Details

Details

Title A Phase 1/2, Multicenter, Open-Label, Dose-Escalation Study of AG-221 in Subjects with Advanced Solid Tumors, including Glioma, and with Angioimmunoblastic T-cell Lymphoma, that Harbor an IDH2 Mutation

IRB AGSP1Y15

CC 15-879

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Solid Tumors

Drug AG-221

Description

Description

Primary Objectives
  • To assess the safety and tolerability of treatment with AG-221 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced solid tumors, including glioma, and in subjects with AITL.
  • To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose of AG-221 in subjects with advanced solid tumors, including glioma, and in subjects with AITL.
Secondary Objectives
  • To describe the DLTs of AG-221 in subjects with advanced malignancies.
  • To characterize the PK of AG-221 and its metabolite in subjects with advanced malignancies.
  • To evaluate the PK/PD relationship of AG-221 and 2-hydroxygluturate (2-HG) in blood samples.
  • To characterize the clinical activity associated with AG-221 in subjects with advanced malignancies.
Exploratory Objectives
  • To evaluate changes in Ki67 levels in tumor samples.
  • To characterize the PD effects of AG-221 in subjects with advanced malignancies, by the assessment of:
    • Changes in the patterns of cellular differentiation of IDH2-mutated tumor cells.
    • Changes in histone and DNA methylation profiles in IDH2-mutated tumor cells.
    • To characterize the PD effects of AG-221 in subjects with glioma by the assessment of changes in 2-HG concentration as detected by proton magnetic resonance spectroscopy (1H-MRS) on magnetic resonance images (MRI).
  • To evaluate gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH2-mutated tumor cells to explore predictors of anti-tumor activity and/or resistance.
  • To evaluate changes in the metabolic profiles in IDH2-mutated tumor cells, urine and plasma.
  • To monitor plasma cholesterol and 4β-OH-cholesterol levels as a potential CYP3A4 induction marker.
Inclusion Criteria

Inclusion Criteria

  1. Subject must be ≥18 years of age.
  2. Subjects must have a histologically or cytologically confirmed advanced solid tumor, including glioma, or AITL that has recurred or progressed following standard therapy, or that has not responded to standard therapy.
  3. Subjects must have documented IDH2 gene-mutated disease based on local site testing. (Centralized testing will be performed retrospectively.)
  4. Subject must have measureable disease by RECIST v1.1 for subjects with solid tumors without glioma, by modified RANO criteria for subjects with glioma, or by the revised IWG criteria for subjects with AITL.
  5. Subjects must be amenable to serial peripheral blood sampling, urine sampling, and biopsies.
  6. Subjects must be able to understand and willing to sign an informed consent. 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 and/or site's Institutional Review Board (IRB).
  7. Subjects must have ECOG PS of 0 to 2.
  8. Subjects must have expected survival of ≥3 months.
  9. Subjects other than those with AITL must have adequate bone marrow function as evidenced by:
    • Absolute neutrophil count ≥ 1.0 x 109/L;
    • Hemoglobin > 9 g/dL (Subjects are allowed to be transfused to this level)
    • Platelets ≥ 50 x 109/L
  10. Subjects must have adequate hepatic function as evidenced by:
    • Serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or disease involvement, following approval by the Medical Monitor;
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤2.5 x ULN. For subjects with bone metastases and/or suspected disease-related liver or biliary involvement, ALP must be ≤5 x ULN.
  11. Subjects must have adequate renal function as evidenced by:
    • Serum creatinine ≤2.0 x ULN OR
    • Creatinine clearance >40 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
  12. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (For example, subjects with residual Grade 1 toxicity or stable Grade 2 peripheral neuropathy due to prior chemotherapy are allowed with approval of the Medical Monitor.)
  13. Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy tests prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and subsequent pregnancy tests on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
  14. Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of 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 (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 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 two highly effective forms of contraception from the time of giving informed consent, during the study and for 90 days (females and males) following the last dose of 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.
  15. Previous allogeneic stem cell transplant is allowed only if subjects are >100 days from stem cell transplant and do not have uncontrolled acute or chronic graft-versus-host disease.
Exclusion Criteria

Exclusion Criteria

  1. Subjects who received systemic anticancer therapy or radiotherapy <21 days prior to their first day of study drug administration.
  2. Subjects who received an investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
  3. Subjects taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2).
  4. Subjects taking the P-gp and BCRP transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
  5. Subjects for whom potentially curative anticancer therapy is available.
  6. Subjects who are pregnant or breast feeding.
  7. Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever >38.5oC during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
  8. Subjects with known hypersensitivity to any of the components of AG-221.
  9. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within approximately 28 days prior to starting study treatment.
  10. Subjects with a history of myocardial infarction within the last 6 months of screening.
  11. Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) at screening are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with documented Medical Monitor approval.
  12. Subjects with known unstable or uncontrolled angina pectoris.
  13. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
  14. Subjects with heart-rate corrected QTcF (QT corrected based on Frederica's equation) 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) at screening. Subjects with bundle branch block and a prolonged QTc interval should be reviewed by the Medical Monitor for potential inclusion.
  15. Subjects 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 (see Section 9.11.2).
  16. Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
  17. Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.
  18. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
  19. Subjects with brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including those used to control symptoms, within 2 months of first dose. Subjects with glioma who are on a stable, steroid-dosing regimen prior to screening MRI may be permitted to enroll with documented Medical Monitor approval.
  20. In subjects with AITL, evidence of meningeal or cerebral disease or a history of progressive multifocal leukoencephalopathy.
  21. Radiotherapy involving <25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment.
  22. Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment.