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

• Register: ClinicalTrials.gov
• Last refreshed on: 13 September 2021
• Main ID: NCT03839771
• Date of registration: 06/02/2019
• Prospective Registration: Yes
• Primary sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Public title: 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 HOVON150AML
• Scientific title: 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.
• Date of first enrolment: March 1, 2019
• Target sample size: 968
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/show/NCT03839771
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 3

Countries of recruitment

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

Contacts

• Name: B.J. Wouters
• Affiliation: Erasmus MC / HOVON

• Name: B.J. Wouters, Dr.

Key inclusion & exclusion criteria

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


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Myelodysplastic Syndrome With Excess Blasts-2

Acute Myeloid Leukemia

Intervention(s)

Drug: Placebo for AG-120

Drug: Placebo for AG-221

Drug: AG-120

Drug: AG-221

Primary Outcome(s)

Event-free survival (EFS) [Time Frame: Approximately up to 60 months following first patient enrollment]

Secondary Outcome(s)

CR/CRi rates after induction cycle 1 and 2 [Time Frame: Approximately up to 60 months following first patient enrollment]

Frequency and severity of adverse events according to CTCAE version 5.0 [Time Frame: Continuously throughout the study, starting from informed consent until 30 days following the last administration of any study drug]

CR/CRi rate after remission induction (i.e., CR or CRi as best response during or at completion of induction therapy) [Time Frame: Approximately up to 60 months following first patient enrollment]

EORTC-QLQ-C30 global health status/QoL scale. [Time Frame: At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)]

Cumulative incidence of death (CID) after CR/CRi [Time Frame: Approximately up to 60 months following first patient enrollment]

Time to hematopoietic recovery after each chemotherapy treatment cycle [Time Frame: Approximately up to 60 months following first patient enrollment]

Complete remission without minimal residual disease (CRMRD-) rate after induction cycle 2 [Time Frame: Approximately up to 60 months following first patient enrollment]

EQ-5D-5L visual analogue scale (VAS) [Time Frame: At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)]

Relapse-free survival (RFS) after CR/CRi [Time Frame: Approximately up to 60 months following first patient enrollment]

Overall survival (OS) [Time Frame: Approximately up to 84 months following first patient enrollment]

Cumulative incidence of relapse (CIR) after CR/CRi [Time Frame: Approximately up to 60 months following first patient enrollment]

Secondary ID(s)

HO150

2018-000451-41

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)