A Multi-centre Phase II Trial of GVHD Prophylaxis Following Unrelated Donor Stem Cell Transplantation Comparing Thymoglobulin vs. Calcineurin Inhibitor or Sirolimus-based Post-transplant Cyclophosphamide
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 400
- 试验地点
- 32
- 主要终点
- GVHD-free, relapse-free survival
研究概览
简要总结
A multi-centre phase II trial of GvHD prophylaxis following unrelated donor stem cell transplantation comparing Thymoglobulin vs. Calcineurin inhibitor or Sirolimus-based post-transplant cyclophosphamide.
详细描述
This is a prospective, phase II, adaptive, multicentre, randomised clinical trial in patients undergoing reduced intensity conditioned (RIC) unrelated donor allogeneic stem cell transplantation (allo-SCT). The trial will compare the novel graft-versus-host disease (GvHD) prophylaxis regimens of post-transplant cyclophosphamide (PTCy) + Calcineurin inhibitor (CNI) (PTCy-CNI) or PTCy + Sirolimus to a current standard-of-care involving the use of T-cell depletion with Thymoglobulin. Patients will be minimised at randomisation by their randomising centre, disease risk score (low/intermediate or high/very high) and human leukocyte antigen (HLA) match (10/10 or 9/10). Patients eligible for entry into the trial will be randomised on a 1:1:1 ratio to receive either one of the experimental treatment arms or the control arm.
The primary objective is to compare GvHD-free, relapse-free Survival (GRFS) in patients treated with the GvHD prophylaxis regimens PTCy-CNI, PTCy-Sirolimus or T-cell depletion with Thymoglobulin.
The secondary objectives are to evaluate the cumulative incidence of acute GvHD (aGvHD), the cumulative incidence of moderate and severe chronic GvHD (cGvHD), the cumulative incidence of non-relapse mortality (NRM), overall survival (OS), progression-free survival (PFS), immune suppression-free survival, the cumulative incidence of engraftment, the incidence of full donor chimerism, the cumulative incidence of infection requiring inpatient admission, the number of inpatient days, the timing and dose of donor lymphocyte infusion (DLI), the cumulative incidence of Epstein-Barr virus (EBV) related-post transplant lymphoproliferative disease (PTLD), the number of doses rituximab administered for EBV reactivation, quality of life (QoL), the cumulative incidence of haemorrhagic cystitis, the cumulative incidence of cytomegalovirus (CMV) viraemia and CMV end-organ disease and safety and tolerability.
The scientific research will address the questions about how plasma biomarkers for GvHD predict GvHD and non-relapse mortality following T-cell depleted methods of transplantation and how the different methods of T-cell depletion impact on immune function and re-constitution.
Outcome Measures
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Availability of suitably matched unrelated donor (9/10 or 10/10)
- •Planned to receive one of the following RIC protocols:
- •Fludarabine-Melphalan (Fludarabine 120-180mg/m2 IV; melphalan ≤ 150mg/m2 IV)
- •BEAM or LEAM (carmustine 300mg/m2 IV or lomustine 200mg/m2 IV with: etoposide 800 mg/m2 IV; cytarabine 1600mg/m2 IV; melphalan 140mg/m2 IV)
- •Fludarabine-Busulphan (Fludarabine 120-180mg/m2 IV; Busulphan ≤ 8mg/kg PO or 6.4mg/kg IV)
- •Fludarabine- Treosulfan (Fludarabine 150mg/m2 IV; Treosulfan 30g/m2 IV)
- •Planned use of PBSCs for transplantation
- •Planned allo-SCT for one of the following haematological malignancies:
- •AML in CR (patients enrolled onto the COSI trial are not eligible for this study)
- •ALL in CR (patients enrolled onto the ALL-RIC trial are not eligible for this study)
- •CMML <10% blasts
- •MDS <10% blasts (patients enrolled onto the COSI trial are not eligible for this study)
- •NHL in CR/PR
- •HL in CR/PR
- •MM in CR/PR
- •CLL in CR/PR
- •CML in 1st or 2nd chronic phase
- •Myelofibrosis
- •Age 16-70 years
- •Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must agree to use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after transplant
排除标准
- •Use of any method of graft manipulation (excluding storage of future DLI)
- •Use of alemtuzumab or any method of T cell depletion except those that are protocol-defined
- •Known hypersensitivity to study drugs or history of hypersensitivity to rabbits
- •Pregnant or lactating women
- •Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period
- •Life expectancy <8 weeks
- •Active HBV or HCV infection
- •Organ dysfunction defined as:
- •LVEF <45%
- •GFR <50ml/min
- •Bilirubin >50µmol/l
- •AST/ALT>3 x ULN
- •Participation in COSI or ALL-RIC trials
- •Contraindication to treatment with the study drugs (Thymoglobulin, cyclophosphamide, sirolimus, ciclosporin and mycophenolate mofetil) as detailed in each study drug SPC.
