E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory acute myeloid leukemia (AML). |
|
E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia is a type of blood cancer. This cancer starts in the blood-forming cells of the bone marrow and is characterised by an over-production of immature white blood cells. |
|
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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
|
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 |
Within the TP53 wild-type population: • To compare overall survival (OS) in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. |
|
E.2.2 | Secondary objectives of the trial |
Within the TP53 wild-type population • To compare the proportions of complete remission (CR) and allogeneic hematopoietic stem cell transplant (HSCT) following CR between treatment arms • To compare ORR (CR, complete remission with incomplete platelet count recovery (CRp), CR with incomplete blood count recovery (CRi)), event-free survival (EFS), and duration of remission (DoR) between treatment arms • To assess OS and CR in clinically actionable mutation-defined AML subpopulations, including FLT3, IDH1, and IDH2 • To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and placebo • To compare the differences in disease and treatment-related symptoms and health related quality of life (HRQoL) between treatment arms. Within the all-patient population • To assess the safety between treatment arms • To characterize the pharmacokinetics of both idasanutlin and cytarabine • To compare the differences in disease and treatment related symptoms and HRQoL. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >=18 years - Documented/confirmed first or second refractory or relapsed AML using World Health Organization classification, except acute promyelocytic leukemia and first relapsed AML patients with a CR1 duration of >1 year AND age < 60 years - No more than 2 prior induction regimens (excluding prior HSCT) in their first line treatment and one must have included cytarabine with an anthracycline (or anthracenedione) - Eastern Cooperative Oncology Group performance status of 0 to 2 - Adequate hepatic and renal function - WBC count at randomization of <=50,000/ cubic millimeter (mm3). |
|
E.4 | Principal exclusion criteria |
- First relapsed patients aged < 60 years with a CR1 duration of > 1 year - Patients with prior documented antecedent hematological disorder (AHD) - AML secondary to any prior chemotherapy unrelated to leukemia - Patients who are either refractory to/or relapsed within 90 days of receiving a regimen containing a cumulative dose of >=18 gram/square meter cytarabine - Patients who have received allogeneic HSCT within 90 days prior to randomization - Patients who have received immunosuppressive therapy for graft-versus-host disease or for engraftment syndrome after autologous stem cell transplantation within 2 weeks prior to randomization - Prior treatment with a Murine Double Minute 2 (MDM2) antagonist - Patients with clinically relevant QTc prolongation (QTcF > 480 ms), a family history of long QT syndrome, or who are currently receiving treatment with medications that are known to prolong the QT interval - Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 30 days from the first receipt of study drug with the exception of HU or leukapheresis in patients who need to continue this therapy to maintain a WBC count <=50000/mm3. HU or leukapheresis must be discontinued at least 24 hours prior to the initiation of study medication - Patients with acute toxicities from any prior anti-leukemia therapy that have not resolved to Grade <=2 per National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE), Version 4.03 - Patients with a history of other malignancy within 5 years prior to screening except for malignancy that has been in remission without treatment for at least 2 years prior to randomization - Patients unable to temporarily interrupt treatment with moderate to strong CYP2C8 inducers and inhibitors (including gemfibrozil, which is also an inhibitor of UGT1A3), CYP2C8 or OATP1B1/3 substrates, or strong CYP3A4 inducers during the treatment phase. These agents must be discontinued 7-14 days prior to the start of study medication - Patients unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment with aspirin [> 325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban) during the treatment phase. These agents must be discontinued 7 days (or 5 half-lives) prior to the start of study medication Note: Treatment with or switch to low molecular weight heparin (LMWH) or unfractionated heparin (UFH) is allowed, according to local practice. However, platelet levels need to be closely monitored in these patients - Patients with a history of systemic hypersensitivity reactions >=Grade 2 attributed to cytarabine - Patients who have any severe and/or uncontrolled medical conditions or other conditions that could impair the ability of the investigator to evaluate the patient, or impair the patient’s ability to complete the study - Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon the induction of neutropenia, that is, patients who are or should be on antimicrobial agents for the treatment of active infection - Patients with extramedullary AML with no evidence of systemic involvement - Pregnant or breastfeeding patients. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (OS) in TP53 wild-type population. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Futility interim analysis, after 120 patients enrolled; Efficacy interim analysis at 80% of OS events (TP53 wild-type) - Primary analysis, approximately 5.5 years after study start. |
|
E.5.2 | Secondary end point(s) |
in TP53 wild-type population • CR proportions • ORR (CR, CRp and CRi) • EFS • DOR • Proportion of HSCT • OS and CR in clinically actionable mutation-defined AML subpopulations, incl. FLT3, IDH1, and IDH2 • Safety, disease and treatment related symptoms, and health related quality of life (HRQoL).
Within the all-patient population • Safety, pharmacokinetics, disease and treatment related symptoms, and HRQoL. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Futility interim analysis, after 120 patients enrolled; Efficacy interim analysis at 80% of OS events (TP53 wild-type) - Primary analysis, approximately 5.5 years after study start. |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 |
Australia |
Austria |
Belgium |
Canada |
Finland |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Netherlands |
New Zealand |
Norway |
Panama |
Russian Federation |
Spain |
Switzerland |
United Kingdom |
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
|
|
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |