| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Acute Leukemia in morphologic complete remission
Myelodisplasia with less than 5% blasts in the marrow and no circulating blasts |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024330 |
| E.1.2 | Term | Leukemia acute |
| 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 |
The primary objective of the randomized trial is to compare chronic GVHD/relapse-free survival (CRFS) after HSCT across two CNI-free interventions and Tac/Mtx control.
|
|
| E.2.2 | Secondary objectives of the trial |
Comparison:
Overall survival
Grades II-IV and III-IV acute GVHD
Chronic GVHD
Immunosuppression-free survival at 1 year
Hematologic recovery
Primary and secondary graft failure
Disease relapse or progression
Transplant-related mortality
Toxicity and rates of infections (CMV and EBV reactivation)
Disease-free survival
Immune reconstitution
Quality of Life
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females aged ≥ 1.0 year and < 66.0 years
2. Patients with acute leukemia in morphologic complete remission with or without hematologic recovery or with myelodysplasia (MDS) with no circulating blasts and with less than 5% blasts in the bone marrow. Patients with CMML must have a WBC count ≤10,000 cells/µL and <5% blasts in the marrow. Patients with ≥ 5% blasts due to a regenerating marrow must contact the protocol chairs for review.
3. Planned myeloablative conditioning regimen (see eligible regimens in Table 2.4)
4. Patients must have a related or unrelated donor as follows:
a. Related donor must be an 8/8 match for HLA-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing. Pediatric related donors must weigh ≥ 25.0 kg., must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter, must be willing to (1) donate bone marrow and (2) receive G-CSF followed by donation of peripheral blood stem cells (product to be determined by randomization post enrollment) and must meet institutional criteria for donation1.
b. Unrelated donor must be an 8/8 match at HLA-A, -B, -C and –DRB1 at high resolution using DNA-based typing. Unrelated donor must be medically eligible to donate according to NMDP (or equivalent donor search organization) criteria. At time of enrollment, the donor should not have any known preferences or contraindications to donate bone marrow or peripheral blood stem cells .
i. Selection of unrelated donors is to be performed according to institutional practice. It is recommended that the time from collection to initiation of the cell processing be considered when prioritizing donors, as data shows better results for CD34 selection when cell processing begins within 36 hours of the end of collection as indicated in section 2.5.1.2.
5. Cardiac function: Ejection fraction at rest ≥45.0% or shortening fraction of ≥ 27.0% by echocardiogram or radionuclide scan (MUGA).
6. Estimated creatinine clearance (for patients > 12 years) greater than 50.0 mL/minute (using the Cockcroft-Gault formula and actual body weight); for pediatric patients (≥ 1 year to 12 years), GFR estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m2. If the estimated creatinine clearance is < 90 mL/min/1.73 m2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 70.0 mL/min/1.73 m2.
7. Pulmonary function: DLCO ≥50% (adjusted for hemoglobin), and FVC and FEV1≥50%; for children who are unable to perform for PFTs due to age or developmental ability, there must be no evidence of dyspnea and no need for supplemental oxygen, as evidenced by O2 saturation ≥ 92% on room air.
8. Liver function: total bilirubin < 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert’s Syndrome) and ALT/AST < 2.5x the upper limit of normal.
9. Signed informed consent.
|
|
| E.4 | Principal exclusion criteria |
1. Prior autologous or allogeneic hematopoietic stem cell transplant
2. Karnofsky or Lansky Performance Score < 70%
3. Active CNS involvement by malignant cells
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
5. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
6. Patients seropositive for HIV-1 or -2
7. Patients seropositive for HTLV-I or -II
8. Patients with active Hepatitis B or C viral replication by PCR
9. Documented allergy to iron dextran or murine proteins
10. Women who are pregnant (positive serum or urine βHCG) or breastfeeding
11. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use 2 effective forms of birth control or abstinence for one year after transplantation
12. History of uncontrolled autoimmune disease or on active treatment
13. Patients with prior malignancies, except resected non-melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
14. Patient unable to comply with the treatment protocol including appropriate supportive care, follow-up and research tests
15. Planned post-transplant maintenance therapy except for FLT3 inhibitors or TKIs
a. Must be declared prior to randomization.
16. If it is known prior to enrollement that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.
17. German centers only: Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or participation in any other interventional clinical study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Chronic GVHD/relapse-free survival (CRFS): this time to event outcome is defined as moderate to severe chronic GVHD by the NIH consensus criteria, disease relapse, or death by any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline assumption of 22% by 1 year |
|
| E.5.2 | Secondary end point(s) |
Overall survival
Grades II-IV and III-IV acute GVHD
Chronic GVHD
Immunosuppression-free survival at 1 year
Hematologic recovery
Primary and secondary graft failure
Disease relapse or progression
Transplant-related mortality
Toxicity and rates of infections (CMV and EBV reactivation)
Disease-free survival
Immune reconstitution
Quality of Life
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival- continuous up to two years
Grades II-IV and III-IV acute GVHD - through 100 days post-Transplant
Chronic GVHD - up to two years post Transplant
Immunosuppression-free survival at 1 year
Hematologic recovery - neutrophil engraftment Day 28 and platelet recovery Day 60
Disease relapse or progression -continuous up to two years
Transplant-related mortality - continuous up to two years
Toxicity and rates of infections (CMV and EBV reactivation) 2 years
Disease-free survival continuous up to two years
Immune reconstitution Days 35, 100, 180, and 365
Quality of Life continuous up to two years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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) | 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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | No |
| 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 |
|
| 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 | 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 | 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 |
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