| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia with an IDH1 Mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia (cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow) with IDH1 mutation. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 AG-120 + azacitidine and placebo + azacitidine. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the complete remission (CR) rate between AG-120 + azacitidine and placebo + azacitidine.
- To compare the overall survival (OS) rate (based on Investigator-assessed International Working Group [IWG] Response Criteria for AML), between AG-120 + azacitidine and placebo + azacitidine.
- To compare the CR (based on Investigator-assessed IWG Response Criteria for AML) + complete remission with partial hematologic recovery (CRh) rate between AG-120 + azacitidine and placebo + azacitidine. CRh is defined as a CR with partial recovery of peripheral blood counts (< 5% bone marrow blasts, platelets > 50,000/μL, ANC > 500/μL) and will be derived by the Sponsor.
- To compare the objective response rate (ORR) between AG-120 + azacitidine and placebo + azacitidine, as assessed by the Investigator. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for inclusion in the study:
1. Be ≥ 18 years of age and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC):
a. ≥ 75 years old
b. ECOG PS = 2
c. Severe cardiac disorder (eg, congestive heart failure requiring treatment, LVEF ≤50%, or chronic stable angina)
d. Severe pulmonary disorder (eg, diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%)
e. Creatinine clearance <45 mL/minute
f. Bilirubin >1.5 times upper limit of normal (× ULN)
g. Any other comorbidity that the Investigator judges to be incompatible with intensive IC must be reviewed and approved by the Medical Monitor before study enrollment.
2. Have previously untreated AML, defined according to World Health Organization criteria, with ≥ 20% leukemic blasts in the bone marrow. Subjects with extramedullary disease alone (ie, no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.
3. Have an isocitrate dehydrogenase 1 (IDH1) mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution, as determined by central laboratory testing (using an investigational polymerase chain reaction [PCR] assay, Abbott RealTime IDH1) in their bone marrow aspirate (or peripheral blood sample if bone marrow aspirate is not available).
(Note: Local testing for eligibility and randomization is permitted; however, results must state an IDH1 mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution. Bone marrow aspirate [or peripheral blood sample if bone marrow aspirate is not available with Medical Monitor approval] or central testing must have been sent with proof of shipment to the central laboratory prior to randomization.
4. Have an ECOG PS score of 0 to 2.
5. Have adequate hepatic function, as evidenced by:
a. Serum total bilirubin ≤ 2 times the upper limit of normal (× ULN), unless considered to be due to Gilbert’s disease or underlying leukemia, where it must be < 3 × ULN
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered to be due to underlying leukemia
6. Have adequate renal function, as evidenced by serum creatinine ≤ 2.0 × ULN or creatinine clearance > 30 mL/min based on the Cockcroft-Gault glomerular filtration rate.
7. Have agreed to undergo serial blood and bone marrow sampling.
8. Be able to understand and willing to sign an informed consent form (ICF).
9. Be willing to complete QoL assessments during study treatment and at the designated time points following treatment discontinuation.
10. If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Female subjects 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 with female partners of reproductive potential, must agree to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of study drug(s). Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from the study:
1. Are candidates for intensive IC for their AML.
2. Have received any prior treatment for AML with the exception of nononcolytic treatments to stabilize disease such as hydroxyurea or leukapheresis.
3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).
4. Subjects who had previously received treatment for an antecedent hematologic disorder, including investigational agents may not be randomized until a washout period of at least 5 half-lives of the investigational agent has elapsed since the last dose of that agent.
5. Have received prior treatment with an IDH1 inhibitor.
6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.
7. Are female and pregnant or breastfeeding.
8. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
9. Exclusion Criterion #9 was removed in Protocol Amendment 5, Version 6.0.
10. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
11. Have a prior history of malignancy other than MDS or myeloproliferative disorder, unless the subject has been free of the disease for ≥ 1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions or similar indolent cancer are allowed to participate in the study:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer
12. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association Class (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
13. Have a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV congestive, heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study.
14. Have an known viral infection caused by human immunodeficiency virus or active hepatitis B virus (HBV), or hepatitis C virus that cannot be controlled by treatment.
15. Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.
16. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).
17. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid during Screening is only required if there is a clinical suspicion of CNS involvement by leukemia during Screening.
18. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
19. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the subject’s ability to give informed consent or participate in the study.
20. Are taking medications that are known to prolong the QT interval (Appendix 15.5) unless they can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the medications can be properly monitored during the study. (If equivalent medication is not available, QTc will be closely monitored as defined in Section 9.12.2).
21. Subjects with a known medical history of progressive multifocal leukoencephalopathy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is EFS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from date of randomization until treatment failure, relapse from remission, or death from any cause., whichever occurs first. Treatment failure is defined as failure to achieve CR by Week 24. |
|
| E.5.2 | Secondary end point(s) |
• CR rate (CR defined as bone marrow blasts < 5% and no Auer rods, absence of extramedullary disease, ANC ≥ 1.0 × 10*9 /L [1000/µL],
platelet count ≥ 100 × 10*9 /L [100,000/µL], and independence of RBC transfusions)
•OS, defined as the time from date of randomization to the date of death due to any cause.
• CR + CRh rate (CRh is defined as a CR with partial recovery of peripheral blood counts where ANC is >0.5 × 10*9/L [500/μL], and platelet count is >50 10*9/L [50,000/µL] CRh will be derived by the Sponsor)
• ORR, defined as the rate of CR, CRi (including CRp), PR, and MLFS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CR rate - defined as bone marrow blasts < 5% and no Auer rods, absence of extramedullary disease, ANC > 1.0 × 109/L [1000/μL], platelet count ≥ 100 × 109/L [100,000/μL], and independence of RBC transfusions.
OS, defined as the time from date of randomization to the date of death due to any cause.
CR + CRh rate - CR with partial recovery of peripheral blood counts where ANC is >0.5 × 10*9/L [500/μL], and platelet count is >50 ×10*9/L]
ORR - rate of CR, CRi (including CRp), PR, and MLFS |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 109 |
| 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 |
| Brazil |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
|
| 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
|
| End of Study is defined as the time at which all subjects have died, discontinued the study, are lost to follow-up, or have withdrawn consent or when the Sponsor ends the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
Print
