Details

Details

Title A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects with Advanced Hematologic Malignancies with an IDH1 Mutation

IRB AGSP1Z15

CC 15-519

Hospital Main Campus

Phase Phase 1

Disease Leukemia - Acute Myeloid (AML)

Drug AG-120

Description

Description

Primary Objectives
  • To assess the safety and tolerability of treatment with AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies. The initial dosing regimen will be twice daily (approximately every 12 hours). Based on the emerging data, a once daily dosing schedule has been implemented. Alternative dosing schedules, including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored as agreed upon by the Clinical Study Team.
  • To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of AG-120 in subjects with advanced hematologic malignancies.
  • To assess the clinical activity of AG-120 in subjects with relapsed or refractory AML with an IDH1 mutation who are enrolled in Arm 1 of the expansion phase.
Secondary Objectives
  • To describe the dose limiting toxicities (DLTs) of AG-120 in subjects with advanced hematologic malignancies.
  • To characterize the PK of AG-120 in subjects with advanced hematologic malignancies.
  • To evaluate the PK/PD relationship of AG-120 and 2-HG.
  • To characterize the clinical activity associated with AG-120 in subjects with advanced hematologic malignancies.
Exploratory Objectives
  • To characterize the PD effects of AG-120 in subjects with advanced hematologic malignancies by the assessment of:
    • Changes in the patterns of cellular differentiation of IDH1-mutated cells.
    • Changes in histone and DNA methylation profiles in IDH1-mutated cells.
  • To evaluate gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH1-mutated cells and plasma, as well as subclonal populations of non-IDH1 mutated cells, to explore predictors of anti-tumor activity and/or resistance.
  • To evaluate changes in the metabolic profiles in IDH1-mutated cells, urine and plasma.
  • To monitor plasma cholesterol and 4β-OH-cholesterol levels as a potential CYP3A4 induction marker for subjects enrolled in the dose escalation phase.
Inclusion Criteria

Inclusion Criteria

  1. Subjects must be ≥18 years of age.
  2. Subjects must have an advanced hematologic malignancy including:

    Dose Escalation Phase:

    • Relapsed and/or primary refractory AML as defined by WHO criteria; or
    • Untreated AML, ≥60 years of age and not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor.
    • Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the IPSS-R (Greenberg, et al. 2012), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor.
    (Subjects with other relapsed and/or primary refractory hematologic cancers, for example CMML, who fulfill the inclusion/excluding criteria may be considered on a case-by case basis, with approval of the Medical Monitor.)

    Expansion Phase:

    • Arm 1: Relapsed or refractory AML defined as:
      • Subjects who relapse after transplantation;
      • Subjects in second or later relapse;
      • Subjects who are refractory to second-line induction or reinduction treatment;
    • Arm 2: Untreated AML.
    • Arm 3: IDH1-mutated advanced hematologic malignancies not eligible for Arms 1 or 2.

  3. Subjects must have documented IDH1 gene-mutated disease:
    • For subjects in the dose escalation phase, IDH1 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.)
    • For subjects in the expansion phase, central testing of IDH1 gene-mutated disease is required during screening to confirm eligibility.
  4. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling, and urine sampling during the study. The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration and biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis may be made from the core biopsy.
  5. Subject 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).
  6. Subjects must have ECOG PS of 0 to 2.
  7. Platelet count ≥20,000/μL (Transfusions to achieve this level are allowed.) Subjects with a baseline platelet count of <20,000/μL due to underlying malignancy are eligible with Medical Monitor approval.
  8. 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 or leukemic disease;
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤3.0 x ULN, unless considered due to leukemic disease.
  9. 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
  10. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.)
  11. Female subjects with reproductive potential must agree to undergo 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), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
  12. 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 female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception form the time of giving informed consent, during the study and for 90 days (females and males) following the last dose of AG-120. 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.
Exclusion Criteria

Exclusion Criteria

  1. Subjects who have undergone a hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-120, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post HSCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.)
    2. 1
  2. Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed prior to enrollment and after the start of AG-120 for the control of peripheral leukemic blasts in subjects with leukocytosis (white blood cell [WBC] counts >30,000/μL).
  3. Subjects who received an investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
  4. Subjects taking the following sensitive CYP3A4 substrate medications are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz.
  5. Subjects taking the following P-gp transporter-sensitive substrate medications are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, fexofenadine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, and tolvaptan.
  6. Subjects for whom potentially curative anticancer therapy is available.
  7. Subjects who are pregnant or breast feeding.
  8. 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).
  9. Subjects with known hypersensitivity to any of the components of AG-120.
  10. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure (Appendix 15.2) or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within approximately 28 days of C1D1.
  11. Subjects with a history of myocardial infarction within the last 6 months of screening.
  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 QTcF (QT corrected based on Fridericia's equation) interval ≥450 msec or with 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 (see Section 9.11.2) unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
  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 clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
  20. Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.