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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02677922




Registration number
NCT02677922
Ethics application status
Date submitted
5/02/2016
Date registered
9/02/2016
Date last updated
24/05/2019

Titles & IDs
Public title
A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML)
Scientific title
A Phase 1b/2 Open-label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy
Secondary ID [1] 0 0
AG-221-AML-005
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Myeloid, Acute 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - AG-120
Treatment: Drugs - Azacitidine
Treatment: Drugs - AG-221

Experimental: Oral AG-120 + Subcutaneous (SC) azacitidine - Subjects with an IDH1 mutation will receive AG-120 at the RP2D orally QD on Days 1-28 of each 28-day cycle + azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.

Experimental: Oral AG-221 + Subcutaneous (SC) azacitidine - Subjects with an IDH2 mutation will receive AG-221 at the RP2D orally QD on Days 1-28 of each 28-day cycle + azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.

Experimental: Subcutaneous (SC) azacitidine - Subjects with either an IDH1 or IDH2 mutation will receive azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.


Treatment: Drugs: AG-120


Treatment: Drugs: Azacitidine


Treatment: Drugs: AG-221


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose limiting toxicities (DLTs)-Phase 1B - DLTs will be defined as any of the following events that commence within 28 days of the first dose of IP in a 28-day treatment cycle, constitute a change from baseline irrespective of outcome and are determined by the investigator to be related to treatment.
Timepoint [1] 0 0
Up to approximately 7 months
Primary outcome [2] 0 0
Adverse Events (AEs) in Ph 1b - Number of participants with adverse events
Timepoint [2] 0 0
Up to approximately 4 years
Primary outcome [3] 0 0
Pharmacokinetics- Cmax - Maximum observed concentration in plasma
Timepoint [3] 0 0
Up to approximately 7 months
Primary outcome [4] 0 0
Pharmacokinetics- Tmax - Time to maximum concentration
Timepoint [4] 0 0
Up to approximately 7 months
Primary outcome [5] 0 0
Pharmacokinetics- AUC - Area under the plasma concentration-time curve
Timepoint [5] 0 0
Up to approximately 7 months
Primary outcome [6] 0 0
Overall response rate (ORR) Ph 2 - Includes responses of Morphologic complete remission (CR), Morphologic complete remission with incomplete platelet recovery (CRp), morphologic leukemia-free state (MLFS), Morphologic complete remission with incomplete neutrophil recovery (CRi), and Partial remission (PR), according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria.
Timepoint [6] 0 0
Up to approximately 30 months
Secondary outcome [1] 0 0
Overall Response Rate - Phase 1b (Ph 1b) - Rate of Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Morphologic leukemia-free state (MLFS) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Timepoint [1] 0 0
Up to approximately 13 months
Secondary outcome [2] 0 0
Event-Free Survival - Phase 2 (Ph 2) - Time from randomization to documented morphologic relapse, progression according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria, or death from any cause, whichever occurs first.
Timepoint [2] 0 0
Up to approximately 30 months
Secondary outcome [3] 0 0
Adverse Events (AEs) - Ph 2 - Number of participants with adverse events
Timepoint [3] 0 0
Up to approximately 4 years
Secondary outcome [4] 0 0
Complete remission rate - Ph 2 - Rate of morphologic complete remission (CR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Timepoint [4] 0 0
Up to approximately 30 months
Secondary outcome [5] 0 0
Hematologic improvement rate - Ph 2 - Rate of Hematologic improvement - neutrophil response (HI-N) + Hematologic improvement - platelet response (HI-P) + Hematologic improvement - erythroid response (HI-E) according to International Working Group (IWG) Myelodysplastic syndromes (MDS) Hematologic improvement(HI) criteria
Timepoint [5] 0 0
Up to approximately 30 months
Secondary outcome [6] 0 0
Duration of Response - Ph 2 - Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria, or death due to any cause, whichever occurs first
Timepoint [6] 0 0
Up to approximately 30 months
Secondary outcome [7] 0 0
Overall Survival - Ph 2 - Time from randomization to death due to any cause
Timepoint [7] 0 0
Up to approximately 30 months
Secondary outcome [8] 0 0
One-year survival- Ph 2 - The probability of survival at 1 year from randomization
Timepoint [8] 0 0
Up to approximately 12 months
Secondary outcome [9] 0 0
Pharmacokinetics- Cmax - Ph 2 - Maximum observed concentration in plasma
Timepoint [9] 0 0
Up to approximately 30 months
Secondary outcome [10] 0 0
Pharmacokinetics- Tmax - Ph 2 - Time to maximum concentration
Timepoint [10] 0 0
Up to approximately 30 months
Secondary outcome [11] 0 0
Pharmacokinetics- AUC - Ph 2 - Area under the plasma concentration-time curve
Timepoint [11] 0 0
Up to approximately 30 months
Secondary outcome [12] 0 0
EORTC QLQ-C30 - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire - Ph 2 - Is a validated quality-of-life measure applicable to subjects with any cancer diagnosis. It is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning. Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms
Timepoint [12] 0 0
Up to approximately 30 months
Secondary outcome [13] 0 0
EQ-5D-5L Health Questionnaire - Ph 2 - Is a standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status, and is applicable to a wide range of health conditions and treatments
Timepoint [13] 0 0
Up to approximately 30 months
Secondary outcome [14] 0 0
Overall Response Rate - Phase 1b (Ph 2) - Rate of Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Morphologic leukemia-free state (MLFS) +Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Timepoint [14] 0 0
Up to approximately 30 months
Secondary outcome [15] 0 0
Time to Response - Phase 2 - Time from first dose of study drug to first documented Morphologic complete remission (CR)/ Morphologic complete remission with incomplete neutrophil recovery (CRi)/ Morphologic complete remission with incomplete platelet recovery (CRp)/ Morphologic leukemia-free state (MLFS)/ Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Timepoint [15] 0 0
Up to approximately 30 months

Eligibility
Key inclusion criteria
Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is = 18 years of age 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 with = 20% leukemic blasts in the bone marrow: -Have an Isocitrate
dehydrogenase 1 (IDH1) or Isocitrate dehydrogenase 2 (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.

