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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Omacetaxine mepesuccinate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omacetaxine mepesuccinate.<br>The study will consist of up to a 7-day screening period, and treatment for up to 12 months, in Phase 1 and Phase 2 portions, depending on response and tolerability. Patients will also have an end-of-treatment follow-up visit approximately 28 days after the last dose of omacetaxine. Each patient will be monitored for progression and survival for at least 1 year after their last dose of omacetaxine, death, or lost to follow-up, whichever comes first, regardless of patients receiving other anticancer treatment. | Drug: Omacetaxine mepesuccinate<br>* 3.5 mg omacetaxine mepesuccinate and 10 mg mannitol; The first dose of the day for cycle 1 will be administered at the investigational center. Subsequent doses (in prefilled syringes) may be administered on an outpatient basis after training takes place<br>* Other names: SYNRIBO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved a Major Response at Any Time During Treatment | The Independent Data Monitoring Committee assessments are summarized. Major response for participants with chronic phase CML was a major cytogenetic response (MCyR) defined as a complete cytogenetic response with no Ph+ metaphases, or a partial cytogenetic response with up to 35% Ph+ metaphases. Note that a complete hematologic response was not considered a major response. Major response for participants with accelerated phase CML was a major hematologic response (MaHR) defined as a complete hematologic response or no evidence of leukemia, and/or a major cytogenic response (MCyR). | Day 1 up to Month 15 (longest treatment duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longest Duration of Response At Study Termination | Duration of response was defined for responders as the time interval from the first reported date of a major cytogenetic response (MCyR) or a major hematologic response (MaHR) to the earliest date of objective evidence of disease progression (ie, development of accelerated-phase CML), relapse (ie, loss of complete hematologic or major cytogenetic response), or death. Kaplan-Meier estimates for duration of response were not performed due the small enrollment population and early termination of the study. What is reported is the longest duration of response observed prior to disease progression, death, lost to follow-up or study termination. | Day 1 to Day 541 (longest progression/survival follow-up) | 
| Number of Participants Who Had a Molecular Response at Any Time During Treatment | Molecular response was defined by the decrease in the amount of BCR-ABL (an abnormality of chromosome 22) messenger ribonucleic acid (mRNA) measured by reverse transcriptase polymerase chain reaction (RT-PCR) or by the actual percentage of BCR-ABL mRNA transcripts (ratio of BCR-ABL transcript numbers to the number of control gene transcripts). | Day 1 up to Month 15 | 
| Number of Participants Who Were Alive and Progression-Free at Study Termination | Progression-free survival was defined as the time interval from the date of first dose to the date of the earliest objective evidence of disease progression (ie, development of accelerated-phase CML), relapse (ie, loss of complete hematologic or major cytogenetic response), or death. Kaplan-Meier estimates for time for progression-free survival were not performed due the small enrollment population and early termination of the study. What is reported is the number of participants who were alive and progression-free at the time of study termination. | Day 1 to Day 541 (longest progression/survival follow-up) | 
| Number of Participants Who Were Alive at Study Termination | Overall survival was defined as the time interval from the date of the first dose to the date of death from any cause. Kaplan-Meier time estimates for overall survival were not performed due to the small enrollment population and early termination of the study. What is reported is the number of participants who were alive at the time of study termination. | Day 1 to Day 541 (longest progression/survival follow-up) | 
| Maximum Observed Plasma Concentration (Cmax) for Omacetaxine | Maximum observed plasma drug concentration (Cmax) by inspection (without interpolation). Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Time to Maximum Observed Plasma Concentration (Cmax) for Omacetaxine | Time to maximum observed plasma drug concentration (Cmax) by inspection (without interpolation). Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Area Under the Drug Concentration by Time Curve From Time 0 to the Time of the Last Measurable Drug Concentration (AUC0-t) for Omacetaxine | Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Area Under the Drug Concentration by Time Curve From Time 0 to Infinity (AUC0-inf) for Omacetaxine | Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Terminal Elimination Half-Life (t1/2) for Omacetaxine | Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Total Oral Clearance (CL/F) for Omacetaxine | Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Apparent Volume of Distribution (V/F) for Omacetaxine | Nominal PK sampling times were used. | Cycle 1 - Day 1 (predose, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48, 72 hours post-dose) Day 10 (predose, 2 samples postdose), Day 13 (predose) Cycles 2+3 - Day 1 (2 samples postdose), Days 10 and 17 (1 sample predose) | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product, regardless of whether it has a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is an AE that that began or worsened after treatment with study drug. Severity rating of 3=Severe or medically significant but not immediately life-threatening 4=Life-threatening consequences and 5=Death. Relation to study drug is determined by the investigator. A serious adverse event (SAE) includes death, a life-threatening AE, hospitalization, persistent or significant disability or incapacity, a congenital anomaly/birth defect, or any important medical event requiring immediate intervention to prevent one of the outcomes above. | Day 1 up to Month 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Phase, Accelerated Phase, CML, Chronic Myeloid Leukemia