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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-005320-42 | EudraCT Number |
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Inability to accrue additional sites and enroll an adequate number of subjects.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Omacetaxine mepesuccinate. | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omacetaxine mepesuccinate | Drug | 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 |
| 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) |
| 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. |
Not provided
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:
Intolerance to TKI therapy will be defined as 1 of the following:
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.
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.
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| Name | Affiliation | Role |
|---|---|---|
| Sponsor's Medical Expert, MD | Teva Branded Pharmaceutical Products R&D, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Teva Investigational Site 12545 | Jacksonville | Florida | 32207 | United States | ||
| Teva Investigational Site 12550 |
Of the 14 patients screened, 9 patients at 3 centers in the US and 1 patient at a single centre in France met entry criteria and were considered to be eligible for enrollment into the study.
A total of 14 patients with chronic myeloid leukemia were screened for enrollment into this study. Of the 4 patients who were not enrolled, 2 were excluded on the basis of inclusion/exclusion criteria and 2 for "other" reasons.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 | Participants whose body surface area (BSA) is less than 1.7 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Treatment Period |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 22, 2015 | Dec 19, 2018 |
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|
|
| 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 |
| Atlanta |
| Georgia |
| 30322 |
| United States |
| Teva Investigational Site 12543 | Indianapolis | Indiana | 46237 | United States |
| Teva Investigational Site 12547 | Buffalo | New York | 14263 | United States |
| Teva Investigational Site 12546 | Cincinnati | Ohio | 45219 | United States |
| Teva Investigational Site 12544 | Houston | Texas | 77030 | United States |
| Teva Investigational Site 37048 | Ghent | 9000 | Belgium |
| Teva Investigational Site 37047 | Leuven | 3000 | Belgium |
| Teva Investigational Site 35157 | Pierre-Bénite | 69 495 | France |
| Teva Investigational Site 87026 | Seoul | 137-701 | South Korea |
| FG001 | Cohort 2 | Participants whose body surface area (BSA) is between 1.7 m^2 to 2.0 m^2 inclusive All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| FG002 | Cohort 3 | Participants whose body surface area (BSA) is greater than 2.0 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| COMPLETED | Treatment completed |
|
| NOT COMPLETED |
|
|
| Follow-up Period |
|
|
Enrolled patients
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 | Participants whose body surface area (BSA) is less than 1.7 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| BG001 | Cohort 2 | Participants whose body surface area (BSA) is between 1.7 m^2 to 2.0 m^2 inclusive All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| BG002 | Cohort 3 | Participants whose body surface area (BSA) is greater than 2.0 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Weight | Mean | Standard Deviation | kg |
| |||||||||||||||
| Height | Mean | Standard Deviation | cm |
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| Body Surface Area (BSA) | Mean | Standard Deviation | m^2 |
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| Phase of Chronic Myeloid Leukemia (CML) at Study Entry | CP: patients typically have less than 10% blasts in their blood or bone marrow samples. Patients usually have fairly mild symptoms and usually respond to standard treatments. AP: patients have >=1 of the following:
| Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Enrolled participants | Posted | Count of Participants | Participants | Day 1 up to Month 15 (longest treatment duration) |
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| Secondary | 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. | Enrolled participants who had a response | Posted | Number | days | Day 1 to Day 541 (longest progression/survival follow-up) |
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| Secondary | 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). | Enrolled participants | Posted | Count of Participants | Participants | Day 1 up to Month 15 |
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| Secondary | 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. | Enrolled participants | Posted | Count of Participants | Participants | Day 1 to Day 541 (longest progression/survival follow-up) |
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| Secondary | 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. | Enrolled participants | Posted | Count of Participants | Participants | Day 1 to Day 541 (longest progression/survival follow-up) |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) for Omacetaxine | Maximum observed plasma drug concentration (Cmax) by inspection (without interpolation). Nominal PK sampling times were used. | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | 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) |
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| Secondary | 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. | PK analysis set | Posted | Median | Full Range | hour | 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) |
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| Secondary | 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. | PK analysis set | Posted | Mean | Standard Deviation | ng*hr/mL | 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) |
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| Secondary | Area Under the Drug Concentration by Time Curve From Time 0 to Infinity (AUC0-inf) for Omacetaxine | Nominal PK sampling times were used. | PK analysis set | Posted | Mean | Standard Deviation | ng*hr/mL | 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) |
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| Secondary | Terminal Elimination Half-Life (t1/2) for Omacetaxine | Nominal PK sampling times were used. | PK analysis set | Posted | Mean | Standard Deviation | hour | 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) |
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| Secondary | Total Oral Clearance (CL/F) for Omacetaxine | Nominal PK sampling times were used. | PK analysis set | Posted | Mean | Standard Deviation | L/hour | 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) |
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| Secondary | Apparent Volume of Distribution (V/F) for Omacetaxine | Nominal PK sampling times were used. | PK analysis set | Posted | Mean | Standard Deviation | L | 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) |
