| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| AML or MDS-EB2 with a mutation in either IDH1 or IDH2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia or myelodysplastic syndrome with a mutation in either IDH1 or IDH2 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare event-free survival (EFS) between ivosidenib/enasidenib and placebo in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed AML or MDS-EB2, with an IDH1 or IDH2 mutation, eligible for intensive chemotherapy. |
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| E.2.2 | Secondary objectives of the trial |
• To determine if treatment with ivosidenib/enasidenib, as compared to placebo prolongs overall survival (OS).
• To compare relapse-free survival (RFS), cumulative incidence of relapse (CIR) and cumulative incidence of death (CID) after CR/CRi between treatment including ivosidenib/enasidenib vs placebo.
• To evaluate minimal residual disease (MRD) status at several time points throughout treatment and CRMRD− rate between treatment including ivosidenib/enasidenib vs. placebo
• To assess the safety and tolerability of treatment including ivosidenib/enasidenib vs. placebo by comparing the frequency and severity of adverse events
• To compare complete remission (CR/CRi) rates for treatment including ivosidenib/enasidenib vs. placebo.
• To assess the time to hematopoietic recovery (ANC 0.5 and 1.0x109/l; platelets 50 and 100x109/l) after each chemotherapy treatment cycle.
• To determine quality of life (QoL) during maintenance treatment with ivosidenib/enasidenib vs. placebo.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
o 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.
o Aspartate amino transferase (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 must either: Be of nonchildbearing potential - postmenopausal (defined as at least 1 year without any mensed prior to screening or documented surgically sterile or status posthysterectomy (at least 1 month prior to screening) 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 uribe or serum pregnancy test at screening, and if heterosexually Active, agree to consistently ise 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 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 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 partner 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
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|
| E.4 | Principal 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:
o Basal or squamous cell carcinoma of the skin
o Carcinoma in situ of the cervix
o Carcinoma in situ of the breast
o 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 deemed critical and without a suitable alternative. In those cases, they may be administered, but with proper monitoring (see section 10.2, Table 13).
• 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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Event-free survival (EFS), 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoint will be evaluated when the data of all eligible patients are available |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
• Overall survival (OS), 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.
Other secondary endpoints:
• Relapse-free survival (RFS), 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.
• Cumulative incidence of relapse (CIR) after CR/CRi, as 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.
• Cumulative incidence of death (CID) after CR/CRi, as 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.
• CR without minimal residual disease (CRMRD−) rate after induction cycle 2, defined as CR/CRi with negativity for a genetic marker by realtime quantitative polymerase chain reaction (RT-qPCR), and with negativity by multi-color flow cytometry, if studied pre-treatment.
• Frequency and severity of adverse events according to CTCAE version 5.0.
• CR and CR with incomplete hematologic recovery (CRi) rates after induction cycle 1 and after induction cycle 2, as determined by the Investigator, based on the European LeukemiaNet (ELN2017) recommended response criteria18.
• 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, defined as the time from the start of the cycle until recovery.
• Quality of life as assessed by EQ-5D-5L visual analogue scale (VAS) and EQ-5D domains.
• Quality of life as assessed by EORTC-QLQ-C30 global health status/QoL scale and other QLQ-C30 subdomains.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Endpoint will be evaluated when the data of all eligible patients are available |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 187 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Estonia |
| Finland |
| France |
| Lithuania |
| Luxembourg |
| Sweden |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Belgium |
| Ireland |
| Norway |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 14 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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