| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myeloid Leukaemia (CML) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009015 |
| E.1.2 | Term | Chronic myeloid leukemia |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the safety and efficacy of subcutaneous administration of homoharringtonine (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed or are intolerant to tyrosine kinase inhibitor therapy. |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients, age 18 years or older
2. Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase.
a) Patients in accelerated phase will meet 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 or bone marrow; platelet count <100 x 10^9/L unrelated to therapy or clonal evolution.
b) CML in blast phase will be defined as >=30% blasts in the bone marrow or presence of extramedullary disease.
c) All other patients will be considered to have chronic phase CML
3. Patients will have either failed, demonstrated intolerance, or a combination of prior failure and intolerance, to prior treatments with at least two 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 one of the following:
a) No complete hematologic response (CHR) by 12 weeks (whether lost or never achieved)
b) No cytogenetic response by 24 weeks (i.e., 100% Ph-positive) (whether lost or never achieved)
c) No major catogenetic response by 52 weeks (i.e., >=35% Ph-positive) (whether lost or never achieved)
d) Progressive leukocytosis: i) increasing white blood cell count on at least two consecutive evaluations, at least 2 weeks apart and doubling from the nadir to >= 20,000/uL or ii) absolute increase WBC by >= 50,000/uL above the post-tretment nadir
Intolerance to TKI therapy will be defined as one of the following:
a) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention
b) Grade 4 hematologic toxicity lasting more than 7 days
c) Any Grade >= 2 toxicity that is unacceptable to the patient
4. Patients must have completed all previous anti-leukemic therapy for at least 2 weeks, prior to the first planned dose of HHT, except as noted below, and must have fully recovered from side effects of a previous therapy, unless disease progression necessitates early therapy, determined by the Principal Investigator or treating physician. In patients with rapidly proliferating disease, hydroxyurea may be administered during the first two cycles of treatment, if clinically indicated, to control disease. In such cases, complete hematologic response (CHR) must be sustained for >= 4 weeks for accelerated and blast phase CML and for >= 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 HHT.
5. Bilirubin ≤ 2.0 times upper limit of normal (ULN)
ALT ≤ 3 times ULN
Creatinine ≤ 1.5 times ULN
6. ECOG performance status 0-2.
7. Be able to comply with the requirements of the entire study.
8. Be able and willing to provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
9. Sexually active patients and their partners must use an effective double barrier method of contraception associated with a low failure rate (i.e. less than 1% per year) during and for six months after completion of study therapy. The following are considered effective contraceptives: (1) oral contraceptive pill, (2) condom, (3) diaphragm plus spermicide, (4) abstinence, (5) patient or partner surgically sterile, (6) patient or partner more than 2 years post-menopausal or (7) injectable or implantable agent/device.
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| E.4 | Principal exclusion criteria |
1. NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure.
2. Myocardial infarction in the previous 12 weeks.
3. Other concurrent illness which 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 and active infection, positive HIV status or positive HTLV I/II status, whether on treatment or not.
4. Pregnant or lactating.
5. Any medical or psychiatric condition, which may compromise the ability to give written informed consent or to comply with the study protocol.
6. Lymphoid Ph+ blast crisis
7. Patient is enrolled in another clinical inverstigation within 30 days of enrollment or is receiving another investigational agent
Patients excluded for any of the aforementioned reasons may be re-screened for participation at any time if the exclusion characteristic has changed, or is likely to change, and after consultation with the Principal Investigator and the Sponsor.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be the proportion of patients achieving a clinical response, defined for each patient subpopulation, as follows:
Chronic phase CML: Achievement of a complete hematologic response (CHR), partial cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases). The response must last >= 8 weeks to be considered meaningful.
Accelerated phase CML: Achievement of either a complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase CML. The response must last >=4 weeks to be considered meaningful. Cytogenetic responses will also be evaluated and would supersede hematologic responses.
Blast phase CML: Achievement of either a complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase CML. The response must last >= 4 weeks to be considered meaningful. Cytogenetic responses will also be evaluated and would supersede hematologic responses.
Analyses will be conducted for each CML patient polpulation (chronic, accelerated, blast phase), individually, and for patients enrolled for prior tyrosine kinase inhibitor failure or intolerance, individually and combined.
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | Yes |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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