Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT

Graft vs Host Disease Clinical Trial

— ATG-CyGVHD  

Official title:

Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02876679
• Other study ID #: P150955
• Secondary ID: 2016-002129-12
• Status: Completed
• Phase: Phase 2
• Start date: April 6, 2017
• Est. completion date: October 12, 2020

Study information

• Verified date: November 2020
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is designed as a two arm randomized Phase II, multicenter trial comparing cyclophosphamide to anti-thymocyte globulin for Graft-versus-Host Disease (GVHD) prophylaxis in patients with hematologic malignancies undergoing reduced intensity conditioning hematopoietic stem cell transplantation.

Description:

Allogeneic stem cell transplantation (allo-SCT) is a well-established therapy for different hematologic malignancies. Reduced-intensity conditioning (RIC) regimens can decrease the rate of toxicity/mortality in elderly patients, or in patients with poor medical condition. GVHD prophylaxis remains a challenging task after allo-SCT. The Flu-ivBu combination is a widely used RIC regimen, endorsed by EMA since July 2014. ATG in combination with cyclosporine-A ±mycophenolate mofetil is the backbone for GVHD prophylaxis in this setting. ATG can prevent GVHD with a good efficacy, but at the cost of a higher toxicity and profound immunosuppression, calling for more effective therapies. The most widely used RIC regimen in France incorporates fludarabine (Flu), intermediate doses of IV-busulfan (Bu) and anti-thymocyte globulins (ATG). While the use of ATG can prevent severe acute and chronic GVHD after allogeneic peripheral blood stem cell (PBSC) transplantation from both HLA-identical sibling and unrelated donors, some data suggested that in-vivo T-cell depletion with ATG in the RIC setting may induce a higher risk of disease relapse. Also, ATG induces profound immune suppression and increase incidence of opportunistic infections, especially EBV-related complications (relative risk=4.9; 95% CI[ 1.1-21.0]; P=0.03).

On the other hand, high-dose post-transplantation cyclophosphamide (PTCy) was developed to facilitate HLA-haploidentical allo-SCT using unmanipulated bone marrow (BM) cells. PTCy was effective in preventing both acute and chronic GVHD given its capacity to preferentially eliminate allo-reactive T cells and preserve regulatory T cells, both of which impact allogeneic immune reactions. Subsequently, the efficacy of PTCy as sole GVHD prophylaxis after myeloablative conditioning when using BM was also shown. However, BM is not the preferred source of stem cells after RIC allo-SCT, and the potential efficacy of PTCy on preventing GVHD when using PBSCs (which is the most frequently used source of allogeneic cells worldwide) is debated.

The advent of PTCy therapy is nowadays on the cutting edge. Thus, the potential efficacy (and cost-effectiveness) of PTCy for GVHD prophylaxis may have a major ATG sparing potential. A recent single centre phase 2 study (n=49) suggested that PTCy alone may not be the preferred GVHD prophylaxis following a RIC transplant with PBSCs. Indeed, A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P =0.02) and treatment-related mortality (HR, 3.3; P =0.035) and worse overall survival (HR, 1.9; P=0..04) with post-CY. Interpretation of the above non-randomized data is further complicated by heterogeneity (related and unrelated donors, BM and PBSC as stem cell source, different conditioning regimen), highlighting the need for a controlled randomized trial in a standardized setting.

The ultimate goal of this Phase IIB study is to assess the feasibility and inform the design of a subsequent phase III study. The present randomized trial is designed to compare the efficacy of the addition of PTCy to current standard of care with ATG after a Flu-Bu-based RIC regimen on GVHD prophylaxis. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free, relapse-free survival which measures freedom from ongoing morbidity and represents an ideal outcome measure after allo-SCT.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: October 12, 2020
• Est. primary completion date: October 12, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria :

• Patients aged between 18 and 65 years

• Presence of a hematologic malignancy for which a reduced-intensity conditioning allo-SCT is indicated (eligibility criteria for RIC allo-SCT include at least one of the following parameters: (i) patient age older than 50 years; (ii) heavily pre-treated patients who received an autologous hematopoietic SCT (auto-SCT) or with more than 2 lines of chemotherapy before allo-SCT; and (iii) patients with poor performance status because of significant medical comorbidities as described by Sorror et al.

• Karnofsky index = 70%

• Availability of a sibling or unrelated stem-cell donor (10/10-HLA matched unrelated donor)

• Efficient contraceptive method within 1 month for women and 3 months for men after the last dose of treatment

• Written informed consent.

Exclusion Criteria:

• Creatinine clearance less than 30 mL/min

• Bilirubin or amino-transferases above 3X upper normal limit

• Cardiac ejection fraction less than 40%

• Pulmonary impairment with <50% lung carbon monoxide diffusing capacity (DLCO)

• Known hypersensitivity or contraindication to the use of post-transplant Cy and ATG

• Any circumstance that precludes the use of the drugs involved in the protocol

• Pregnancy

Related Conditions & MeSH terms

• Graft vs Host Disease

Intervention

Drug:
• Cyclophosphamide
GVHD prophylaxis: All patients will receive post-transplant 50mg/Kg/day cyclophosphamide (day +3 and +4) AND cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil in case of an HLA-matched unrelated donor
• Anti-Thymocyte Globulin
GVHD prophylaxis: 2.5 mg/Kg/day ATG (Thymoglobuline®) for 2 consecutive days (day -2 and -1) All patients will receive cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil (MMF) in case of an HLA-matched unrelated donor.
• Conditioning regimen
30 mg/m2/day fludarabine for 5 days (day-6 to day-2) 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)

Locations

Country	Name	City	State
France	Saint Antoine Hospital - Hematology Department	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite endpoint of GVHD-free, relapse-free survival (GRFS)	Absence of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death	12 Months
Secondary	Cumulative incidence of grade 2-4 and grade 3-4 severe acute GVHD	Acute GVHD grading should be performed by the revised Glucksberg criteria (Przepiorka et al., 1995). The time of onset of acute grades II-IV and III-IV acute GVHD will be recorded, as well as the maximum grade achieved	6 Months
Secondary	Cumulative incidence of non-relapse mortality within the first 12 months after transplantation.	Death without evidence of disease recurrence. Disease recurrence will be considered a competing event.	12 Months
Secondary	Disease-free survival	Relapse-free survival : time from date of transplant to death or relapse, whichever comes first. The event for this endpoint is relapse or death. Patients alive and free from disease relapse will be censored at last follow-up	12 months
Secondary	Overall survival.	Overall survival : time interval between date of transplant and death from any cause or for surviving patients, to last follow-up. The event for this endpoint is death from any cause.	12 months
Secondary	Quality of Life (QoL) with EORTC QLQ-C30	Evaluation by the questionnaire EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)	12 Months
Secondary	Quality of Life (QoL) with FACT-BMT	Evaluation by the questionnaire FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)	12 Months
Secondary	Immune recovery measurement	Immune recovery measurement: number of patients with complete immune recovery (T, B and dendritic cells subsets)	12 Months