) transporter-sensitive substrate medications or inhibitors unless they can be transferred to other medications or unless the patient can be properly monitored during the study, use of Dabigatran is strictly contra-indicated.
9. Has an active, uncontrolled, systemic fungal, bacterial, or viral infection (including human immunodeficiency virus [HIV], active hepatitis B (HBV), or hepatitis C virus [HCV]) without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
10. Has a prior history of malignancy other than MDS or myeloproliferative disorder under active treatment. However, a patient with the following history/concurrent conditions or similar indolent cancer are allowed to participate in the study: a. Basal or squamous cell carcinoma of the skin b. Carcinoma in situ of the cervix c. Carcinoma in situ of the breast d. Incidental histologic finding of prostate cancer
11. Has had significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke
12. Has dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs
13. Has immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, organ failure and/or disseminated intravascular coagulation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESIs), AEs leading to ivosidenib + azacytidine discontinuation, AEs leading to ivosidenib or azacitidine interruption, AEs leading to ivosidenib or azacitidine dose reduction, AEs leading to death • Clinical laboratory anomalies assessed as AEs • Patients requiring transfusion (platelet and RBC) and number of units transfused • Rate of infections

Secondary endpoints 4

1. • Event-free survival (EFS) • Complete remission (CR) • CR + CR with partial hematologic recovery (CRh) • CR + CR with incomplete hematologic recovery (CRi) • Duration of response (DOR) (overall and by response type) • Time to response (TTR) • Overall survival (OS) • Objective response (OR)
2. • Hematological Malignancy-Patient-Reported outcome (HM-PRO) • Family Reported Outcome Measure 16 (FROM-16) (for caregivers/family)
3. • 5 level EuroQol 5-dimensions (EQ-5D-5L) • Length of hospital stay (LOS) • Outpatient visits • Emergency room (ER) visits • Proportion of days at home
4. • Molecular profiling method • Time to results • Allele subtypes • Co-occurring mutation profiles

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Servier Affaires Medicales

Sponsor organisation

Servier Affaires Medicales

Address

35 Rue De Verdun

City

Suresnes Cedex

Postcode

92284

Country

France

Scientific contact point

Organisation

Servier Affaires Medicales

Contact name

Global Evidence Generation Manager

Public contact point

Organisation

Servier Affaires Medicales

Contact name

Global Evidence Generation Manager

Third parties 8

Locations

11 EU/EEA countries · 82 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 347 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications