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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)

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ClinicalTrials.gov Identifier: NCT03839771
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : July 18, 2019
Sponsor:
Collaborator:
Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)
Information provided by (Responsible Party):
Stichting Hemato-Oncologie voor Volwassenen Nederland

Brief Summary:
AML and MDS-EB2 are malignancies of the bone marrow. The standard treatment for these diseases is chemotherapy. Patients participating have a special type of this disease because the leukemia cells (blasts) have developed an error in the genetic material (DNA). This error is called an IDH1 mutation or an IDH2 mutation (a mutation is a change in the DNA), which leads to changes in specific substances in the leukemia cells. This trial will investigate whether the addition of the new drugs Ivosidenib (for patients with IDH1 mutation) or Enasidenib (for patients with IDH2 mutation) to the standard treatment of chemotherapy controle the disease more effectively and for a longer period.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome With Excess Blasts-2 Drug: AG-120 Drug: Placebo for AG-120 Drug: AG-221 Drug: Placebo for AG-221 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 968 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official 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.
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2033


Arm Intervention/treatment
Placebo Comparator: Arm A: Placebo

Cycle 1: day 1-start cycle 2 | Cycle 2: day 1 - start consolidation treatment | Consolidation treatment: day 1 - start maintenance | Maintenance treatment: day 1- day 730 (2 years) |

The dosage for Placebo for AG-120 (IDH1): 500 mg dose/day

The dosage for Placebo for AG-221 (IDH2): 100mg dose/day

Drug: Placebo for AG-120
250mg tablets

Drug: Placebo for AG-221
100mg tablets

Experimental: Arm B: Ivosidenib (IDH1) or Enasidenib (IDH2)

Cycle 1: day 1-start cycle 2 | Cycle 2: day 1 - start consolidation treatment | Consolidation treatment: day 1 - start maintenance | Maintenance treatment: day 1- day 730 (2 years) |

The dosage for AG-120 (IDH1): 500 mg dose/day

The dosage for AG-221 (IDH2): 100mg dose/day

Drug: AG-120
250mg tablets
Other Name: Ivosidenib

Drug: AG-221
100mg tablets
Other Name: Enasidenib




Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    EFS is defined as the time from randomization to failure to achieve CR or CRi after remission induction, death after achieving CR or CRi or relapse after achieving CR or CRi, whichever occurs first. A patient is said to have failed to achieve CR or CRi after induction therapy, if his/her best response during or at completion of the induction treatment is less than CRi. Patients who achieved CR/CRi after remission induction and are not known to have relapsed or died will be censored at the date of last clinical assessment.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Approximately up to 84 months following first patient enrollment ]
    OS is defined as the time from date of randomization to date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.

  2. Relapse-free survival (RFS) after CR/CRi [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    RFS is defined as time from the date of achievement of CR/CRi until relapse or death from any cause, whichever comes first. Patients still in first CR/CRi and alive or lost to follow up will be censored at the date of last clinical assessment.

  3. Cumulative incidence of relapse (CIR) after CR/CRi [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    CIR is measured from the date of achievement of CR/CRi until the date of relapse. Patients not known to have relapsed will be censored on the date of last clinical assessment. Patients who died without relapse will be counted as a competing cause of failure.

  4. Cumulative incidence of death (CID) after CR/CRi [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    CID is measured from the date of achievement of CR/CRi until the date of death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients who experienced relapse in CR/CRi will be counted as competing cause of failure.

  5. Complete remission without minimal residual disease (CRMRD−) rate after induction cycle 2 [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    CRMRD− rate is defined as the percentage of patients who achieved CR or CRi with no evidence of MRD in bone marrow

  6. 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 ]
    Adverse events will be evaluated using the National Cancer Institute's Common Terminology Criteria for AEs (CTCAE) version 5.0

  7. CR/CRi rates after induction cycle 1 and 2 [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    CR and CRi are determined by the Investigator based on the European LeukemiaNet (ELN2017) recommended response criteria

  8. 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 ]
    CR+CRi rate after remission induction is defined as the percentage of patients with best response of CR or CRi during or at completion of induction therapy

  9. Time to hematopoietic recovery after each chemotherapy treatment cycle [ Time Frame: Approximately up to 60 months following first patient enrollment ]
    Time to hematopoietic recovery is defined as the time from the start of the cycle until recovery

  10. 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) ]
    The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today". Each domain has 5 levels. Each level has a 1 digit number expressing the level selected for that dimension. These levels are summed up and the self-rated health is recorded on a 20 cm vertical, visual analogue scale, with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'.

  11. 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) ]
    The EORTC QLQ-C30 is a 30-item questionnaire that assesses 5 functional subdomains (physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning), 1 global health status, 3 symptom subdomains (fatigue, nausea and vomiting and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Estimate the average of the items that contribute to the scale; this is the raw score. a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 patients of reproductive potential must undergo a pregnancy test prior to starting study drug and this test must have a negative result. The first pregnancy test will be performed at entry (within 7 days prior to first study drug administration). A pregnancy test should also be repeated within 72 hours before the first study drug administration and confirmed negative prior to dosing. Patients with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal for at least 24 consecutive months.
  • Females of reproductive potential as well as fertile men and their partners who are females of reproductive potential must agree to abstain from sexual intercourse or to use a highly effective form of contraception from the time of giving informed consent, during the study, and for 4 months (females and males) following the last dose of ivosidenib/enasidenib or placebo. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or gel) or male partner sterilization.
  • 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).
  • 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 start of study treatment.
  • QTc interval using Fridericia's formula (QTcF) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the Principal Investigator.
  • Taking medications that are known to prolong the QT interval (see Appendix K), unless the patient can be transferred to other medications within ≥ 5 half-lives prior to dosing or unless the medications can be properly monitored during the study.
  • Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
  • 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.
  • A known medical history of progressive multifocal leukoencephalopathy (PML).
  • Immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular coagulation
  • Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03839771


Contacts
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Contact: B.J. Wouters, Dr. +31 10 704 15 60 b.wouters@erasmusmc.nl
Contact: P. Paschka +49 (0) 731 500 45740 peter.paschka@uniklinik-ulm.de

Locations
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Netherlands
Erasmus MC Recruiting
Rotterdam, Netherlands
Contact: B. Wouters         
Sponsors and Collaborators
Stichting Hemato-Oncologie voor Volwassenen Nederland
Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)
Investigators
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Principal Investigator: B.J. Wouters Erasmus MC / HOVON

Additional Information:
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Responsible Party: Stichting Hemato-Oncologie voor Volwassenen Nederland
ClinicalTrials.gov Identifier: NCT03839771     History of Changes
Other Study ID Numbers: HO150
2018-000451-41 ( EudraCT Number )
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Ivosidenib
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Anemia, Refractory, with Excess of Blasts
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Anemia, Refractory
Anemia
Glycine
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs