| 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 | 21.0 |
| 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 Dose Finding Stage: - To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with subcutaneous (SC) azacitidine and oral AG-221 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
- To establish the recommended combination dose (RCD) of oral AG-120 and oral AG-221 when administered with SC azacitidine.
Ph Ib AG-120 Expansion Stage:- To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 mutation who are not candidates to receive intensive IC.
Ph II AG-221 Randomized Stage: - To assess the efficacy of oral AG-221 when administered with SC azacitidine versus SC azacitidine alone in subjects with newly diagnosed AML with an IDH2 mutation, who are not candidates to receive intensive IC. |
|
| E.2.2 | Secondary objectives of the trial |
Ph Ib Dose Finding Stage: - To assess the preliminary efficacy of the combination treatments of oral AG-120 when administered with SC azacitidine and oral AG-221 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
Ph Ib AG-120 Expansion Stage: - To assess the preliminary efficacy of the combination treatments of oral AG-120 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 mutation, who are not candidates to receive intensive IC.
Ph II AG-221 Randomized Stage: - To evaluate the safety of oral AG-221 when administered with SC azacitidine.
- To characterize the PK of oral AG-221 when administered with SC azacitidine.
- To evaluate the effect of 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 | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Extension Phase:
During the Extension Phase, the subjects will continue to be treated with
AG-120/AG-221 + SC azacitidine or single agent AG-120, AG-221, or
azacitidine if in the investigator's assessment the subject continues to
show clinical benefit and all protocol-specified criteria for continuing
study treatment are met.
Objective
• To allow all Phase 1b and Phase 2 subjects still on treatment to have
continued access to the study treatment to assess the long-term efficacy
and safety of the study treatment and to follow the subjects for survival.
During the Extension Phase, the subjects will continue to be assessed for
efficacy until EOT and safety on an ongoing basis and as clinically
indicated until 28 days after the last study drug dose and as outlined in
Table 5. After the End of Treatment visit, the subjects will be followed
for survival until death, lost to follow-up, withdrawal of consent, or the
End of Trial, whichever occurs first.
The Extension Phase applies to all Phase 1b and Phase 2 subjects that
are still on study treatment or in long-term Follow-up after the primary
analysis CSR and after the 24-month follow-up update for DMC. Once
Amendment 3.0 is approved by regulatory authorities and ethics
committees and subjects sign informed consent, they may continue to
receive study treatment until disease progression, development of
unacceptable toxicity, or as per investigator discretion. During the
Extension Phase, all subjects will be required to complete study visits
and assessments as outlined in Table 5: Extension Phase - Table of
Events. Subjects will be assessed for safety (AEs, SAEs and concomitant
medications and procedures) on an ongoing basis and as clinically
indicated until 28 days after the last study drug dose. Safety
assessments including laboratory tests will be performed locally and as
clinically indicated. Disease response assessments will be performed
locally per modified IWG AML response criteria and according to
standard of care (SoC) and as clinically indicated. Subjects who
discontinue from the study treatment for any reason should undergo an
End of Treatment (EOT) visit and should be assessed for safety and
efficacy at this visit. After the Extension Phase - End of Treatment visit,
subjects will be followed for survival until death, lost to follow-up,
withdrawal of consent, or the End of Trial, whichever occurs first. No
central lab samples will be collected nor samples for exploratory analysis
(pharmacodynamics, correlative studies, MRD, Buccal swabs) will be
collected during the Extension Phase. |
|
| 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 newly diagnosed, 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 Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR):
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
7. Agree to serial bone marrow aspirate/biopsies.
8. Females of childbearing potential (FCBP)* may participate, providing they meet the
following conditions:
- Agree to practice true abstinence ** from sexual intercourse or to use highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization [note that a vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that a vasectomized partner has received medical assessment of the surgical success]) at screening and throughout the study, and for at least 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 or urine (investigator’s discretion under local regulations) 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 must agree to practice true abstinence from sexual intercourse or agree to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of child bearing potential at screening and throughout the course of the study and should avoid conception with their partners during the course of the study and for at least 4 months following the last study treatment (6 months following last dose of azacitidine in Canada).
Furthermore, the male subject must agree to use a condom while treated with azacitidine and for at least 4 months following the last azacitidine dose. |
|
| 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: Hydroxyurea is allowed prior to enrollment for the control of peripheral leukemic blasts in subjects with leukocytosis. (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. The use of all trans retinoic acid (ATRA) for suspected APL is not exclusionary provided it is discontinued prior to initiation of treatment in the protocol.
5. Subject has received more than 1 cycle of prior treatment with azacitidine, or subject has received any prior treatment with 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 Dose Finding and AG-120 Expansion:
1. Recommended Combination Dose - Review of dose-limiting toxicities (DLTs), safety, 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 (as assessed by the investigator)- Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ph Ib Dose Finding and AG-120 Expansion:
1. Recommended Combination Dose - Approximately 8 months
2. Safety / tolerability - Approximately 13 months
Ph II:
3. Overall Response Rate (as assessed by the investigator- Approximately 30 months |
|
| E.5.2 | Secondary end point(s) |
Ph Ib Dose Finding and AG-120 Expansion:
1. Overall Response Rate (as assessed by the investigator) - Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).
2. Sponsor Derived CR and CRh - Rate of CR/ CRh and CR + CRh based on laboratory data
3. 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:
4. 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.
5. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
6. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
7. Sponsor Derived CR - Rate of CR based on laboratory data
8. Sponsor Derived CR and CRh - Rate of CR +CRh based on laboratory data
9. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
10. 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
11. Time to response - Time from first dose of study drug to first documented CR/CRi/CRp/MLFS/PR according to modified IWG AML response criteria (Appendix F)
12. Time to sponsored assessed CR and CRh - Time from first dose of study drug to first documented CR / CRh
13. Duration of sponsor assessed CR and CRh - Time from the first documented CR/CRh to documented morphologic relapse, progression
14. Overall Survival - Time from randomization to death due to any cause.
15. One-year survival - The probability of survival at 1 year from randomization
16. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
17. 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)
18. Healthcare resource utilization (Exploratory) - Information about all resource use
(eg, hospitalization)
19. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
20. Pharmacodynamics (Exploratory) - Evaluation of 2-HG and α-KG levels in plasma and/or bone marrow.
Evaluate methylation in PB and/or transcription in BM.
21. 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) by flow cytometry and by 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 IDH2 mutated leukemic cells. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ph Ib Dose Finding and AG-120 Expansion: All secondary and Exploratory objectives - Approximately 13 months
Ph II: All secondary and Exploratory objectives - Approximately 30 months
The full length of the study is expected to be approximately 96 months
including recruitment, screening, treatment, and follow up for Phase 1b
Phase 2 and the Extension Phase. For a single subject, the expected
duration of the study is approximately 30 months, including a screening
period for up to 28 days, inclusive of overall survival. |
|
| 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 | 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 | 1 |
| 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 |
| Korea, Republic of |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| 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
|
| 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 | 5 |
| 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 | 6 |
| 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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