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
AG-221 (AG-221 mesylate),AG120,Azacitidine
The goal of this clinical research study is to find the highest tolerable dose of the combinations of AG-120 and azacitidine and AG-221 and azacitidine that can be given to patients with AML. Researchers also want to learn more about the effects of the drugs in combination with azacitidine compared to azacitidine alone.
Disease Group: Other diseases of blood and blood-forming organs
Treatment Agent: AG-221 (AG-221 mesylate),AG120,Azacitidine
Treatment Location: Both at MDACC & and Other Sites
Phase 1b (Dose-Escalation Stage) Primary Objectives To assess the safety and tolerability of the combination treatments of oral AG-120 plus subcutaneous (SC) azacitidine and oral AG-221 plus SC azacitidine in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive inductive chemotherapy (IC). To establish the recommended Phase 2 dose (RP2D) of oral AG-120 and oral AG-221 when administered with SC azacitidine. Secondary Objective To assess the preliminary efficacy of the combination treatments of oral AG-120 plus SC azacitidine and oral AG-221 plus SC azacitidine in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC. Exploratory Objective - Phase 1 (Dose Escalation) To evaluate the PD of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination in this population. Phase 2 (Randomized Stage) Primary Objective To assess the efficacy of the combination treatments of oral AG-120 plus SC azacitidine and oral AG-221 + SC azacitidine versus SC azacitidine in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC. Secondary Objective To evaluate the safety of oral AG-120 and oral AG-221 when administered with SC azacitidine. To characterize the pharmacokinetics (PK) of oral AG-120, AG-221, when administered in combination with SC azacitidine. To evaluate the effect of oral AG-120 and oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes. Exploratory Objective - Phase 2 (Randomized) To evaluate pharmacodynamic effects of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination as well as azacitidine as a single agent in this population. To evaluate molecular and cellular markers which may be predictive of antitumor activity and/or resistance. Other correlative analysis may include the evaluation of minimal residual disease (MRD), to assess IDH1 and IDH2 variant allele fraction (VAF) in blood and bone marrow cells. To assess changes in cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH1 and IDH2 mutated leukemic cells as well as wild-type IDH leukemic cells induced by oral AG-120 and oral AG-221 when administered with SC azacitidine. To evaluate the effect of oral AG-120 and oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on healthcare resource utilization.
IRB Review and Approval Date: 06/26/2016
Recruitment Status: Open
Projected Accrual: 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 previously untreated 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: 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 identified. 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.
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 Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female) / 72 x serum creatinine
7) Agree to serial bone marrow aspirate/biopsies.
8) Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: Agree to abstain from sexual intercourse or to use at least two highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen alone associated with inhibition of ovulation, oral, injectable, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization) at screening and throughout the study, and for 4 months following the last study treatment; and
9) (continuation of inclusion #8) -and Have a negative serum b-subunit of human chorionic gonadotropin (b-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and Have a negative serum b-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).
10) Male subjects (with a female partner of childbearing potential who must agree to conditions in criterion 8) abstain from sexual intercourse or to the use of at highly effective contraceptive methods at screening and throughout the course of the study and should avoid fathering a child during the course of the study and for 4 months following the last study treatment (6 months following the last dose of azacitidine in Canada).
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
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 that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis in subjects with white blood cell (WBC) counts >/= 30 x 109/L (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.
5) Subject has received prior treatment with azacitidine or 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 ; 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).
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. (If equivalent medication is not available, QTc will be closely monitored.)
18) Subject has 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.
Information and next steps
Other diseases of blood and blood-forming organs
Phase I/Phase II
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