E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Acute Lymphoblastic Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
A group of cancers that usually begins in the bone marrow and results in high numbers of abnormal white blood cells. |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025230 |
E.1.2 | Term | Lymphatic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Phase 1b
- To assess the safety and tolerability of carfilzomib, alone and in combination with induction chemotherapy, for the treatment of children with relapsed or refractory acute lymphoblastic leukemia (ALL)
-To determine the maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy.
Phase 2
-To estimate the combined rate of bone marrow CR and bone marrow CRp at the end of the Induction Cycle |
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E.2.2 | Secondary objectives of the trial |
Phase 1b
-To characterize the pharmacokinetics (PK) of carfilzomib alone and in
combination with induction chemotherapy
-To evaluate the combined rate of bone marrow complete response (CR) and bone marrow CR without platelet recovery (CRp) at the end of the Induction Cycle
-To estimate the proportion of subjects who achieve minimal residual disease (MRD) status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle
Phase 2
-To estimate the proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle
-To assess the safety and tolerability of carfilzomib in combination with induction chemotherapy, for the treatment of children with multiply relapsed ALL
-To characterize the PK of carfilzomib in combination with induction
chemotherapy |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 years or younger at the time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed (Phase 1b and 2) or refractory (Phase 1b only) ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
- To be eligible for Phase 1b, subjects must have had 1 or more prior
therapeutic attempts, defined as:
o Early first relapse (< 36 months from original diagnosis) after
achieving a CR OR
o Relapse after achieving a CR following the first or subsequent relapse
(i.e., ≥ 2 relapses) OR
o Failing to achieve a CR from original diagnosis after at least 1 induction attempt
- To be eligible for Phase 2, subjects must have had 2 or more prior
therapeutic attempts and have relapsed, but not refractory disease, defined as relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses)
3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
Total bilirubin ≤ 1.5 × institutional ULN
AST and ALT ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively. |
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E.4 | Principal exclusion criteria |
1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous allergy to PEG-asparaginase but can receive
Erwinia are eligible.)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib; for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc. website)
3. Left ventricular fractional shortening < 30%
4. History of pancreatitis; serum amylase > 2 × the institutional ULN
5. Active treatment for graft-versus-host disease
6. Positive culture for bacteria or fungus within 14 days of the initiation of therapy
7. Down Syndrome
8. Prior therapy restrictions:
-Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before enrollment, or at least 14 days before enrollment, if pegylated myeloid growth factors were administered.
-Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be approved by the Onyx study medical monitor.
-At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (i.e., 66 days for rituximab and 69 days for
epratuzumab) before subjects may enroll in the study.
-Subjects must have completed any type of active immunotherapy
(e.g., tumor vaccines) at least 42 days before enrollment.
-Subjects must not have received any other antineoplastic agents within 7 days prior to enrollment.
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1b
-Safety and tolerability of carfilzomib alone and in combination with induction chemotherapy as defined by the type, incidence, severity, and outcome of AEs; changes from baseline in key laboratory analytes, vital signs, and physical findings. Time to toxicity will be evaluated to differentiate single-agent carfilzomib from carfilzomib in combination with induction chemotherapy
-Determination of the MTD as the dose that has the highest posterior probability of having a DLT rate within the target toxicity interval (20%–33%), while the posterior probability of excessive /unacceptable toxicity (>33%–100%) is less than 40%
Phase 2
-Combined proportion of subjects who achieve CR or CRp at the end of the Induction Cycle |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of the Induction Cycle |
|
E.5.2 | Secondary end point(s) |
Phase 1b
-Pharmacokinetic parameters, principally maximum plasma concentration (Cmax) and area under the curve (AUC), alone and in combination with induction chemotherapy, derived from levels of carfilzomib assayed in PK samples
-Combined proportion of subjects who achieve CR or CRp at the end of the Induction Cycle
-Proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)
Phase 2
-Proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative Ig/TcR PCR
-Safety and tolerability of carfilzomib in combination with induction
chemotherapy as defined by the type, incidence, severity, and outcome of AEs; changes from baseline in key laboratory analytes, vital signs, and physical findings
-Pharmacokinetic parameters, principally Cmax and AUC, of carfilzomib in combination with induction chemotherapy derived from levels of carfilzomib assayed in PK samples. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of the Induction Cycle |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
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) | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
Denmark |
France |
Germany |
Netherlands |
Spain |
Switzerland |
United Kingdom |
United States |
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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
|
End of study per protocol is defined as, the end of study assessments must be completed 30 days (± 4 days) following the last dose of study treatment. |
|
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |