Table 1.
Selected Clinical Trials of Immunomodulatory Therapies in GvHD.
| Trial Number | Treatment | Trial Description | Status, Outcome Measures, Comments |
|---|---|---|---|
| NCT 01012492a | CTLA4-Ig (Abatacept) | Abatacept-based immunosuppression to prevent aGvHD during URD-HCT | Completed |
| Safety and tolerability of additional Abatacept (to cyclosporine/methotrexate) in aGvHD prophylaxis after URD-HCT with BM or PB grafts | |||
| Phase 2 | |||
| GvHD severity and incidence by day +100; hematologic/immune reconstitution; protective immunity | |||
| NCT 01743131a | CTLA4-Ig (Abatacept) | Abatacept as GvHD prophylaxis | Active |
| Randomized | |||
| Phase 2 | Evaluation of Abatacept with calcineurin inhibitors and methotrexate to protect aGvHD without causing more infections | ||
| GvHD incidence and severity at day +100 and +180; incidence of infections, engraftment, relapse, OS; GvHD-free survival | |||
| NCT 02683525a | DPP-4 inhibition (Sitagliptin) | Sitagliptin to prevent aGvHD after allo-HCT | Completed |
| Efficacy of DPP-4 inhibition (Sitagliptin) to reduce grade II–IV aGvHD by day +100 with sirolimus/tacrolimus GvHD prophylaxis | |||
| Phase 2 | |||
| Neutrophil and platelet counts; infections, NRM; cGvHD incidence; relapse rate | |||
| NCT 00862719a | DPP-4 inhibition (Sitagliptin) | Sitagliptin to speed up engraftment after UCB-transplant | Completed |
| Non-randomized | |||
| Phase 2 | Recovery of blood counts after UCB-transplantation | ||
| Patients with engraftment at day +30; time to neutrophil and platelet engraftment; treatment-related adverse events (grade 3); non-hematological toxicities | |||
| NCT 04448587a | DPP-4 inhibition (Sitagliptin) | Sitagliptin for treatment of grade III/IV and refractory aGvHD | Recruiting |
| Safety and efficacy of sitagliptin in severe and refractory aGvHD | |||
| Phase 2 | Response (CR, VGPR, PR) by day +28 and +56 | ||
| Treatment-related adverse events (safety/tolerability); GvHD-free survival at 6 months; biomarker blood profiling | |||
| NCT 02953678a | JAK1/2 inhibition (Ruxolitinib) | Ruxolitinib with corticosteroids in SR-aGvHD (REACH-1) | Completed |
| Ruxolitinib with prednisolone/methylprednisolone in grade II-IV SR-aGvHD | |||
| Phase 2 | ORR (CR, VGPR, PR) at day +28, +56 and +100 | ||
| Three- and 6-mo DOR; relapse rate; NRM; relapse-related mortality; FFS; OS, adverse events | |||
| NCT 02913261a | JAK1/2 inhibition (Ruxolitinib) | Safety/efficacy of ruxolitinib vs BAT in SR-aGvHD after allo-HCT (REACH2) | Active |
| Randomized | |||
| ORR (CR, PR) at day +28 | |||
| Phase 3 | Durable ORR (patients with CR/PR at day +28 maintaining until day +56; OR at day +14; DOR; OS; cumulative steroid dose; event-free survival; FFS; NRM; MR; incidence of cGvHD; PK parameters: plasma concentration peak, AUC, total body clearance; exposure-efficacy relationship of Ruxolitinib in SR-aGvHD; BOR until day +28 | ||
| NCT 01747499a | HMA (Azacitidine) | Azacitidine in patients undergoing MUD-HCT | Terminated |
| Non-randomized | |||
| Phase 1/2 | Determination of MTD of 5-AzaC and effect on grade II-IV GvHD in MUD-transplantation | ||
| Grade II-IV aGvHD until day +180 with 5-AzaC treatment; OS; TRM; cGvHD incidence | |||
| NCT 01390311a | HMA (Azacitidine) | Azacitidine in relapsed AML and MDS after allo-HCT | Completed |
| Randomized | |||
| Phase 1 | Aza after chemotherapy and DLI in relapse AML/MDS previously received allo-HCT | ||
| MTD | |||
| Grade II-IV aGvHD (day +100 post-DLI); ORR (1 y); OS (day +100 post-DLI); effects of Aza dose increase on resting and activated Tregs | |||
| ISRCTN 36825171b | HMA (Azacitidine) | Azacitidine in reduced-intensity conditioned allo-HCT | Completed |
| Aza treatment in AML and MDS patients undergoing reduced-intensity allo-HCT | |||
| Phase 2 | RR at 12 mo post-HCT; OS at 3 y post-HCT | ||
| NCT 00529035a | Ultra-low dose IL-2 | Ultra-low dose IL-2 in refractory cGvHD | Completed |
| MTD and toxicity profile of IL-2 in cGvHD with inadequate response to steroids; ORR (CR and PR); immune cell phenotyping (CD4, CD8, Treg, Tcon, NK, B cells); Treg/Tcon ratio | |||
| Phase 1 | |||
| NCT 00539695a | Low Dose IL-2 | IL-2 for GvHD | Completed |