- •Patient has any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory, cardiovascular) or significant disorder which, in the opinion of the investigator would jeopardise the safety of the patient by taking part in the trial.
研究组 & 干预措施
Experimental arm (PTCy + Sirolimus + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Sirolimus will be initially given PO as a loading dose of 6 mg on day 5 followed by 2 mg daily; doses will be adjusted to maintain a trough level (in whole blood) of 8 to 14 ng/mL until day 60, thereafter 5-8 ng/mL until day 90. In the absence of active GvHD, the dose of sirolimus will be tapered from day 90. We recommend that the daily maintenance dose of sirolimus is reduced empirically to 0.5-1mg daily with concomitant treatment with a triazole anti-fungal agent.
MMF will be given IV/O according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Mycophenolate Mofetil (Drug)
Control Arm Thymoglobulin + Cyclosporine + MMF
Thymoglobulin is given as an intravenous infusion of 2.5 mg/kg/day over 2 days (days -2 and -1; total dose 5 mg/kg) via a central line through a 0.2 micron inline filter. Each dose will be infused over 6-8 hours. No test dose will be given. 30 minutes before Thymoglobulin, the patient should receive methylprednisolone 1mg/kg intravenously, 1g paracetamol PO and 10mg chlorphenamine IV. Patients should be monitored carefully and receive appropriate therapy for any infusion-related or anaphylactic reactions as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day -1 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of any active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day -1 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Thymoglobulin (Drug)
Control Arm Thymoglobulin + Cyclosporine + MMF
Thymoglobulin is given as an intravenous infusion of 2.5 mg/kg/day over 2 days (days -2 and -1; total dose 5 mg/kg) via a central line through a 0.2 micron inline filter. Each dose will be infused over 6-8 hours. No test dose will be given. 30 minutes before Thymoglobulin, the patient should receive methylprednisolone 1mg/kg intravenously, 1g paracetamol PO and 10mg chlorphenamine IV. Patients should be monitored carefully and receive appropriate therapy for any infusion-related or anaphylactic reactions as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day -1 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of any active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day -1 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Mycophenolate Mofetil (Drug)
Control Arm Thymoglobulin + Cyclosporine + MMF
Thymoglobulin is given as an intravenous infusion of 2.5 mg/kg/day over 2 days (days -2 and -1; total dose 5 mg/kg) via a central line through a 0.2 micron inline filter. Each dose will be infused over 6-8 hours. No test dose will be given. 30 minutes before Thymoglobulin, the patient should receive methylprednisolone 1mg/kg intravenously, 1g paracetamol PO and 10mg chlorphenamine IV. Patients should be monitored carefully and receive appropriate therapy for any infusion-related or anaphylactic reactions as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day -1 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of any active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day -1 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Cyclosporine (Drug)
Experimental arm (PTCy + Cyclosporine + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day 5 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Cyclophosphamide (Drug)
Experimental arm (PTCy + Cyclosporine + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day 5 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Cyclosporine (Drug)
Experimental arm (PTCy + Cyclosporine + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Patients will receive IV/PO cyclosporine according to local policy to begin on day 5 maintaining a trough level of 100-200 µg/L until day 90 before a subsequent taper in the absence of active GvHD.