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| Secondary | 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. | Safety Analysis set | Posted | Count of Participants | Participants | Day 1 up to Month 15 |
|
Day 1 up to Month 15
Not provided
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | COHORT 1 | Participants whose body surface area (BSA) is less than 1.7 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. | 2 | 2 | 2 | 2 | 2 | 2 |
| EG001 | COHORT 2 | Participants whose body surface area (BSA) is between 1.7 m^2 to 2.0 m^2 inclusive All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. | 0 | 4 | 2 | 4 | 4 | 4 |
| EG002 | COHORT 3 | Participants whose body surface area (BSA) is greater than 2.0 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. | 1 | 4 | 4 | 4 | 4 | 4 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Cardiac failure congestive | Cardiac disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
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| Oral pain | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
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| Death | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Non-cardiac chest pain | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pain | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Abscess limb | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Herpes zoster | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Septic shock | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Tooth abscess | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Toxicity to various agents | Injury, poisoning and procedural complications | MedDRA 16.1 | Systematic Assessment |
| |
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Cerebrovascular accident | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Nephrolithiasis | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Renal failure acute | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypofibrinogenaemia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Lymphopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pancytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Thrombocytosis | Blood and lymphatic system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Bradycardia | Cardiac disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Tachycardia | Cardiac disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypothyroidism | Endocrine disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Oral pain | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Toothache | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Injection site pain | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Injection site rash | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Injection site reaction | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Mucosal dryness | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Temperature intolerance | General disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypersensitivity | Immune system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Injection site cellulitis | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Legionella infection | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Oral candidiasis | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA 16.1 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA 16.1 | Systematic Assessment |
| |
| Limb injury | Injury, poisoning and procedural complications | MedDRA 16.1 | Systematic Assessment |
| |
| Spinal fracture | Injury, poisoning and procedural complications | MedDRA 16.1 | Systematic Assessment |
| |
| Activated partial thromboplastin time prolonged | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Blood calcium decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Blood lactate dehydrogenase decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| International normalised ratio increased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Lymphocyte count decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Platelet count decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Weight increased | Investigations | MedDRA 16.1 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Gout | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hyperphosphataemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dysaesthesia | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dysgeusia | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Lethargy | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Neuralgia | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Sleep disorder | Psychiatric disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Renal failure acute | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Urethritis noninfective | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Scrotal oedema | Reproductive system and breast disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Skin hypopigmentation | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA 16.1 | Systematic Assessment |
| |
| Pallor | Vascular disorders | MedDRA 16.1 | Systematic Assessment |
|
Small sample size made it not possible to make meaningful comparisons between cohorts.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director, Clinical Research | Teva Branded Pharmaceutical Products, R&D Inc. | 1-888-483-8279 | USMedInfo@tevapharm.com |
| Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 28, 2018 | Dec 19, 2018 | SAP_000.pdf |
| ID | Term |
|---|---|
| D015464 | Leukemia, Myelogenous, Chronic, BCR-ABL Positive |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009196 | Myeloproliferative Disorders |
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D000077863 | Homoharringtonine |
| ID | Term |
|---|---|
| D006248 | Harringtonines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
Not provided
Not provided
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Accelerated Phase (AP) |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Units | Counts |
|---|
| Participants |
|
|
|
|
|
|
|
|
|
|
|
| OG001 | Cohort 2 | Participants whose body surface area (BSA) is between 1.7 m^2 to 2.0 m^2 inclusive All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
| OG002 | Cohort 3 | Participants whose body surface area (BSA) is greater than 2.0 m^2. All participants were given a fixed dose of 2.5 mg omacetaxine by subcutaneous injection twice daily. Induction cycles of 14 days twice daily treatment were followed by 14 days without treatment (1 induction cycle) for as long as they adequately recover their blood counts and/or until they achieve hematologic response. [Cycle 1 was an exception since participants were not dosed a second time on Day 1, nor at all on Days 2+3 to accommodate the PK study objective.] Participants then received maintenance cycles of 7 days twice daily treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they continued to benefit up to a period of 12 months following the first dose. |
|
|