| Phase 2 | Safety and efficacy of low-dose IL-2 in aGvHD; rate of dose-limiting toxicities; rate of severe aGvHD (grade III/IV, 12 wk on treatment); reconstitution of Tregs; suppressive activities of Tregs, cytokine secretion, immune phenotypes of PBMCS, NK analysis | ||
| NCT 01927120a | IL-2 tacrolimus, sirolimus | In vivo Treg expansion and GvHD prophylaxis; | Completed |
| Determination if GvHD prophylaxis with IL-2/tacrolimus/sirolimus enhances Treg reconstitution and differentiation after allo-HCT; safety and effect on aGvHD/cGvHD; evaluation of T-cell specific signaling | |||
| Phase 2 | |||
| Treg frequencies day +30 and +90; 1-y OS; relapse rate; aGvHD (grade II–IV) day +100; cGvHD (day +365); non-relapse mortality; adverse events; phosphorylation of STAT3, STAT5 and S6 | |||
| NCT 02318082a | IL-2 | Individual dose-escalated IL-2 in refractory cGvHD | Completed |
| MTD 8-wk dose-escalated IL-2 (adult and pediatric patients); DLT; cGvHD ORR; OS (1 y); malignancy relapse rate (1 y) | |||
| Phase 1 | |||
| ACTRN 12614000266662c | Anti-IL6R (Tocilizumab) | Tocilizumab to prevent aGvHD after allo-HCT | Completed |
| Tocilizumab at 8 mg/kg on day -1 of conditioning | |||
| Phase 3 | Control to placebo (saline) | ||
| Incidence of grade II–IV GvHD at day +100 post allo-HCT; IL-6/IL-6R levels in serum; immune reconstitution; infection rate; PFS, TRM; OS | |||
| NCT 00726375a | TNFα blockade (Etanercept) | Etanercept (Enbrel) as sole treatment for grade I aGvHD | Completed |
| Treatment of early skin GvHD (grade I) with Etanercept instead of high-dose steroid | |||
| Phase 3 | Disease progression within 28 d of Etanercept treatment; CR at 4 wk | ||
| NCT 00602693a | Treg (cellular therapy) | Treg infusion post UCB-transplant in advanced hematologic cancer | Completed |
| MTD of UCB-derived Tregs (dose escalation, DLTs); Treg numbers in PB; grade II–IV aGvHD (day +100); donor engraftment; chimerism; neutrophil/platelet recovery; cGvHD incidence; infectious complications; relapse | |||
| Phase 1 | |||
| NCT 01911039a | Treg (cellular therapy) | Treg infusion in SR-cGvHD | Safety and tolerability of Treg infusion in SR-cGvHD; adverse events; infusion-related toxicities; Treg counts in PB; FFS; ORR; improvement of quality of life |
| Phase 1 | |||
| NCT 01903473a | Treg (cellular therapy) | Donor-Treg infusion in cGvHD patients | Recruiting |
| Phase 2 | Non-randomized | ||
| Safetly evaluation of rapamycin with donor-Treg infusion and low-dose IL-2 in SR-cGvHD patients; immunological changes, Treg counts, Treg phenotype | |||
| Efficacy of Treg selection; response of cGvHD to Treg + IL-2 + rapamycin; infectious complications; OS (1 y); PFS (1 y); ORR (1 y) |
aRegistered at https://clinicaltrials.gov.
bRegistered at http://isrctn.com.
cRegistered at https://www.anzctr.org.au/.
5-AzaC = 5-Azacitidine; aGvHD = acute graft-versus-host disease; AML = acute myeloid leukemia; AUC = area under the curve; BAT = best available therapy; BM = bone marrow; BOR = best overall response; CD = cluster of differentiation; cGvHD = chronic graft-versus-host disease; CR = complete remission; CTLA4-Ig = cytotoxic T-cell-lymphocyte-4-immunoglobulin; DLI = donor lymphocyte infusion; DLT = dose-limiting toxicities; DOR = duration of response; DPP4 = dipeptidyl peptidase 4; FFS = failure-free survival; GvHD = graft-versus-host disease; HCT = hematopoietic stem cell transplantation; HMA = hypomethylating agents; IL = interleukin; JAK = Janus kinase; MDS = myelodysplastic syndrome; MR = malignancy relapse/progression; MTD = maximum tolerated dose; MUD = matched unrelated donor; NK = natural killer; NRM = non-relapse mortality; ORR = overall response rate; OS = overall survival; PB = peripheral blood; PBMCs = peripheral blood mononuclear cells; PFS = progression free survival; PK = pharmacokinetic; PR = partial response; RR = response rate; SR = steroid refractory; STAT = signal transducer and activator of transcription; Tcon = conventional T-cells; TNF = tumor necrosis factor; Tregs = regulatory T-cells; TRM = treatment-related mortality; UCB = umbilical cord blood; URD = unrelated donor; VGPR = very good partial response.