E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic graft-versus-host disease . |
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E.1.1.1 | Medical condition in easily understood language |
Attack of the patient tissues by the graft after bone marrow transplantation. |
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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 | 10008907 |
E.1.2 | Term | Chronic GVH disease |
E.1.2 | System Organ Class | 100000004870 |
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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 |
Response rate at 3 months of extensive cGVH (complete or partial remission ) in nilotinib-treated patients who have not responded to imatinib mesylate. |
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E.2.2 | Secondary objectives of the trial |
* For Imatinib mesylate (IM):
- To confirm the effectiveness of IM in patients with extensive cGVH requiring treatment and resistant to at least one therapeutic line.
* For Nilotinib:
- Evaluate the effectiveness of nilotinib in patients with a resistance or intolerance to IM.
- Avoid long-term use of immunosuppresive drugs, including corticosteroids (and their long-term adverse effects).
- Reduce non-relapse mortality (NRM) of infectious or non-infectious origin.
- Improve quality-of-life parameters.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Induction phase (imatinib)
- Age: ≥ 18 and <75 years.
- Patients who underwent allogeneic hematopoietic stem cell transplantation for a hematological disease.
- Body weight ≥ 40 kg.
- Confirmed diagnosis of an extensive cGVH resistant to at least one systemic immunosuppressive therapy.
- Any source of hematopoietic stem cells is authorized.
- Myeloablative and non-myeloablative regimes are allowed.
- No contra-indication to the use of IM or nilotinib.
Salvage Phase (nilotinib):
Patients enrolled in the first phase who did not respond to IM:
- Patients who discontinued IM after 3 months du to a lack of response.
(stable disease = no response)
- Patients who experienced disease progression at any time.
- Patients who relapsed after an initial response at any time.
- Patients who discontinued treatment due to toxicity at any time.
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E.4 | Principal exclusion criteria |
- Appearance of acute GVHD ( early form or " late onset ").
- First episode of cGVHD or cGVHD not requiring systemic treatment.
- Patient treated with IM or nilotinib , a tyrosine kinase inhibitor given after transplantation within 3 months before enrollment.
- Patients treated with ITK for GVHD.
- Contra-indication to IM or nilotinib.
- Neutropenia < 0,5.10E9 / l.
- Uncontrolled systemic infection which the investigator may associate to an increased death risk during the first month of treatment .
- Severe neurological or psychiatric disorders .
- Pregnant or breastfeeding women .
- Known uncontrolled arrhythmias or symptomatic heart disease or ventricular ejection fraction < 45% (cardiac tests according to clinical indication).
- Performance index: WHO ≥ 3 unrelated to chronic GVHD.
- Relapse of the blood disease for which transplantation was performed except presence of minimal residual disease confirmed by PCR.
- Appearance of a secondary cancer ≤ 2 years before enrollment, subject to the following exceptions :
-cutaneous basal cell carcinoma.
-squamous cell carcinoma of skin.
-carcinoma in situ of the cervix.
-carcinoma in situ of the breast.
-prostate cancer (Stage TNM [ Tumor , Node , Metastasis ] T1a or T1b) .
- Refusal to sign the consent form .
- Patients in an emergency situation or unable to consent . |
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E.5 End points |
E.5.1 | Primary end point(s) |
Response rate at 3 months (complete and partial remission) after salvage therapy by nilotinib in patients with a cGVHD who did not respond to imatinib mesylate (IM). |
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E.5.2 | Secondary end point(s) |
Induction phase with imatinib mesylate :
1) Best response to IM within 12 months and duration of the response in patients who continued IM.
2) Failure rate of IM for intolerance.
3) Failure rate of IM for lack of response.
4) Tolerance profile of IM.
Nilotinib salvatage phase:
5) Best response to nilotinib in 12 months and duration of this response.
6) Failure rate of nilotinib for intolerance.
7) Failure rate of nilotinib for lack of response.
8) Tolerance profile of nilotinib.
Separately for the 2 groups : patients who have not been recruited for the 2nd phase (no treatment with nilotinib ) and patients who were recruited for the second phase.
9) Rates of dose decrease and treatment discontinuation.
10) Overall survival (OS) at one year and EFS (Event-Free Survival).
11) Cumulative incidence of relapse and cGVHD.
12) Quality-of-life parameters .
13) Decrease of transplanted-related mortality without recurrence of the haematological underlying disease.
14) Percentage of patients who no longer require immunosuppresive medications and patients who no longer need corticosteroids. |
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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 | No |
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 | 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) | 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) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 | No |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |