E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
cronic myeloid leukemia with mutation BCR-ABL T3151 and acule linfopblastic leukemia PH+ |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10024291 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of MK-0457, as defined by major cytogenetic response in chronic phase CML and as major hematological response in accelerated phase CML, blastic phase CML, and Ph+-ALL, when given as a 5-day CIV infusion every 14 days. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the durability of responses with MK-0457. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Patient is male or female, and >=18 years of age on day of signing informed consent. 2. ECOG performance status: a) For Accelerated Phase CML, Blastic phase CML, and Ph+-ALL patients: ECOG <=3 b) For Chronic Phase CML patients: ECOG <= 2 3. The interval from prior treatment (standard or investigational) to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for non-cytotoxic agents. The only exception is hydroxyurea which can be used to control peripheral leukemic cell counts prior to initiating study drug and during the first treatment cycle. Persistent clinically significant chronic toxicities from prior chemotherapy must not be greater than Grade 2 (except alopecia). 4. Patients must have the following laboratory values unless considered due to leukemia: a) ALT and AST <= 3 x upper limit of normal (ULN) b) Serum total bilirubin <= 1.5 x ULN (except for known Gilbertメs syndrome) c) Serum creatinine <= 2.0 x ULN 5. Patient, or patientメs legal representative, has voluntarily agreed to participate by giving informed consent. 6. Patients with active CNS disease may be included and will be treated concurrently with intrathecal therapy.Patients under consideration for inclusion into this study must have Ph+ (or BCRABL+) CML or ALL and meet one of the following disease inclusion criteria: a) Patients diagnosed with CML in blastic phase. Any number of prior therapies is permitted. Patients are considered to have CML in blastic phase if they meet either of the following criteria: (1) At least 30% blasts in the peripheral blood or bone marrow or extramedullary disease other than spleen. b) Patients diagnosed with accelerated phase CML. Any number of prior therapies is permitted. Patients are considered to have CML in accelerated phase if they do not qualify as blastic phase and meet at least one of the following criteria: (1) At least 15% to < 30% blasts in peripheral blood or 15% to < 30% blasts in bone marrow. (2) The sum of the percent blasts plus percent promyelocytes in peripheral blood or in the bone marrow is at least 30% (but the percent blasts alone is < 30%). (3) Peripheral basophils > 20%. (4) Thrombocytopenia <100 x 109/L unrelated to therapy. c) Patients diagnosed with chronic phase CML and further therapy is clinically indicated. Chronic phase CML patients must have failed at least imatinib therapy to be eligible. Patients are considered to have CML in chronic phase, defined as never in accelerated phase or blastic phase, if they meet the following criteria: (1) <15% blasts in the peripheral blood and bone marrow. (2) <30% blasts plus promyelocytes in peripheral blood and bone marrow. (3) <20% basophils in the peripheral blood. (4) >=100 x 109/L platelets. (5) No evidence of extramedullary leukemic involvement, with the exception of the liver or spleen. d) Patients diagnosed with Ph+-ALL. Any number of prior therapies is permitted. Patients with Ph+-ALL are also eligible if they have one of the following criteria:Patients with minimal residual disease (MRD) are eligible only if there is indication of evolving relapse defined as a >= 2 log increase of BCR-ABL transcript level (as reported by local laboratories), as compared to the minimum level achieved with prior therapies in the peripheral blood or bone marrow [8]. (2) Patients with Ph+-ALL whose disease exhibits features of biphenotypic acute leukemia are eligible [9]. 8. Patients with documented BCR-ABL T315I mutation. The choice of assay used for documenting the BCR-ABL T315I mutation is at the discretion of the investigator. Assays that can be used for T315I detection include: a) Direct sequencing of PCR-amplified BCR-ABL transcripts (available from commercial reference laboratories such as Quest Diagnostics, Genzyme Diagnostics and specialized academic laboratories). |
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E.4 | Principal exclusion criteria |
Patient has not fully recovered from acute side effects of prior anti-leukemic therapy to <= Grade 2 toxicity, except alopecia. 2. Patient within 3 months of allogeneic bone marrow transplant and/or has active and uncontrolled Graft-versus-Host disease following allogeneic bone marrow transplant and/or not on a stable dose of immunosuppressants for at least one month. 3. Patient has uncontrolled symptomatic congestive heart failure, angina, or had a myocardial infarction in the preceding 3 months. 4. Patient has known hypersensitivity to the components of study drug or its analogs. 5. Patient has uncontrolled active infection. 6. Patient has a known psychiatric or substance abuse disorder that in the opinion of the Investigator would interfere with cooperation with the requirements of the trial. 7. Patient is pregnant or breastfeeding or expecting to conceive within the projected duration of the study.Patient has any other severe concurrent disease, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 9. Patients with モcurrently activeヤ second malignancy, other than non-melanoma skin cancer, should not be enrolled. Patients are not considered to have a モcurrently activeヤ malignancy if they have completed therapy for a prior malignancy and are considered by their treating physician to be at less than 30% risk of relapse. 10. Patient is known to be HIV seropositive or who has an AIDS-related illness. 11. Patient has known active hepatitis B or C (and/or treated previously with abnormal liver function tests). 12. Patient has a LVEF >40% by multigated radionucleotide angiography (MUGA) or echocardiography. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary
endpoint will be major cytogenetic response for chronic phase (CP) CML, and major
hematological responses, which include complete and no evidence of leukemia (NEL)
hematological responses for accelerated phase (AP) and blastic phase (BP) CML, and
Ph+-ALL. Patients who have a suitable bone marrow donor can go off study for bone
marrow transplant as curative therapy. Hematologic, cytogenetic, and molecular
responses will be evaluated from peripheral blood, bone marrow, and lumbar puncture
(when applicable) throughout the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |