Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation
- Clements University Hospital
Prapti Patel, M.D.
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 Mutation
The purpose of this Phase I, multicenter, clinical trial is to evaluate the safety of AG-120 and AG-221 when given in combination with standard AML induction and consolidation therapy. The study plans to evaluate 1 dose level of AG-120 in subjects with an IDH1 mutation and 1 dose level (and 2 dose schedules) of AG-221 in subjects with an IDH2 mutation. AG-120 or AG-221 will be administered with 2 types of AML induction therapies (cytarabine with either daunorubicin or idarubicin) and 2 types of AML consolidation therapies (mitoxantrone with etoposide [ME] or cytarabine). After consolidation therapy, subjects may continue on to maintenance therapy and receive daily treatment of AG-120 or AG-221 for up to 2 years from Day 1 of the first induction cycle, or until relapse, development of an unacceptable toxicity, or hematopoietic stem cell transplant (HSCT).
- Subjects must ≥18 years of age
- Previously untreated AML (de novo or secondary) defined according to World Health Organization (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 myelodysplastic syndromes (MDSs) or other antecedent hematologic disorders (AHDs) or AML arising after exposure to genotoxic injury including radiation and/or chemotherapy. Subjects may have had previous treatment for MDS or other AHD, including hypomethylating agents (HMAs), provided that the last dose of administration is ≥ 14 days prior to study drug initiation
- ECOG PS score of 0 to 2
- Adequate hepatic function as evidenced by: serum total bilirubin ≤1.5 × ULN unless considered due to Gilbert's disease, a gene mutation in UGT1A1 (only for patients who will be receiving AG-221), or leukemic involvement following approval by the study Sponsor; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic involvement following approval by the study Sponsor
- Adequate renal function as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance 40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)
- Agree to serial blood and bone marrow sampling
- Meet any criteria necessary for the safe and proper use of the induction and consolidation agents involved in this trial
- 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).
- 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
- 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 female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study, and for 4 months (females and males) following the last dose of AG-120 or AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or gel) or male partner sterilization
- Prior chemotherapy for AML. Hydroxyurea is allowed for the control of peripheral leukemic blasts in subjects with leukocytosis
- Taking medications with narrow therapeutic windows, unless they can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study
- Taking known strong cytochrome P450 (CYP) 3A4 inducers, 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) using Fridericia's formula (QTcF)
- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter-sensitive substrate medications unless they can be transferred to other medications within ≥5 half-lives prior to administration of AG-120 or AG-221, or unless the medications can be properly monitored during the study (with the exception of digoxin, which is not permitted for use with AG-120)
- Pregnant or breastfeeding
- 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
- 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: 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
- 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 by other methods according to institutional practice, obtained within 28 days prior to the start of study treatment
- QTc interval using Fridericia's formula (QTcF) ≥450 msec or other factors that increase the risk of QT interval prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTc are permitted with approval of the study Sponsor
- 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)
- Known infection caused by human immunodeficiency virus (HIV) or active hepatitis B or C
- Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
- Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is required only if there is a clinical suspicion of CNS involvement by leukemia during screening.
- Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
- Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a subject's ability to give informed consent or participate in the study