E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Refractory Chronic Myelogenous Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009013 |
E.1.2 | Term | Chronic myeloid leukaemia |
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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 |
Primary
(1) To determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of MK-0457 administered in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL.
Hypothesis: Administration of MK-0457 in combination with dasatinib will be sufficiently safe and tolerated to permit further study in CML and Ph+ ALL.
(2) To determine pharmacokinetics of MK-0457 given in combination with dasatinib. |
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E.2.2 | Secondary objectives of the trial |
Secondary
To evaluate the efficacy of MK-0457 in combination with dasatinib as measured by the induction or durability of hematologic response, cytogenetic response, or molecular response.
Hypothesis: MK-0457 administered in combination with dasatinib will either induce response in patients not responding to dasatinib after 3 months of dasatinib monotherapy, or will prolong the duration of response in patients responding to dasatinib after 3 months of dasatinib monotherapy.
2.1.3 Exploratory
To assess the pharmacodynamics (inhibition of Aurora kinases and BCR-ABL) of MK¬0457 in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1 Patients must have chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
2 Patients must be at least 3 months from the start of dasatinib therapy and are currently receiving dasatinib therapy for CML or Ph+ ALL and be evaluable for hematologic response prior to entering the study.
3 Patient is able to be treated with a 70 mg bid dose of dasatinib without significant toxicity at the time of study entry.
4 Patient is male or female of any race, and ≥18 years of age on day of signing informed consent.
1 Patient must have performance status ≤ 2 on the ECOG Performance Scale (Appendix 6.1).
6. Patients must have the following laboratory values unless considered due to leukemia: i) ALT and AST ≤ 2.5 x upper limit of normal (ULN) ii) Serum total bilirubin ≤ 2.0 x ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 2.0 ULN
iii) Serum creatinine ≤ 1.5 x ULN OR
≥ 60ml/min for patients with creatinine levels >1.5 X institutional ULN
2 Female patient of childbearing potential has a negative serum or urine pregnancy test within 14 days of study enrollment.
3 Patient, or the patients legal representative, has voluntarily agreed to participate by giving written informed consent.
4 Patients with active CNS disease are included and may be treated concurrently with intrathecal therapy as per institutional standards. |
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E.4 | Principal exclusion criteria |
1 Patient has had treatment with any anti-leukemia therapy (investigational or approved) other than dasatinib during the preceding 3 months. Pheresis or hydroxyurea treatment in the preceding 3 months will not exclude patients from eligibility.
2 Patient has unresolved ≥ grade 2 clinically significant toxicity attributed to dasatinib at the time of study entry.
3 Patient has known hypersensitivity to the components of study drug or its analogs.
4 Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patients participation for the full duration of the study, or is not in the best interest of the patient to participate.
5 Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
1 Patient is, at the time of signing informed consent, a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.
2 Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study.
3 Patient has symptomatic ascites, pericardial or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.
4 Patient has had prior radiation therapy to more than 10% of the bone marrow; patients must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy.
5 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) |
Primary
(1) To determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of MK-0457 administered in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL.
Hypothesis: Administration of MK-0457 in combination with dasatinib will be sufficiently safe and tolerated to permit further study in CML and Ph+ ALL.
(2) To determine pharmacokinetics of MK-0457 given in combination with dasatinib.
Hypothesis: Administration of dasatinib with MK-0457 will not significantly alter the pharmacokinetics of MK-0457. |
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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 | No |
E.6.3 | Therapy | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |