EUCTR2015-003951-23-PTActive, not recruitingPhase 1
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
Conditions
Drugs
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Celgene Corporation
- Enrollment
- 138
Study Overview
Brief Summary
No summary available.
Study Design
- Study Type
- Interventional clinical trial of medicinal product
Eligibility Criteria
- Sex
- All
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 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
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
- •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
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