E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with acute myeloid leukaemia (AML) that are not eligible for intensive treatment |
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E.1.1.1 | Medical condition in easily understood language |
patients with acute myeloid leukaemia (AML) that are not eligible for intensive treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The trial will be performed in two parts, a phase I part and a phase IIa part.
In the phase I part, BI 6727 will be investigated as monotherapy and in combination with low dose cytarabine (LD-Ara-C) in patients with relapsed/refractory AML ineligible for intensive treatment. The dose of BI 6727 will be escalated to determine the maximum tolerated dose (MTD) of BI 6727 monotherapy and BI 6727 in combination with LD-Ara-C.
A safety analysis and conclusion on the MTD will be performed after the MTD is determined in treatment schedule A. The selection of the recommended dose for the phase II part will be based on the MTD and the safety observed during treatment beyond the 1st cycle.
In the phase IIa part, the combination of BI 6727 (at the recommended dose for phase II) with LD-Ara-C and LD-Ara-C monotherapy will be investigated to explore the efficacy of the combination in comparison to LD-Ara-C monotherapy in previously untreated AML patients ineligible for intensive treatment. |
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E.2.2 | Secondary objectives of the trial |
Further analysis of safety parameters including: Incidence and intensity of adverse events graded according to CTCAE (version 3.0), Incidence of dose limiting toxicity, QTc changes during and after intravenous infusion of BI 6727.
Pharmakokinetic analysis inluding: Pharmacokinetics of BI 6727 when given alone and in combination with cytarabine, Pharmacokinetics of cytarabine after a single dose when given alone and in combination with BI 6727,
Pharacodynamic analysis: drug effect on leukaemia cells
Furhter analysis of efficacy parameters including: Partial remission (PR); Event free survival (EFS), Relapse free survival, Remission duration, Overall survival (OS),
Supportive care requirements (blood products, antibiotic usage, hospitalisation)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male or female adult with relapsed/refractory AML ineligible for intensive treatment. (phase I part only)
•Male or female adult with previously untreated (except hydroxyurea) AML ineligible for intensive treatment (phase IIa part only)
•Confirmed diagnosis of AML according to the WHO definition (except for acute promyelocytic leukaemia, APL)
•Patient is eligible for LD-Ara-C treatment
•Life expectancy ≥ 3 months
•Eastern co-operative oncology group (ECOG, R01-0787) performance score <=2 at screening
•Signed written informed consent consistent with international conference on harmonisation – good clinical practice (ICH-GCP) and local legislation |
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E.4 | Principal exclusion criteria |
•Previously untreated AML (phase I part only)
•Relapsed or treatment refractory AML (phase IIa part only)
•Patient with APL (AML subtype M3 according to the French-American-British (FAB) classification)
•Hypersensitivity to one of the trial drugs or the excipients
•Other malignancy requiring treatment
•Symptomatic central nervous system involvement
•Clinically relevant QT prolongation (e.g. long QT syndrome, QTcF > 470 ms)
•Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (ULN)
•Prothrombin time (PT) > 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin)
•Bilirubin greater than 1.5 mg/dl (> 26 µmol/L)
•Serum creatinine greater than 2.0 mg/dl
•Concomitant intercurrent illness, which would compromise the evaluation of efficacy or safety of the trial drug, e.g. active severe infection, unstable angina pectoris, cardiac arrhythmia or severe heart failure/cardiac insufficiency.
•Psychiatric illness or social situation that would limit compliance with trial requirements
•Concomitant therapy, which is considered relevant for the evaluation of the efficacy or safety of the trial drug
•Contraindications for cytarabine treatment according to the SPC
•Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial, i.e. combination of two forms of effective contraception (hormonal contraception, intrauterine device, condom with spermicide, etc.). Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial
•Pregnant or nursing female patients
•Patient unable to comply with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I part: MTD of BI 6727 monotherapy and BI 6727 in combination with LD-Ara-C
Phase IIa part: Efficacy (complete remission, CR; complete remission with incomplete blood count recovery, CRi)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MTD: at the end of phase I part
Efficacy: will be analyzed and reported after all patients have either stopped treatment or received at least four treatment cycles. |
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E.5.2 | Secondary end point(s) |
1.) Incidence and intensity of adverse events graded according to CTCAE (version 3.0)
2.) Incidence of dose limiting toxicity (DLT)
3.) Pharmacokinetics of BI 6727 when given alone and in combination with cytarabine
4.) Pharmacokinetics of cytarabine after a single dose when given alone and in combination with BI 6727
5.) Pharmacodynamic monitoring: drug effect on leukaemia cells
6.) Partial remission (PR)
7.) Event free survival (EFS)
8.) Relapse free survival
9.) Remission duration
10.) Overall survival (OS)
11.) QTc changes during and after intravenous infusion of BI 6727
12.) Supportive care requirements (blood products, antibiotic usage, hospitalisation)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
when the last patient has completed his / her last visit. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | No |
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 |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Norway |
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E.8.7 | Trial has a data monitoring committee | No |
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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The clinical trial will be analyzed and reported when the last patient has completed treatment according to the protocol. The clinical trial database will be kept open to collect additional survival data, the trial will be considered finally completed as soon as the last patient has completed his / her last follow-up visit according to the protocol. The additional results will be reported in an addendum to the report. |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |