| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory acute myeloid leukemia in adult patients who are considered not to benefit from / not to be eligible for intensive salvage therapy and/or stem cell transplantation and have no established treatment options |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or refractory acute myeloid leukemia in adult patients who are not eligible for intensive treatment and have no established treatment options |
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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 | 10066638 |
| E.1.2 | Term | Acute myeloid leukemia progression |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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) |
|
| 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 | 10060558 |
| E.1.2 | Term | Acute myeloid leukemia recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 test whether patients with relapsed or refractory acute myeloid leukemia with no established therapeutic options treated with combination of volasertib (BI 6727) plus low-dose cytarabine will derive greater benefit over patients treated with investigator's choice of the best alternative antileukemic therapy |
|
| E.2.2 | Secondary objectives of the trial |
| Additional information on safety, health-related quality of life, pharmacogenetics, and pharmacokinetics will be collected |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female adult with relapsed or refractory AML (except for acute promyelocytic leukemia, APL), considered not to benefit from / not to be eligible for standard intensive salvage therapy and / or stem cell transplantation based one of the following criteria:
a. AML patient ≥ 60 years who fails to achieve complete remission after standard anthracycline-based induction or at least 2 cycles of non-anthracycline based induction
b. Relapsed AML patient ≥ 60 years and at least one of the following:
•CR1 (first complete remission) < 18 months
•previous allogeneic stem cell transplant
•adverse genetic group •>1st relapse
c. AML patient <60 years who fails to achieve complete remission after at least 2 cycles of standard anthracycline-based induction or at least 1 cycle of high-dose cytarabine-based induction containing at least 6g/m2 of cytarabine
d. Relapsed AML patient <60 years who has already received high-dose cytarabine salvage (at least 6g/m2 of cytarabine) and/or allogeneic stem cell transplant
2)Signed and dated written informed consent by start date of Screening Visit in accordance with GCP and local legislation
|
|
| E.4 | Principal exclusion criteria |
1) Previously untreated AML
2) Patient with Acute Promyelocytic Leukemia [AML subtype M3 according to the French-American-British (FAB) classification]
3) Hypersensitivity to one of the trial drugs or the excipients
4) Second malignancy currently requiring active therapy.
However, patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or a radical prostatectomy or definitive radiotherapy has been performed.
5) Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukemic CNS involvement (no lumbar puncture required, clinical assessment per investigator’s judgement is sufficient)
6) QTcF prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome, QTcF > 470 ms, etc.).
7) Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 x the upper limit of normal (ULN), or AST or ALT > 5 x the ULN in case of known leukemia liver involvement
8) Prothrombin time (PT) > 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin)
9) Total Bilirubin > 1.5 mg/dL (> 26 µmol/L, SI unit equivalent) (unless elevation is thought to be due to hepatic infiltration by AML, Gilbert syndrome, or hemolysis)
10) Serum creatinine > 2 mg/dL
11) Severe illness or organ dysfunction involving the heart, kidney, liver or other organ system (e.g. active infection, clinically relevant impairment of cardiac function, severe heart failure/cardiac insufficiency, unstable angina pectoris or history of recent myocardial infarction), which in the opinion of the investigator would interfere with the evaluation of the safety of the test drug or limit compliance with trial requirements
12) Any significant concurrent psychiatric disorder or social situation that according to the investigator’s judgement would compromise patient’s safety or compliance, interfere with consent, study participation, or interpretation of study results
13) Concomitant anti-leukemic treatment
14) Concomitant anti-infective therapy which, in the opinion of the investigator, is considered relevant for the evaluation of the efficacy or safety of the trial drug
15) Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate treatment)
16) Contraindications for cytarabine treatment according to the manufacturer’s product information provided in the ISF (applicable to patients randomized to Arm A)
17) Contraindications for the specific cytotoxic anti-leukemic product selected by the investigator according to the manufacturer’s product information (applicable to patients randomized to Arm B)
18) Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for a minimum of 6 months after study treatment
19) Pregnant or breast feeding patients
20) Treatment with any investigational drug within 2 weeks of administration of first study medication dose or within less than five half times of the investigational drug before treatment with the present trial drug and / or persistence of toxicities of prior anti-leukemic therapies which are deemed clinically relevant
21) Prior treatment with a Plk1 inhibitor such as volasertib or treatment in a clinical trial using a Plk inhibitory compound
22) Patient unable to comply with the protocol
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Primary endpoints for efficacy are Complete Remission (CR) for the phase II portion of the trial and Overall Survival (OS) for the phase III portion of the trial |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CR: assessment of response is done at the end of each treatment cycle. One interim analysis will be performed when approximately 300 patients are treated and evaluable for response. This cutoff defines the end of the Phase II portion of the trial.
OS: Patient's vital status is collected at each follow-up visit (at 12-week intervals ).The Phase III data for this trial will be analyzed with a cutoff date for safety and efficacy data collection after all ongoing patients have discontinued treatment/dropped out or received at least four cycles of treatment. Overall mortality rates during the first 4 and 8 weeks after the initial dose of study medication will also be tabulated for each treatment group. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints for efficacy are the following:
1) Event free survival (EFS)
2) Complete Remission with incomplete blood count recovery (CRi)
3) Relapse Free Survival (RFS)
4) Remission duration
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment of response (remission, relapse, progression) is done at the end of each treatment cycle (which will vary according to the treatment cycle duration for the different study drugs).
Event free survival (EFS), Relapse Free Survival (RFS), and Remission duration
will be analyzed after database lock.
|
|
| 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 | No |
| 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 | Yes |
| 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) | Yes |
| 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 | 2 |
| 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 | 65 |
| 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 |
| Czech Republic |
| Finland |
| France |
| Germany |
| India |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| Taiwan |
| United States |
|
| 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
|
| The trial will be completed as soon as the last patient has completed his / her last follow-up assessment |
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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 | |
| E.8.9.1 | In the Member State concerned months | 20 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
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