E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic lymphocytic leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Chronic lymphocytic leukemia |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008978 |
E.1.2 | Term | Chronic lymphocytic leukemia refractory |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008977 |
E.1.2 | Term | Chronic lymphocytic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 assess, on an intention-to-treat basis, the efficacy and safety of a treatment protocol including salvage chemoimmunotherapy (R-DHAP) followed, in the absence of progression, by RIC alloSCT from sibling or unrelated donors, in high-risk CLL patients as measured by the progression free survival |
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E.2.2 | Secondary objectives of the trial |
- To assess the safety and toxicity of three courses of R-DHAP
- To assess the response to three courses of R-DHAP.
- To assess PFS and OS after alloSCT.
- To asses PFS and OS after maximally 6 R-DHAP in case no alloSCT was performed
- To assess disease status at two years after SCT.
- To assess the incidence and course of MRD in patients with CR
- To assess overall survival from registration.
- To assess the incidence of complete, partial and no engraftment.
- To evaluate the incidence and severity of acute and chronic GVHD, and of other treatment related toxicity;
- To evaluate the response of progressive disease or increasing MRD to lowering of immunosuppression or DLI.
- To assess the time to next treatment excluding MRD triggered lowering of immunosuppression or DLI.
- To assess the prognostic value of risk factors at entry including IgH mutation status and karyotypic abnormalities with respect to PFS.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- B-CLL confirmed according to WHO Classification;
- Fludarabine refractory, defined as
no response or relapse within 12 months after the last administration of fludarabine monotherapy or fludarabine containing regimen, and needing treatment, or
Refractory or relapsed and needing treatment and having deletion of 17p13, or
Refractory or relapsed within 24 months after the last administration of fludarabine combined with a monoclonal antibody and needing treatment;
- Age 18-70 years inclusive;
- WHO performance status ≤ 2 (see appendix E);
- HCT-CI ≤ 2 (see appendix F);
- Written informed consent.
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E.4 | Principal exclusion criteria |
- Intolerance to exogenous protein administration
- Previously treated with DHAP
- Richter’s transformation;
- Suspected or documented CNS involvement by CLL;
- Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease);
- Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);
- Severe neurological or psychiatric disease;
- Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times upper limit of normal) except when caused by leukemic infiltration;
- Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration);
- History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- Active, uncontrolled infections;
- Patient known to be HIV-positive;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
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E.5 End points |
E.5.1 | Primary end point(s) |
progression-free survival from registration with progression defined as time to:
a. death due to any cause, or
b. progression or relapse excluding progressive MRD triggering cessation of immunosuppression or DLI whichever comes first
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
On Study, after 3 R-DHAP cycles, after 3 mnths SCT (until 24 mnths), in case no donor after last R-DHAP cycle (max 6 cycles), follow-up |
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E.5.2 | Secondary end point(s) |
• incidence and severity of tumor lysis during first course of R-DHAP
• response to three courses of R-DHAP including SD;
• percentage of successful donor searches,
• percentage of patients who received alloSCT
• best response on protocol
• engraftment after alloSCT;
• incidence and severity of acute and chronic GVHD;
• toxicity;
• overall survival (OS) from registration;
• response of MRD to immunomodulation (either accelerated cessation of immunosuppression or DLI)
• response of PD to recommended off-protocol immunomodulation (either accelerated cessation of immunosuppression or DLI)
• disease status at two years after registration;
• PFS and OS after alloSCT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
On Study, after 3 R-DHAP cycles, after 3 mnths SCT (until 24 mnths), in case no donor after last R-DHAP cycle (max 6 cycles), follow-up |
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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 | 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 | Information not present in EudraCT |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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End of treatment will be the date on which of all patients clean data including at least 1 year of follow up (from registration) will be available |
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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 | 4 |
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 | 4 |
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 |