Details

Details

Title A Phase I/II, open-label multicenter study to determine safety, pharmacokinetics and efficacy of GMI-1271 in combination with chemotherapy in patients with acute myeloid leukemia

IRB GMI1915

CC 15-933

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Leukemia - Acute Myeloid (AML)

Drug GMI-1271

Description

Description

Primary Objective
  • Evaluate the safety of GMI-1271 in combination with chemotherapy
Secondary Objectives
  • Characterize the PK profile of GMI-1271
  • Evaluate efficacy of GMI-1271 in combination with chemotherapy (relapsed/refractory subjects: MEC; treatment-naive subjects: '7+3' cytarabine/ idarubicin) as measured by ORR, i.e. CR and CR with incomplete blood count recovery (CRi)
  • Time to response (TTR)
  • Evaluate duration of response (DOR)
  • Evaluate the event-free survival (EFS)
  • Evaluate 6-month and 12- month OS probability
Exploratory Objectives
  • Evaluate minimal residual disease (MRD) at time of count recovery in the subjects with CR or Cri
  • Describe the incidence, severity, and duration of neutropenia and thromboembolic events
  • Evaluate biomarker response in relation to dose
  • Describe mobilization of leukemic blasts, LSCs and HSCs by GMI-1271 at specified time points
  • Efficacy (ORR, MRD, TTR, DOR and OS) of GMI-1271 in combination with chemotherapy in the following sub-populations: favorable-, intermediate- and unfavorable-risk subject as per South West Oncology Group (SWOG) categorization, per karyotype and cytogenetics, per E-selectin ligand expression on leukemic cells (see Appendix 4)
Inclusion Criteria

Inclusion Criteria

  1. Signed ICF
  2. AML (including secondary AML) diagnosed as per WHO criteria as per local analysis report. (Complete immunohistochemistry and/or cytochemistry plus molecular genetic analysis to be provided within approximately 4 weeks after first GMI-1271 dose; not required for study entry.)
  3. For relapsed/refractory subjects only:
    • Subjects age ≥ 18 years
    • For subjects with (primary) refractory AML, ≤ 2 prior induction regimens, at least one containing anthracyclines (see Appendix 2 for definitions)
    • For subjects with relapsed AML, first or second relapse (see Appendix 1); subjects with one prior HSCT may be included
    • Have not previously received MEC and are medically eligible to receive MEC
    • Absolute blast count (ABC) ≤ 20,000/mm3 (ABC = total white blood cells [WBC] x blast %)
      • Entry ABC will be raised to ≤ 40,000/mm3 after evaluation of first two dose levels
  4. For treatment-naive subjects only:
    • Subjects ≥ 60 years of age with newly diagnosed AML
    • Medically eligible to receive '7+3' cytarabine/idarubicin
    • ABC count ≤ 40,000/mm3
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  6. Life expectancy > 4 weeks
  7. Hemodynamically stable with adequate organ function
    • Aspartate aminotransferase (AST)* and alanine aminotransferase (ALT) ≤ 2.5 upper limit of normal (ULN)
    • Total and Direct Bilirubin ≤ 1.5 ULN#
    • Creatinine ≤ 1.5 ULN
    • Fridericia corrected QT interval (QTcF) ≤ 480 ms7
  8. Willing and able to participate in all required evaluations and procedures in this study protocol

* If AST is elevated as a result of leukemia, and liver function is otherwise adequate (such as indicated by review of ALT, alkaline phosphatase, and bilirubin), a subject may be enrolled into the study with agreement of the Medical Monitor and the Investigator.

# This does not apply to subjects with Gilbert�s syndrome who can be enrolled after the Medical Monitor agrees with the Investigator�s diagnosis based on medical history and/or additional laboratory tests such as ALT, AST, and direct/indirect bilirubin. Any such decision will be documented in the study record.

Exclusion Criteria

Exclusion Criteria

  1. APL
  2. Acute leukemia of ambiguous lineage (biphenotypic leukemia)
  3. Active signs or symptoms of CNS involvement by malignancy (lumbar puncture [LP] not required)
  4. Prior G-CSF, granulocyte macrophage-colony stimulating factor (GM-CSF) or plerixafor within 14 days of study drug dosing
  5. Known history or evidence of active hepatitis A, B, or C or human immunodeficiency virus (HIV)
  6. Uncontrolled acute life threatening bacterial, viral or fungal infection
  7. Active graft versus host disease (GVHD) ≥ Grade 2 or extensive chronic GVHD requiring immunosuppressive therapy
  8. HSCT ≤ 4 months of dosing
  9. Any immunotherapy, chemotherapy, radiotherapy or experimental therapy within 4 weeks of dosing:
    • with the exception of hydroxyurea, which may be used to control peripheral blast count prior to initiation of GMI-1271 dosing; AND
    • with the exception of FLT3 inhibitors or TKI inhibitors, which are not considered cytotoxic chemotherapy; to avoid any drug-drug interactions such agents must be discontinued 5 days before protocol treatment begins.
  10. Major surgery within 4 weeks before first dose of study drug
  11. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
  12. Previous or concurrent malignancy except for adequately treated basal or squamous cell carcinoma, in situ carcinoma of the cervix, or other cancer from which the subject has been disease free for at least 5 years
  13. Pregnant or nursing (lactating) women
  14. WOMEN of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 8 weeks after the last dose of study drug. Highly effective contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject)
    • Female sterilization (has had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study drug. In case of oophorectomy alone, the subject would be eligible only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to Screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
    • BOTH of the following forms of contraception consistently used together:
      • Use of injected, transdermal or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%) with the exception of intrauterine devices which are excluded due to the risk of infection and bleeding
      • Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
  15. MEN who are sexually active and not willing to use condoms during the study (until Safety Evaluation Completion [SEC]), unless they have undergone vasectomy for sterilization (at least 6 months prior to Screening).