- By the investigator's assessment who are not candidates to receive intensive
Inductive chemotherapy (IC).

5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
2.

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 ß-subunit of human chorionic gonadotropin (ß-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) ß-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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- The presence of any of the following will exclude a subject from enrollment:

1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype.

2. Subject has AML secondary to chronic myelogenous leukemia (CML).

3. Subject has received a targeted agent against an Isocitrate dehydrogenase 1 (IDH1) or
Isocitrate dehydrogenase 2 (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 Myelodysplastic syndromes (MDS).

- Clarification: Subjects with newly diagnosed Acute myeloid leukemia (AML) who are
currently receiving their 1st cycle of azacitidine (7 days) can be screened for the
study. On study, Cycle 1 must be started at 28 days (+/- 3 days) after initiation of
the pre-study azacitidine.

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; 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, Myeloproliferative neoplasm
(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).

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.

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 unless he/she
can be transferred to other medications within = 5 half-lives prior to the start of
study treatment.

18. Subject has Heart rate-corrected QT (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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Parkville Cancer Clinical Trials Unit - Melbourne
Recruitment hospital [3] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [4] 0 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 0 0
SA 5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment postcode(s) [3] 0 0
3141 - Melbourne
Recruitment postcode(s) [4] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
Tennessee
Country [7] 0 0
United States of America
State/province [7] 0 0
Texas
Country [8] 0 0
Canada
State/province [8] 0 0
Ontario
Country [9] 0 0
France
State/province [9] 0 0
Lille
Country [10] 0 0
France
State/province [10] 0 0
Marseille Cedex 9
Country [11] 0 0
France
State/province [11] 0 0
Nantes
Country [12] 0 0
France
State/province [12] 0 0
Paris Cedex 10
Country [13] 0 0
France
State/province [13] 0 0
Pessac
Country [14] 0 0
France
State/province [14] 0 0
Pierre Benite
Country [15] 0 0
France
State/province [15] 0 0
Toulouse
Country [16] 0 0
France
State/province [16] 0 0
Tours cedex
Country [17] 0 0
France
State/province [17] 0 0
Villejuif CEDEX
Country [18] 0 0
Germany
State/province [18] 0 0
Berlin
Country [19] 0 0
Germany
State/province [19] 0 0
Dresden
Country [20] 0 0
Germany
State/province [20] 0 0
Düsseldorf
Country [21] 0 0
Germany
State/province [21] 0 0
Frankfurt
Country [22] 0 0
Germany
State/province [22] 0 0
Hannover
Country [23] 0 0
Germany
State/province [23] 0 0
Ulm
Country [24] 0 0
Italy
State/province [24] 0 0
Bologna, Emilia-Romagna
Country [25] 0 0
Italy
State/province [25] 0 0
Firenze
Country [26] 0 0
Italy
State/province [26] 0 0
Genova
Country [27] 0 0
Italy
State/province [27] 0 0
Orbassano
Country [28] 0 0
Italy
State/province [28] 0 0
Padova
Country [29] 0 0
Italy
State/province [29] 0 0
Pesaro
Country [30] 0 0
Italy
State/province [30] 0 0
Roma
Country [31] 0 0
Korea, Republic of
State/province [31] 0 0
Seoul
Country [32] 0 0
Netherlands
State/province [32] 0 0
Amsterdam
Country [33] 0 0
Netherlands
State/province [33] 0 0
Groningen
Country [34] 0 0
Netherlands
State/province [34] 0 0
Rotterdam
Country [35] 0 0
Netherlands
State/province [35] 0 0
Utrecht
Country [36] 0 0
Portugal
State/province [36] 0 0
Lisboa
Country [37] 0 0
Portugal
State/province [37] 0 0
Porto
Country [38] 0 0
Spain
State/province [38] 0 0
Barcelona
Country [39] 0 0
Spain
State/province [39] 0 0
Breña Alta
Country [40] 0 0
Spain
State/province [40] 0 0
Caceres
Country [41] 0 0
Spain
State/province [41] 0 0
Madrid
Country [42] 0 0
Spain
State/province [42] 0 0
Malaga
Country [43] 0 0
Spain
State/province [43] 0 0
Valencia
Country [44] 0 0
Switzerland
State/province [44] 0 0
Basel
Country [45] 0 0
Switzerland
State/province [45] 0 0
Lausanne
Country [46] 0 0
Switzerland
State/province [46] 0 0
Zurich
Country [47] 0 0
United Kingdom
State/province [47] 0 0
Birmingham
Country [48] 0 0
United Kingdom
State/province [48] 0 0
Headington
Country [49] 0 0
United Kingdom
State/province [49] 0 0
Leeds
Country [50] 0 0
United Kingdom
State/province [50] 0 0
London
Country [51] 0 0
United Kingdom
State/province [51] 0 0
Sutton (Surrey)

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Celgene
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This Phase 1b/2 study is an open-label, randomized, multicenter trial to evaluate the safety
and efficacy of oral AG-120 + Subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine
in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively. The
study population consists of subjects who are not candidates to receive intensive Inductive
chemotherapy (IC). The study comprises a Phase 1b dose-finding and AG-120 expansion stage and
a Phase 2 randomized stage.
Trial website
https://clinicaltrials.gov/show/NCT02677922
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Ira Gupta, MD
Address 0 0
Celgene Corporation
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications