A clinical trial to evaluate the safety and effectiveness of a combination of either AG-120 or AG-221 tablets with azacitidine injections in patients with newly diagnosed Acute Myeloid Leukemia (AML) and who have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH 1 or IDH2) and are not candidates to receive intensive induction chemotherapy.
- Conditions
- ewly 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)MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
- Registration Number
- EUCTR2015-003951-23-PT
- Lead Sponsor
- Celgene Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 138
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 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
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 stu
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method