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Disease Attributes

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Myeloid Leukemia

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Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Central Nervous System Depressants

Other Dietary Supplements

Amino Acids

Homoharringtonine

Benzocaine

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tannic Acid

Tyrosine

Participants are administered homoharringtonine (omacetaxine) 2.5 mg/m\^2 by continuous 24-hour intravenous infusion daily on Days 1-5 of each 4 week treatment cycle, and imatinib mesylate (Gleevec) by mouth with a daily dose of 400 mg for participants in the chronic phase of chronic myeloid leukemia (CML) or 600 mg for participants in the accelerated or blast phase of CML.

Participants are administered homoharringtonine (omacetaxine) 2.5 mg/m\^2 by continuous 24-hour intravenous (IV) infusion daily on Days 1-5 of each 4 week treatment cycle. Participants who do not achieve a meaningful hematologic or cytogenetic response by the end of the fourth cycle are discontinued from the study. Otherwise, participants may continue additional cycles of this combined treatment for a maximum of 12 cycles.

Participants who achieved a molecular or cytogenetic response, or a complete hematologic remission (CHR), could undergo subsequent cycles with a maintenance schedule of homoharringtonine 2.5 mg/m\^2 by continuous 24-hour IV infusion daily for 2 days every 4 weeks. Dose escalations in subsequent cycles were allowed by one day at a time if the participant was unable to maintain CHR in the maintenance schedule.

Taken by mouth with a daily dose of 400 mg for participants in the chronic phase of chronic myeloid leukemia (CML) or 600 mg for participants in the accelerated or blast phase of CML. For the first cycle of therapy only, imatinib was started on Day 4 of homoharringtonine treatment.

Adam R Craig, M.D., PhD

Jorge Cortes, M.D.

This will be an open label, multi-center study of up to 77 patients with CML in chronic, accelerated or blast phase who have developed resistance to or have failed previous treatment with Gleevec (imatinib mesylate). Because these patients may still be sensitive to Gleevec, adding Homoharringtonine may restore a response to Gleevec or the combined treatment may promote a better response than using Gleevec alone.

Every 4 weeks, the study medicine Homoharringtonine will be given by vein daily for 5 days along with continuing daily doses of the approved medicine Gleevec taken by mouth. The safety and effectiveness of this combined treatment in CML patients will be studied. Patients who do not achieve a meaningful hematologic or cytogenetic response after 4 cycles or less will be discontinued. Otherwise, patients may continue additional cycles of this combined treatment for a maximum of 12 cycles.

Homoharringtonine With Oral Gleevec in Chronic, Accelerated and Blast Phase Chronic Myeloid Leukemia (CML)

A Phase II Open-Label Study of the Intravenous Administration of Homoharringtonine (CGX-635) Combined With the Oral Administration of Gleevec in the Treatment of Patients With Chronic Myeloid Leukemia (CML) in Chronic, Accelerated, and Blast Phase

Participants in accelerated or blast phase who converted to at least CML-chronic phase.

CML in accelerated phase meets one or more of the following criteria: \>=15% - \<30% blasts in peripheral blood or bone marrow, \>=30% blasts + promyelocytes in peripheral blood or bone marrow, \>=20% basophils in peripheral blood; platelet count \<100\*10\^9/L unrelated to therapy or clonal evolution. CML in blast phase have \>=30% blasts in the bone marrow or presence of extramedullary disease.

Meaningful responses include (in descending order of health)

* Complete Hematologic Remission (CHR)
* Partial Hematologic Remission (PHR)
* Hematologic Improvement (HI)
* Partial Response (PR)
* Return to Chronic Phase (RCP). A return to chronic phase involves the disappearance of blastic phase features and a return to chronic phase CML picture, i.e., peripheral blasts \<15%, peripheral blasts and promyelocytes \<30%, peripheral basophils \<20%, and platelets \>100\*10\^9/L.

Participants who are not in complete hematologic remission (CHR) at study start must achieve at least a CHR, and participants who are in CHR at onset must demonstrate an improvement in their cytogenetics.

A Complete Hematologic Remission (CHR) involves normalization of the bone marrow (less than 5% blasts) and peripheral blood with white blood cells \< 10\*10\^9/L, absolute neutrophil count \>=1\*10\^9/L, platelets \>=100\*10\^9/L and no peripheral blasts, promyelocytes or myelocytes. This is in addition to disappearance of all signs and symptoms of the disease.

Summary of participants who had adverse events (AEs), who discontinued treatment due to the AE, who had serious adverse events (SAEs), and who had SAEs that were related to treatments.