MMF will be given IV/PO according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Mycophenolate Mofetil (Drug)
Experimental arm (PTCy + Sirolimus + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Sirolimus will be initially given PO as a loading dose of 6 mg on day 5 followed by 2 mg daily; doses will be adjusted to maintain a trough level (in whole blood) of 8 to 14 ng/mL until day 60, thereafter 5-8 ng/mL until day 90. In the absence of active GvHD, the dose of sirolimus will be tapered from day 90. We recommend that the daily maintenance dose of sirolimus is reduced empirically to 0.5-1mg daily with concomitant treatment with a triazole anti-fungal agent.
MMF will be given IV/O according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Cyclophosphamide (Drug)
Experimental arm (PTCy + Sirolimus + MMF)
Cyclophosphamide is given as an IV infusion of 50 mg/kg/day over 2 days (days 3 and 4; total dose 100 mg/kg) together with IV hydration and Mesna, as per local policy.
Sirolimus will be initially given PO as a loading dose of 6 mg on day 5 followed by 2 mg daily; doses will be adjusted to maintain a trough level (in whole blood) of 8 to 14 ng/mL until day 60, thereafter 5-8 ng/mL until day 90. In the absence of active GvHD, the dose of sirolimus will be tapered from day 90. We recommend that the daily maintenance dose of sirolimus is reduced empirically to 0.5-1mg daily with concomitant treatment with a triazole anti-fungal agent.
MMF will be given IV/O according to local policy at a dose of 1g TDS to begin on day 5 and discontinued on day 35 without taper if there is no evidence of active GvHD. In adults weighing <55kg, MMF should be given at a lower dose of 0.75g IV/PO TDS.
干预措施: Sirolimus (Drug)
结局指标
主要结局
GVHD-free, relapse-free survival
时间窗: at 1 year
GVHD assessment scoring will be performed as per the modified Glucksberg criteria (revised by MAGIC) and the National Institutes of Health (NIH) criteria. GvHD-free, relapse-free survival (GRFS) defined as the time from date of day 0 (defined as the day of stem cell infusion) to the date of first event or death from any cause. An event is defined as GvHD (both acute and chronic), relapse or progression. Patients who are alive and event free at the end of the trial will be censored at their date of last follow-up
次要结局
- Overall survival(at 1 year)
- Cumulative incidence of patients with haemorrhagic cystitis(at 1 year)
- Cumulative incidence of moderate and severe chronic GvHD(at 1 year)
- Cumulative incidence of acute grade II-IV and III-IV GvHD(at 1 year)
- The cumulative incidence of infection requiring inpatient admission(at 1 year)
- The timing of mixed chimerism, persistent disease or relapse(during first 12 months)
- Safety defined as the incidence of ≥ grade 3 toxicities reported as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.0(from the date of commencement of protocol defined treatment until 28 days after the administration of the last dose of IMP.)
- Cumulative incidence of NRM(at 1 year)
- Progression-free survival(at 1 year)
- Cumulative incidence of engraftment(at 1 year)
- The number of inpatient days(during first 12 months)
- The number of doses of Rituximab administered for EBV reactivation(during first 12 months)
- QoL measured by FACT-BMT questionnaire(at baseline, 6 months and 12 months)
- Cumulative incidence of CMV viremia and CMV end-organ disease(at 1 year)
- Dose of Donor lymphocyte infusion (DLI) for mixed chimerism, persistent disease or relapse(during first 12 months)
- Immune suppression-free survival(at 1 year)
- The incidence of full donor chimerism(at 100 days)
- Cumulative incidence of EBV-related PTLD(during first 12 months)
- Tolerability defined to be the number of patients able to complete therapy as scheduled(during first 12 months)