HOVON HO173 AML
Main info
- Identifier:
- HO173
- Sponsor:
- HOVON
- Working group party:
- Leukemia
- Age:
- >= 18
- Stage:
- 1st Line
- Included patients:
-
1(of 227)
- Active sites:
-
25(of 120)95 sites are pending
- Title:
Ivosidenib and azacitidine with or without venetoclax in adult patients with newly diagnosed IDH1-mMutated AML or MDS/AML considered ineligible for intensive chemotherapy
Timeline
News
Please note that the CTIS submission for the first wave countries took place on 18DEC2024.
The expected approval timeline is end of April 2025.
The first site is expected to be activated in July/August 2025.
Details
- Phase:
- Prospective randomized Phase III study
- Monitoring Type:
- Study Specific
- Objectives:
Primary objective
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, prolongs event-free survival (EFS) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
Secondary objectives
Key secondary objectives
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, prolongs overall survival (OS) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, increases the combined rate of CR and CR with partial hematologic recovery (CRh) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
Other secondary objectives
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, increases the rate of complete remission (CR) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To evaluate the impact of venetoclax, in combination with ivosidenib and azacitidine, on the combined rate of CR and CR with incomplete hematologic recovery (CRi) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, increases the rate of CR, CR/CRh and CR/CRi without measurable residual disease (CRMRD-, and CR/CRhMRD-, and CR/CRiMRD-) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, shortens the time to response (CR, CR/CRh or CR/CRi) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, prolongs duration of response (CR, CR/CRh or CR/CRi; DoR) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with venetoclax, in combination with ivosidenib and azacitidine, improves the transfusion independence rate (platelets and RBC) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To evaluate the pharmacokinetics of ivosidenib and venetoclax including plasma concentrations and PK parameters.
Explorative objectives
To evaluate the impact of venetoclax, in combination with ivosidenib and azacitidine, on quality of life, using EORTC QLQ-C30 and EQ-5D-5 in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To evaluate the impact of venetoclax, in combination with ivosidenib and azacitidine, on cumulative incidence of relapse (CIR) and death (CID) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To evaluate EFS, OS, DoR, and rates of CR, CR/CRh and CR/CRi by prognostic variables, including clinical variables (e.g., age at randomization, sex, ECOG performance status, white blood cell count), 2022 European LeukemiaNet (ELN) risk groups, and by specific AML genotypes in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To evaluate EFS, OS, rates of CR, CR/CRh, CR/CRi, CRMRD-, CR/CRhMRD-, CR/CRiMRD-, time to response, DoR, CIR, CID in adult patients with IDH1-mutated MDS/AML ineligible for intensive chemotherapy.
To evaluate transfusion independence rate (platelets and RBC) and safety objectives defined below in adult patients with IDH1-mutated MDS/AML ineligible for intensive chemotherapy.
To evaluate the pharmacodynamic effect of ivosidenib.
Safety objectives:
To assess safety of venetoclax, in combination with ivosidenib and azacitidine, in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy by evaluating incidence and severity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0.
To assess time to hematopoietic recovery (absolute neutrophil counts [ANC] ≥ 0.5 and ≥ 1.0 x 109/L; platelet counts ≥ 50 and ≥ 100 x 109/L) after each treatment cycle (but at least for each of the first 6 cycles) in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
To assess number of patients requiring blood transfusions (platelets and RBC) and the number of units transfused, and the need for hospitalization in adult patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy.
Eligibility
- Inclusion Criteria:
In order to be eligible to participate in this study, a patient must meet all of the following criteria:
Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification (Appendix A). Patients with AML with both IDH1 and IDH2 mutation are eligible as well.
Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173/AMLSG 34-23/ACT-HOV-AML-001) and EVOLVE-2 (HO177/AMLSG 35-24/ACT-HOV-AML-002are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories.
Age ≥ 18 years, no upper age limit.
Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
≥ 75 years of age ineligible for intensive chemotherapy per physician’s discretion (with an ECOG performance status 0-2; Appendix C).
18-74 years: patient is not eligible for standard chemotherapy because of any of the following co-morbidities:
ECOG performance status 2 or 3 (Appendix C).
Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina.
DLCO ≤ 65% or FEV1 ≤ 65%.
Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the Cockcroft Gault formula.
Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upper limit of normal (ULN).
Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl
Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
Patient must have a white cell blood (WBC) count of < 25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce the WBC count to meet this criterion.
Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of normal (ULN) or creatinine clearance ≥ 30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
Adequate hepatic function as evidenced by:
Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl)
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl
Female patients :
of nonchildbearing potential must be:
postmenopausal (defined as at least 1 year without any menses).
documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or status posthysterectomy (at least 1 month prior to screening).
of childbearing potential (not surgically sterile and not postmenopausal) must
agree to avoid pregnancy during the study and for 6 months after the final study drug administration
and have a negative urine or serum pregnancy test at screening.
and, if heterosexually active, agree to consistently apply one highly effective* method of birth control.for the duration of the study and for 6 months after the final study drug administration. Hormonal contraception must be combined with a barrier method.
*Highly effective forms of birth control includeConsistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception – both associated with inhibition of ovulation - is used.
Established intrauterine device (IUD) or intrauterine system (IUS)
Bilateral tubal occlusion
Vasectomy – a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
Male is sterile due to a bilateral orchiectomy.
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
must agree not to breastfeed starting at screening and throughout the study period, and for 1 month after the final study drug administration.
must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
Able to understand and willing to sign an informed consent form (ICF).
Institutional Review Board/Independent Ethics Committee-approved written informed consent and privacy language as per national regulations must be obtained from the participant prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
- Exclusion Criteria:
Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
AML with BCR-ABL1; or myeloid blast crisis of CML.
Significant active cardiac disease within 3 months prior to the start of study treatment, including:
New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix F)
Myocardial infarction
Unstable angina
Severe cardiac arrhythmias
Congenital long QT syndrome of family member with this condition
QTcF >450 msec on screening electrogram for males and >470 msec on screening electrogram for females (mean of triplicate recordings, calculated using Fridericia’s correction).
Familial history of sudden death or polymorphic ventricular arrhythmia.
Severe obstructive or restrictive ventilation disorder.
History of stroke or intracranial hemorrhage within 6 months prior to randomization.
Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial.
Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
Basal or squamous cell carcinoma of the skin;
Carcinoma in situ of the cervix;
Carcinoma in situ of the breast;
Incidental histologic finding of prostate cancer.
Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy or B-cell recovery, whichever is later).
Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
Contraindication to any of the anti-leukemic agents used (as per SmPC).
Participation in other prospective studies with anti-leukemic and/or investigational agents.
Patient taking Dabigatran unless they can be transferred to other medications at least 3 days prior to dosing. Patients taking other P-gP transporter-sensitive medications (see Appendix J) should be properly monitored during the study if they cannot be transferred to other medications.”
Patients taking known strong cytochrome P450 (CYP) 3A4 inducers (see Appendix H), unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
Patient who has once been screened and randomized into this HO173 trial but was considered ineligible cannot re-enter this trial at a later date.
Registration Details
Eligible patients should be registered and randomized before start of treatment. Patients need to be registered at HOVON by one of the following options:
HOVON registration database (see HOVON website www.hovon.nl for the most recent link to ALEA). Account for registration and a registration manual can be requested at HOVON.
By sending the completed registration/randomization CRF by e-mail to hovon@erasmusmc.nl, Monday through Friday, from 09:00 to 17:00 CET
By phone +31.10.7041560, Monday through Friday, from 09:00 to 17:00 CET
All eligibility criteria will be checked with a checklist.
Patients will be randomized (1:1) to receive either venetoclax or placebo, in combination with ivosidenib and azacitidine, using a stratified block randomization method and stratification factors including patient age at randomization (<75 years of age vs. ≥75 years of age), disease status (de novo vs. disease secondary to other hematological disorder including MDS, in which prior disease should have been documented to have existed for at least 3 months) and disease category (AML vs.MDS/AML).
Each patient will be given a unique patient study number (a sequence number by order of enrollment in the trial). Patient study number and result of randomization will be given immediately by the online registration database or by phone and confirmed by email.
Participating Sites
Ziekenhuizen die deelnemen aan het onderzoek staan benoemd op de HOVON website bij het onderzoek. Het kan zijn dat uw ziekenhuis niet genoemd wordt, maar wel aan het onderzoek deelneemt. Informeer hiernaar bij uw arts.
= Active hospitals 
= Inactive hospitals