Details

Details

Title A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

IRB APGD1914

CC 14-863

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Leukemia - Acute Myeloid (AML)

Drug ASP2215

Description

Description

Primary Objectives
  • Assess the safety and tolerability, including determination of the maximum tolerated dose (MTD) of oral ASP2215 in subjects with relapsed or treatment-refractory AML.
  • Determine the pharmacokinetic (PK) parameters of ASP2215.
Secondary Objectives
  • Investigate the anti-leukemic activity of various doses of ASP2215 in subjects with AML.
  • Evaluate the effect of strong or moderate cytochrome P450-isozyme3A4 (CYP3A4) inhibitors on the PK of ASP2215.
  • Evaluate the potential induction of CYP3A4 by ASP2215 by assessment of midazolam PK.
  • Evaluate the effect of ASP2215 on MATE1 substrates by assessment of cephalexin PK.
Inclusion Criteria

Inclusion Criteria

  1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
  2. Subject is ≥ 18 years of age at the time of obtaining informed consent.
  3. Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following:
    • Refractory to at least 1 cycle of induction chemotherapy
    • Relapsed after achieving remission with a prior therapy
  4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  5. Subject's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents.
  6. Subject must meet the following criteria as indicated on the clinical laboratory tests:
    • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit normal (ULN)
    • Total serum bilirubin ≤ 1.5 x institutional ULN
    • Serum creatinine ≤ 1.5 x institutional ULN or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
  7. Subject is suitable for oral administration of study drug.
  8. Female subject must be either:
    • Of non child bearing potential:
    • post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
    • documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening)
    • Or, if of childbearing potential,
    • must have a negative urine pregnancy test at Screening, and
    • must use two forms of birth control (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 45 days after the final study drug administration.
  9. Female subject must not be breastfeeding at Screening or during the study period, and for 45 days after the final study drug administration.
  10. Female subject must not donate ova starting at Screening and throughout the study period, and for 45 days after the final study drug administration.
  11. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 105 days after the final study drug administration.
  12. Male subject must not donate sperm starting at Screening and throughout the study period and for 105 days after the final study drug administration.
  13. Subject agrees not to participate in another interventional study while on treatment.
  14. Subject has documented FLT3 mutation positive AML (ITD and/or activating point mutations) Screening labs and diagnostic tests may be performed at local laboratories to determine eligibility. However, samples will also be submitted for central read. Acceptable forms of birth control include:
    • Established use of oral, injected or implanted hormonal methods of contraception.
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS).
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Exclusion Criteria

Exclusion Criteria

  1. Subject was diagnosed as acute promyelocytic leukemia (APL).
  2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
  3. Subject has active malignant tumors other than AML or Myelodysplastic syndrome (MDS).
  4. Subject has persistent nonhematological toxicities of ≥ Grade 2 (CTC AE v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
  5. Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:
    • Is within 2 months of transplant from C1D1
    • Has clinically significant graft-versus-host disease requiring treatment
    • Has ≥ Grade 2 persistent non-hematological toxicity related to the transplant Donor lymphocytes infusion (DLI) is not permitted ≤ 30 days prior to study registration or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in Cohort 2.
  6. Subject has clinically active central nervous system leukemia.
  7. Subject has disseminated intravascular coagulation abnormality (DIC).
  8. Subject has had major surgery within 4 weeks prior to the first study dose.
  9. Subject has had radiation therapy within 4 weeks prior to the first study dose
  10. Subject has congestive heart failure NYHA class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
  11. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A4 or of P-glycoprotein (P-gp) or substrates of multidrug and toxin extrusion 1 (MATE 1) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject.
  12. Subject required treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
  13. Subject has an active uncontrolled infection.
  14. Subject is known to have human immunodeficiency virus infection.
  15. Subject has active hepatitis B or C, or other active hepatic disorder.
  16. Subject has any condition which, in the investigator's opinion, makes the subject unsuitable for study participation (e.g., ophthalmic conditions such as advanced cataracts, subject is unable to undergo a comprehensive ophthalmologic exam, inability to visualize the fundus).

    17. MATE1 Sub-study (Schedule 2E) Subjects Only:

  17. Subject has known severe allergy to penicillins or cephalosporins.
  18. Subject was previously treated with ASP2215.