A Study to Evaluate the Pharmacokinetics, Safety,and Efficacy of Omacetaxine Given Subcutaneously as a Fixed Dose in Patients With Chronic Phase (CP) or Accelerated Phase (AP) Chronic Myeloid Leukemia (CML) (Referred to as the SYNSINCT Study)

An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, Safety,and Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed Dose inPatients With Chronic Phase or Accelerated Phase Chronic Myeloid Leukemia Who Have Failed 2 or More Tyrosine Kinase Inhibitor Therapies

To satisfy a postmarketing requirement, the sponsor has been requested to conduct a Phase 1/Phase 2 single-group clinical study to investigate the pharmacokinetics and preliminary safety and efficacy of omacetaxine following a fixed-dose administration to patients with CP or AP CML who have failed 2 or more tyrosine kinase inhibitor (TKI) therapies.

Because the trial was not feasible due to the inability to accrue additional clinical study sites and enroll an adequate number of subjects, the FDA released the sponsor from the postmarketing requirement on 13 November 2017 and the study was stopped prematurely. Therefore, the study did not progress to the Phase 2 portion.

Inclusion Criteria:

• The patient has a confirmed diagnosis of Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either CP or AP. Accelerated phase will be defined as disease having 1 of the following: ≥15% to <30% blasts in peripheral blood or bone marrow; ≥30% blasts + promyelocytes in peripheral blood or bone marrow; ≥20% basophils in peripheral blood or bone marrow; platelet count <100x109/L unrelated to therapy; or clonal evolution.

• The patient has either failed, demonstrated intolerance, or a combination of prior failure and intolerance, to prior treatments with at least 2 tyrosine kinase inhibitors (TKI's). Failure of TKI treatment may either be primary (never achieved a response) or secondary resistance (loss of response).

• TKI treatment failure will be defined as 1 of the following:

  • no CHR by 12 weeks (whether lost or never achieved)
  • no partial cytogenetic response by 24 weeks (ie, 1 to 35% Ph-positive) (whether lost or never achieved) no major cytogenetic response by 52 weeks (ie, ≤35% Ph-positive) (whether lost or never achieved)
  • progressive leukocytosis, defined as increasing white blood cell (WBC) count on at least 2 consecutive evaluations, at least 2 weeks apart and doubling from the nadir to ≥20000/μL or absolute increase in WBC by ≥50000/μL above the post-treatment nadir

• Intolerance to TKI therapy will be defined as 1 of the following:

  • grade 3 to 4 nonhematologic toxicity that does not resolve with adequate intervention
  • grade 4 hematologic toxicity lasting more than 7 days, or a documented inability to sustain the TKI therapy because of recurrent grade 3 or 4 hematologic toxicity with re-initiation of the same therapy
  • any grade 2 or greater toxicity that is unacceptable to the patient

• Patients must have completed all previous anticancer therapy for at least 2 weeks prior to the first planned dose of omacetaxine, except as noted below, and must have fully recovered from side effects of a previous therapy.

• In patients with rapidly proliferating disease, hydroxyurea may be administered before study entry, if clinically indicated, to control disease. In such cases, complete hematologic response (CHR) must be sustained for at least 4 weeks for accelerated CML, and at least 8 weeks for chronic phase CML, following the discontinuation of hydroxyurea, to be considered as a CHR.

• Patients may receive anagrelide for up to 28 days (in countries where the product is registered). Leukapheresis is allowed up to 24 hours prior to the first treatment cycle with omacetaxine.

• Patients must have adequate hepatic and renal function as evidenced by bilirubin 2.0 times the upper limit of the normal range (ULN) or lower, alanine aminotransferase (ALT) and asparate aminotransferase (AST) 3 times the ULN or lower, serum creatinine 1.5 times the ULN or lower. Patients with nonclinically significant elevations of bilirubin up to 5.0 g/dL (85500 μmol/L) due to known or suspected Gilbert's disease are eligible; this must be documented on the medical history page of the case report form (CRF).

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• Patients are men or women at least 18 years of age.

• Patients must be able and willing to provide written informed consent prior to any study related procedure.

• The patient must take precautions to not become pregnant or produce offspring. Women must be of non-childbearing potential (surgically sterile or postmenopausal for at least 12 months, confirmed by follicle-stimulating hormone [FSH] >40 IU/L) or agree to use a medically accepted method of contraception for the duration of the study and 90 days after treatment. Men must be surgically sterile or agree to use a medically accepted method of contraception for the duration of the study and 90 days after treatment. Acceptable methods of contraception include abstinence, barrier method with spermicide (excluding cervical cap and sponge), intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.

  • Other criteria may apply, please contact the investigator for additional information

Exclusion Criteria:

• The patient has New York Heart Association (NYHA) class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.

• The patient has had a myocardial infarction in the previous 12 weeks. (Prior to study entry, electrocardiogram [ECG] abnormalities at screening must be documented by the investigator as not medically relevant.)

• The patient has received radiotherapy within 30 days prior to the start of study drug, or has not recovered from the acute toxicities associated with prior approved therapies including investigational drugs.

• The patient has another concurrent illness that would preclude study conduct and assessment, including, but not limited to, another active malignancy (excluding squamous or basal cell skin cancer and in situ cervical cancer), uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life threatening, or clinically significant), uncontrolled risk of bleeding, or uncontrolled diabetes mellitus.

• The patient underwent autologous or allogeneic stem cell transplant within 60 days prior to receiving the first dose of omacetaxine and has any evidence of ongoing graft versus host disease (GVHD), or GVHD requiring immunosuppressive therapy.

• The patient has a human leukocyte antigen (HLA)-matched donor and is eligible for allogeneic transplantation for CML treatment.

• The patient has known positive human immunodeficiency virus (HIV) or known active human t-cell lymphotropic virus (HTLV) I/II disease, whether on treatment or not.

• The patient has known active hepatitis B or C. The determination of active hepatitis B or C is left to the investigator.

• The patient has lymphoid Ph+ blast crisis or blast phase CML.

• The patient participated in another clinical investigation within 30 days of enrollment or is receiving another investigational agent.

• The patient received omacetaxine or has a history of hypersensitivity.

  • Other criteria may apply, please contact the investigator for additional information