HOVON 150 Treatment with Ivosidenib or Enasidenib in combination with intensive chemotherapy for patients with previously untreated acute myeloid leukemia (AML) or previously untreated advanced myelodysplastic syndrome (MDS-EB2) with IDH1 or IDH2 mutation.

Australia, Austria, Belgium, Estonia, Finland, France, Germany, Ireland, Lithuania, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland (ICTRP)

ID di studio ICTRP
NCT03839771 (ICTRP)

Titolo ufficiale (approvato dal comitato etico)
HOVON 150 AML/ AMLSG 29-18 A phase 3, multicenter, double-blind, randomized, placebo-controlled study of ivosidenib or enasidenib in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome with excess blasts-2, with an IDH1 or IDH2 mutation, respectively, eligible for intensive chemotherapy. (BASEC)

Titolo accademico
A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy. (ICTRP)

Titolo pubblico
A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy (ICTRP)

Malattie studiate
Acute Myeloid Leukemia;Myelodysplastic Syndrome With Excess Blasts-2 (ICTRP)

Intervento studiato
Drug: AG-120;Drug: Placebo for AG-120;Drug: AG-221;Drug: Placebo for AG-221 (ICTRP)

Tipo di studio
Interventional (ICTRP)

Disegno dello studio
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator). (ICTRP)

Criteri di inclusione/esclusione
Gender: All
Maximum age: N/A
Minimum age: 18 Years
Inclusion Criteria:

- Age =18 years

- Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a documented
IDH1 or IDH2 gene mutation (as determined by the clinical trial assay) at a specific
site (IDH1 R132, IDH2 R140, IDH2 R172). AML may be secondary to prior hematological
disorders, including MDS, and/or therapy-related (in which prior disease should have
been documented to have existed for at least 3 months). Patients may have had
previous treatment with hypomethylating agents (HMAs) for MDS. HMAs have to be
stopped at least four weeks before registration

- Patients with dual mutant FLT3 and IDH1 or IDH2 mutations may be enrolled only if,
for medical or other reasons, treatment with a FLT3 inhibitor is not considered.

- Considered to be eligible for intensive chemotherapy.

- ECOG/WHO performance status = 2

- Adequate hepatic function as evidenced by:

- Serum total bilirubin = 2.5 ? upper limit of normal (ULN) unless considered due
to Gilbert's disease (e.g. a mutation in UGT1A1) (only for patients in IDH2
cohort), or leukemic involvement of the liver - following written approval by
the (Co)Principal Investigator.

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) = 3.0 ? ULN, unless considered due to leukemic involvement of
the liver, following written approval by the Principal Investigator.

- Adequate renal function as evidenced by creatinine clearance > 40 mL/min based on
the Cockroft-Gault formula for glomerular filtration rate (GFR).

- Able to understand and willing to sign an informed consent form (ICF).

- Written informed consent

Female patient must either:

o Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any
menses) prior to screening, or Documented surgically sterile or status posthysterectomy
(at least 1 month prior to screening)

o Or, if of childbearing potential: Agree not to try to become pregnant 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
use highly effective* contraception per locally accepted standards in addition to a
barrier method starting at screening and throughout the study period and for 6 months
after the final study drug administration.

- Highly effective forms of birth control include:

- Consistent and correct usage of established hormonal contraceptives that
inhibit ovulation,

- Established intrauterine device (IUD) or intrauterine system (IUS),

- Bilateral tubal occlusion,

- Vasectomy (A vasectomy is a 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 enrollment, the investigator is responsible for
confirming patient will utilize highly effective forms of birth control per the
requirements of the CTFG Guidance document 'Recommendations related to contraception
and pregnancy testing in clinical trials', September 2014 (and any updates thereof)
during the protocol defined period.

- Female patient must agree not to breastfeed starting at screening and
throughout the study period, and for 2 months and 1 week after the final study
drug administration.

- Female patient must not donate ova starting at screening and throughout the
study period, and for 6 months after the final study drug administration.

- Male patient and their female partners who are of childbearing potential
must be using highly effective contraception per locally accepted
standards in addition to a barrier method starting at screening and
continue throughout the study period and for 4 months and 1 week after the
final study drug administration

- Male patient must not donate sperm starting at screening and throughout
the study period and for 4 months and 1 week after the final study drug
administration.

- Subject agrees not to participate in another interventional study
while on treatment

Exclusion Criteria:

- Prior chemotherapy for AML or MDS-EB2 (with the exception of HMA). Hydroxyurea is
allowed for the control of peripheral leukemic blasts in patients with leukocytosis
(e.g., white blood cell [WBC] counts > 30x109/L).

- Dual IDH1 and IDH2 mutations.

- Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic
variant fusion genes/chromosome translocations.

- Blast crisis after chronic myeloid leukemia (CML).

- Known allergy or suspected hypersensitivity to Ivosidenib or Enasidenib and/or any
exipients.

- Taking medications with narrow therapeutic windows with potential interaction with
investigational medication (see Appendix I), unless the patient can be transferred
to other medications prior to enrolling or unless the medications can be properly
monitored during the study.

- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)
transporter-sensitive substrate medications (see Appendix J) unless the patient can
be transferred to other medications within = 5 half-lives prior to administration of
ivosidenib or enasidenib, or unless the medications can be properly monitored during
the study.

- Breast feeding at the start of study treatment.

- Active infection, including hepatitis B or C or HIV infection that is uncontrolled
at randomization. An infection controlled with an approved or closely monitored
antibiotic/antiviral/antifungal treatment is allowed.

- Patients 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

- Significant active cardiac disease within 6 months prior to the start of study
treatment, including New York Heart Association (NYHA) Class III or IV congestive
heart failure (appendix G); myocardial infarction, unstable angina and/or stroke; or
left ventricular ejection fraction (LVEF) < 40% by ultrasound or MUGA scan obtained
within 28 days prior to the (ICTRP)

non disponibile

Endpoint primari e secondari
Event-free survival (EFS) (ICTRP)

Overall survival (OS);Relapse-free survival (RFS) after CR/CRi;Cumulative incidence of relapse (CIR) after CR/CRi;Cumulative incidence of death (CID) after CR/CRi;Complete remission without minimal residual disease (CRMRD-) rate after induction cycle 2;Frequency and severity of adverse events according to CTCAE version 5.0;CR/CRi rates after induction cycle 1 and 2;CR/CRi rate after remission induction (i.e., CR or CRi as best response during or at completion of induction therapy);Time to hematopoietic recovery after each chemotherapy treatment cycle;EQ-5D-5L visual analogue scale (VAS);EORTC-QLQ-C30 global health status/QoL scale. (ICTRP)

Data di registrazione
non disponibile

Inclusione del primo partecipante
non disponibile

Sponsor secondari
Deutsch-?sterreichische Studiengruppe Akute Myeloische Leuk?mie (AMLSG) (ICTRP)

Contatti aggiuntivi
B.J. Wouters, Erasmus MC / HOVON (ICTRP)

ID secondari
2018-000451-41, HO150 (ICTRP)

Risultati-Dati individuali dei partecipanti
non disponibile

Ulteriori informazioni sullo studio
https://clinicaltrials.gov/ct2/show/NCT03839771 (ICTRP)