A serious adverse event is one that at any dose of the study drug or at any time during the period of observation:

* Results in death;
* Is life threatening;
* Requires inpatient hospitalization or prolongation of existing hospitalization;
* Results in persistent or significant disability/incapacity;
* Is a congenital anomaly/birth defect;
* Is medically important.

The Investigator assessed each AE for potential causal relationship between the event and study drug. An investigator assessment of possibly, probably or unknown relation is considered related.

Complete hematologic remission was further classified according to the suppression of the Philadelphia chromosome (Ph) as:

No cytogenetic response - Ph positive 100% Minimal cytogenetic response - Ph positive 35-90% Partial cytogenetic response - Ph positive 1-34% Complete cytogenetic response - Ph positive 0%

ChemGenex Pharmaceuticals

Homoharringtonine + Imatinib Mesylate

Age, Continuous

Sex: Female, Male

Black

Caucasian

Hispanic

Race/Ethnicity, Customized

This study was intended to follow a Simon two stage design to test 18 patients in each stratum (chronic, accelerated and blast phase) for efficacy. Only 15 were enrolled, an insufficient number for a formal statistical analysis of efficacy.

Director, Clinical Research

No participants were analyzed since the study was intended to follow a Simon two stage design to test 18 participants in each stratum (chronic, accelerated and blast phases) for efficacy. Enrollment was insufficient.

Proportion of Participants With Accelerated Phase or Blast Phase Chronic Myeloid Leukemia (CML) Who Achieve a Meaningful Response

Proportion of Participants With Chronic Phase Chronic Myeloid Leukemia (CML) Who Achieve a Meaningful Response

Discontinued due to AE

Serious AEs

SAEs considered related

Number of Participants With Adverse Experiences (AEs)

Participants With Complete Hematologic Remission Suppression of the Philadelphia Chromosome

Overall Study

Oral dose of 400mg Imatinib once daily. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.

Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.

Imatinib is packaged in bottles as 100mg and 400mg tablets

Imatinib mesylate

Novartis Pharmaceuticals

This study investigated the safety and efficacy of 400mg Versus 800mg imatinib in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints.

Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)

A Randomized Open-label Study of 400 mg Versus 800 mg of Imatinib Mesylate in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints.

MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally).

Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent.

Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement.

"Undetectable levels" or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) \<= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline).

MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally).

Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method

Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method.

Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method.

EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

(Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included)

Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration

A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value.

Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene.

Oral dose of 400mg imatinib once daily. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.

Imatinib 400mg

Patients randomized to receive 800 mg imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.

Imatinib 800mg

Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.

Imatinib 400 mg

Imatinib 800 mg

Total

Age Continuous

Study Director

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months

24 months

36 months

42 months

Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months

12 months

Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months

Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months

12 Months

24 Months

36 Months

42 Months

Intent-to-treat (ITT) population consisted of all patients who were randomized into the study.

Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts

Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment.

Time to First Major Molecular Response

Time to First Complete Cytogenetic Response

Time to First Complete Hematological Response (CHR)]

48 Months

60 Months

Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms

Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms

Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms

Estimated Rate of Overall Survival (OS) in Two Treatment Arms

3 Months

6 Months

9 Months

15 Months

18 Months

21 Months

30 Months

Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss

Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)

Safety analysis population (SAP): consisted of all patients who received at least one dose of study medication.Subjects are summarized according to the safety treatment allocation (the dose they actually received).

Mean Actual Dose Intensity Per Day

Pharmakokinetic (PK) population consisted of number of patients with a pre-dose PK sample at Month 12

Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12

No MMR at 6 Months

MMR at 6 Months

No MMR at 12 Months

MMR at 12 Months

No MMR at 18 Months

MMR at 18 Months

Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment. Patients without a valid polymerase chain reaction (PCR) assessment or those who had experienced an event before the landmark were excluded from analysis

Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)

This analysis was not done because no major molecular improvement was observed in the 800mg dose compared to 400mg dose. Hence, analysis for complete molecular response was not necessary.

Time to First Complete Molecular Response (CMR)]

Due to the small number of diabetic patients enrolled into the study, the analysis was never done.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Homoharringtonine With Oral Gleevec in Chronic, Accelerated and Blast Phase Chronic Myeloid Leukemia (CML)	NCT00114959	Myeloid Leukemi... Myeloid Leukemi... Blast Phase Myeloid Leukemi...	Homoharringtoni... Imatinib Mesyla...	16 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)	NCT00124748	Leukemia, Myelo...	Imatinib mesyla...	18 Years - 75 Years	Novartis

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