A phase 1, multicenter, open-label, safety study of AG-120 or AG-221 in combination with induction therapy and consolidation therapy in patients with newly diagnosed acute myeloid leukemia with an IDH1 and/or IDH2 mutatio
- Conditions
- acute myelogenous leukemia10024324
- Registration Number
- NL-OMON53153
- Lead Sponsor
- Institut de Recherches Internationales Servier (I.R.I.S)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 20
1. >=18 years of age
2. Previously untreated AML (de novo or secondary) defined according to
WHO criteria, excluding APL [AML with t(15;17)], with locally
documented IDH1 and/or IDH2 gene mutation scheduled for induction
therapy followed by consolidation therapy. Secondary AML is defined as
AML arising after MDS or another antecedent hematologic disorder (AHD) or AML
arising after exposure to genotoxic injury including radiation and/or
chemotherapy. Patients may have had previous treatment with
hypomethylating agents (HMAs) for MDS, provided that the last dose of
administration was >14 days prior to study drug initiation.
3. ECOG PS score of 0 to 2
4. Adequate hepatic function as evidenced by:
a. Serum total bilirubin <=1.5 × upper limit of normal (ULN) unless
considered due to Gilbert's disease, a gene mutation in UGT1A1 (only for
subjects who will be receiving AG-221), or leukemic involvement
following approval by the Medical Monitor
b. AST, ALT, and ALP <=3.0 × ULN, unless considered due to leukemic
involvement following approval by the study sponsor
5. Adequate renal function as evidenced by serum creatinine <=2.0 × ULN
or creatinine clearance >40 mL/min based on the Cockroft-Gault
glomerular filtration rate (GFR)
6. Agree to serial blood and bone marrow sampling
7. Meet any criteria necessary for the safe and proper use of the
induction and consolidation agents involved in this trial
8. Able to understand and willing to sign an informed consent form. A
legally authorized representative may consent on behalf of a subject
who is otherwise unable to provide informed consent, if acceptable to,
and approved by, the site's Institutional Review Board
(IRB)/Independent Ethics Committee (IEC)
9. Female subjects with reproductive potential must agree to undergo a
medically supervised pregnancy test prior to starting study drug. The
first pregnancy test will be performed at screening (within 7 days prior
to first study drug administration). A pregnancy test should also be
performed on the day of the first study drug administration and
confirmed negative prior to dosing as well as before dosing on Day 1 of
all subsequent cycles.
10. Female subjects with reproductive potential must have a negative
serum pregnancy test within 7 days prior to the start of the therapy.
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 and their partners who are females of reproductive
potential must agree to abstain from sexual intercourse or to use one
highly effective form (for subjects receiving AG-221) or two highly
effective forms (for subjects receiving AG-120) of contraception from
the time of giving informed consent, during the study, and for 2 months
(for subjects receiving AG-221) and for 4 months (for subjects receiving
AG-120) following the last dose of AG-120 or AG-221 (females and
males). A highly effective form of contraception is defined as hormonal
oral contraceptives, injectables, patches, intrauterine devices, doublebarrier
methods (e.g., synthetic condoms, diaphragm or cervical cap
with spermicidal foam, cream, or gel) or male partner sterilization
1. Have received prior chemotherapy for AML. Hydroxyurea is allowed prior to
enrollment for the control of peripheral leukemic blasts in subjects with
leukocytosis; hydroxyurea may be allowed on study with study sponsor approval.
2. Taking medications with narrow therapeutic windows listed in
Appendix 15.6 (for subjects taking AG-221) or Appendix 15.7 (for subjects
taking AG-120), unless they can be transferred to other medications prior
to enrolling or unless the medications can be properly monitored during
the study.
3. Taking known strong cytochrome P450 (CYP) 3A4 inducers or
inhibitors unless they can be transferred to other medications prior to
enrolling. For subjects taking AG-120, systemic administration of a moderate or
strong CYP3A4 inhibitor requires careful monitoring of the heart rate-corrected
QT interval (QTc) interval using Fridericia*s formula (QTcF).
4. Taking P-glycoprotein (P-gp) or BCRP transporter-sensitive substrate
medications unless they can be transferred to alternative medications within
>= 5 half-lives prior to administration of AG-221, or unless the
medications can be properly monitored during the study. There are no
restrictions regarding the co-administration of such medications with AG-120.
5. Pregnant or breast feeding
6. Uncontrolled active infection or uncontrolled invasive fungal infection
(positive blood or tissue culture). An infection controlled with an
approved or closely monitored antibiotic/antifungal treatment is
allowed.
7. Prior history of malignancy, other than MDS 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:
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
8. 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; myocardial infarction, unstable angina
and/or stroke; or LVEF <40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of
study treatment
9. QTc interval >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). Bundle branch block and prolonged QTc interval are
permitted with approval of the study sponsor.
10. Taking medications that are known to prolong the QT interval unless
they can be transferred to other medications within >=5 half-lives prior to
dosing (If equivalent medication is not available QTc will be closely
monitored)
11. Known infection caused by human immunodeficiency virus (HIV) or active
hepatitis B or C
12. Dysphagia, short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of orally
administered drugs
13. 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.
14. Immediate life-threatening, severe com
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Safety Outcome Measures<br /><br><br /><br>Safety will be evaluated by:<br /><br><br /><br>• Dose-limiting toxicities (DLTs)<br /><br>• Adverse events (AEs), serious adverse events (SAEs), and AEs leading to<br /><br>discontinuation<br /><br>• Safety laboratory test results, physical examination, vital signs, 12-lead<br /><br>electrocardiograms (ECGs), left ventricular ejection fraction (LVEF), and<br /><br>Eastern Cooperative Oncology Group (ECOG) performance status (PS)<br /><br>• Drug exposure, including dose intensities and dose modifications</p><br>
- Secondary Outcome Measures
Name Time Method