| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed acute myeloid leukemia (AML) habouring an isocitrate dehydrogenase 1 (IDH1) or an isocitrate dehydrogenase 2 (IDH2) mutation, respectively, who are not candidates to receive intensive induction chemotherapy (IC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of subjects with newly diagnosed AML that have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) and who are not candidates to receive intensive induction chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| 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 |
Ph Ib: - To assess the safety and tolerability of the combination treatments of oral AG-120 + subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed acute myeloid leukemia (AML) harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive induction chemotherapy (IC).
- To establish the recommended Phase 2 dose (RP2D) of oral AG-120 and oral AG-221 when administered with SC azacitidine.
Ph II: - To assess the efficacy of the combination treatments of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine compared with SC azacitidine alone in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC. |
|
| E.2.2 | Secondary objectives of the trial |
Ph Ib: - To assess the preliminary efficacy of the combination treatments of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
Ph II: - To evaluate the safety of oral AG-120 and oral AG-221 when administered with SC azacitidine.
- To characterize the pharmacokinetics (PK) of oral AG-120 and AG-221 when administered in combination with SC azacitidine.
- To evaluate the effect of oral AG-120 and oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
4. Subject has previously untreated, primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to the
WHO classification (Appendix B) with ≥ 20% leukemic blasts in the bone marrow:
a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172)
- IDH mutational status will be assessed locally; for sites without local testing capabilities, a referral lab will be identified.
b. By the investigator’s assessment who are not candidates to receive intensive IC.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1
or 2 (Appendix D).
6. Subject has adequate organ function defined as:
- Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless
considered due to leukemic organ involvement.
- Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, 3 times the upper limit of normal for Gilbert’s syndrome (eg, a gene mutation in
UGT1A1), or leukemic organ involvement.
- Serum creatinine < 2 x ULN or creatinine clearance > 30 mL/min based on the
Cockroft-Gault glomerular filtration rate (GFR) estimation:
(140 - Age) x (weight in kg) x (0.85 if female) / 72 x serum creatinine
7. Agree to serial bone marrow aspirate/biopsies.
8. Females of childbearing potential (FCBP)* may participate, providing they meet the
following conditions:
- Agree to abstain from sexual intercourse or to use at least two highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen alone associated with inhibition of ovulation, oral, injectable, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization) at screening and throughout the study, and for 4 months following the last study treatment ; and
- Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG)
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
- Have a negative serum β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Period (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Period if it is performed within the 72-hour timeframe).
9. Male subjects (with a female partner of childbearing potential who must agree to conditions in criterion 8) must agree to abstain from sexual intercourse or agree to the use of at least 2 highly effective contraceptive methods at screening and throughout the course of the study and should avoid fathering a child during the course of the study and for 4 months following the last study treatment (6 months following the last dose of azacitidine in Canada). |
|
| E.4 | Principal exclusion criteria |
1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype (Appendix B).
2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C).
3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML.
Note that hydroxyurea is allowed prior to the start of study treatment for the control of
leukocytosis in subjects with white blood cell (WBC) counts > 30 x 10^9/L (however,
hydroxyurea should not be given within 72 hours prior to and after administration of
azacitidine). For subjects with secondary AML (eg, MDS or MPN) treatment for prior
cancer is not exclusionary; full treatment information will be collected within the CRF.
5. Subject has received prior treatment with azacitidine or decitabine for MDS.
6. Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening.
7. Subject has immediate life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.
8. Subject has 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 E); acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.
9. Subject has prior history of malignancy, other than MDS, MPN, or AML, 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 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 (T1a or T1b using the tumor, node,
metastasis clinical staging system)
10. Subject is known seropositive for or has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs administered
orally
12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 100 mmHg)
13. Subject is taking the following sensitive CYP substrate medications that have a narrow
therapeutic range are excluded from the study unless the subject can be transferred to
other medications at least 5 half-lives prior to the start of study treatment: phenytoin
(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2) (Appendix K).
14. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
substrate rosuvastatin; subject should be excluded from the study unless he/she can be
transferred to other medications at least 5 half-lives prior to the start of study treatment
(Appendix L).
15. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment).
16. Subject has known or suspected hypersensitivity to any of the components of study
therapy.
17. Subject is taking medications that are known to prolong the QT interval (Appendix M)
unless he/she can be transferred to other medications within ≥ 5 half-lives prior to the start of study treatment. (If equivalent medication is not available, QTc will be closely monitored as defined in Section 8.1.)
18. Subject has QTc interval (ie, Fridericia’s correction [QTcF]) ≥ 450 ms or other factors
that increase the risk of QT prolongation or arrhythmic events (eg, heart failure,
hypokalemia, family history of long QT interval syndrome) at screening.
19. Female subject who is pregnant or lactating.
20. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
21. Subject has any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he/she were to participate in the study.
22. Subject has any condition that confounds the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Ph Ib:
1. Recommended Phase 2 Dose - Review of dose-limiting toxicities (DLTs), safety, and possibly, PK / pharmacodynamic, biomarker, and preliminary efficacy data by DRT.
2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
Ph II:
3. Overall Response Rate - Rate of MLFS + CR + CRi + CRp + PR according to modified IWG AML response criteria (Appendix F). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ph Ib:
1. Recommended Phase 2 Dose - Approximately 8 months
2. Safety / tolerability - Approximately 13 months
Ph II:
3. Overall Response Rate - Approximately 30 months |
|
| E.5.2 | Secondary end point(s) |
Ph Ib:
1. Overall Response Rate - Rate of MLFS + CR + CRi + CRp + PR according to modified IWG AML response criteria (Appendix F).
2. Pharmacodynamics (Exploratory) - To evaluate the pharmacodynamics of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination in this population.
Ph II:
3. Event-Free Survival - Time from randomization to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death from any cause, whichever occurs first.
4. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
5. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
6. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
7. Duration of Response - Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death due to any cause, whichever occurs first
8. Overall Survival - Time from randomization to death due to any cause.
9. One-year survival - The probability of survival at 1 year from randomization
10. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
11. HRQoL outcomes - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) (Appendix N) and EuroQoL Group EQ-5D-5L instrument (Appendix O)
12. Healthcare resource utilization (Exploratory) - Information about all resource use
(eg, hospitalization)
13. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
14. Pharmacodynamics (Exploratory) - Evaluation of 2-HG and α-KG levels in plasma and bone marrow.
Evaluate methylation in PB and/or transcription in BM.
15. Correlative studies (Exploratory) - Evaluation of molecular, cellular and metabolic markers which may be predictive of antitumor activity and/or resistance.
Evaluation of minimal residual disease (MRD), to assess IDH1 and IDH2 variant allele fraction (VAF) in blood and bone marrow cells.
Evaluation of changes in cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH1 and IDH2 mutated leukemic cells as well as wildtype IDH leukemic cells induced by oral AG-120 and oral AG-221 when
administered with SC azacitidine. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ph Ib: All secondary and Exploratory objectives - Approximately 13 months
Ph II: All secondary and Exploratory objectives - Approximately 30 months |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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