scholarly journals Pharmacokinetics and Safety of KRN7000 Following Intravenous Infusion of RGI-2001 in Allogeneic Transplant Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Yi-Bin Chen ◽  
Dana D Lee ◽  
Hayley Lane ◽  
Steve Smith ◽  
Yasuyuki Ishii ◽  
...  
Keyword(s):  
Stem Cell ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Half Life ◽  
Board Member ◽  
Safety Monitoring ◽  
Inkt Cells ◽  
Hematopoietic Stem ◽  
Graft Versus Leukemia ◽  
Safety Monitoring Board

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an important therapeutic option, and, in some indications, the only potentially curative therapy, for the treatment of a variety of hematologic malignancies. The success of myeloablative alloHSCT derives both from the ability to treat subjects with intensive chemo radiotherapy and from potent graft-versus-leukemia (GvL) effects mediated by donor immunity. Donor T cells in the infused stem cell graft are used to attack malignant cells, but may also strike normal host tissues and organs, resulting in graft versus host disease (GvHD). Despite the use of immunosuppressive agents, GvHD, acute or chronic, is one of the leading causes of morbidity and mortality from alloHSCT. RGI-2001 is a liposomal formulation which contains the active pharmaceutical ingredient, KRN7000. KRN7000 is the first synthetic derivative of α-galactosylceramide (α-GalCer) compound isolated originally from the marine sponge Agelas mauritianus, which is a representative ligand for invariant natural killer (iNKT) cells. RGI-2001 activates a tolerogenic cellular pathway via iNKT cell activation, which ultimately leads to the activation of cellular cascades including regulatory dendritic cells (DCreg) and Tregs. Tregs are upregulated via an IL-4 dependent mechanism produced by iNKT cells. These antigen-specific Tregs have been shown to down regulate the immune response directed toward specific antigens without causing generalized immunosuppression while preserving graft-versus-leukemia effect (GvL). RGI-2001 is being evaluated for the potential to reduce or prevent GvHD post allogeneic transplantation. The aim of this analysis was to characterize the pharmacokinetic (PK) profile of RGI-7000 following weekly intravenous infusions of RGI-2001. Methods: RGI-2001-003 is an open label, multi-center phase 2b study to evaluate the safety and efficacy of RGI-2001 for the prevention of acute GvHD in subjects following alloHSCT. Blood samples were collected for quantification of plasma concentrations of RGI-7000 predose and 0.5, 2, 4, 6, 8, 24, and 48 h after the first dose and predose, 0.5, and 4 h post dose on Day 14. Maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), area under the concentration time curve (AUC) and terminal half-life (T1/2) we calculated by non-compartmental analysis. Results: A total of 6 subjects were evaluated in this safety phase of the study. All subjects received RGI-2001 100 µg/kg as a 30-minute IV infusion weekly for a total of 6 doses post alloHSCT. Subjects were 66.7% male, 33.3% white, 66.7% not-Hispanic or Latino. Mean age was 44 years (range 25-61 years), matched unrelated donors 83.3%. All subjects received donor PBSCT. Dose limiting toxicities (DLT) was evaluated for each subject on day 30. Mean preliminary and interim pharmacokinetic parameters (%CV) are shown in Table 1. Repeat weekly infusion of RGI-2001 lead to generally similar exposure on the first dose and Day 14. There were no deaths, no serious adverse events and no discontinuations related to study drug. There were no DLT reported. The most common treatment emergent adverse events were mucositis, pruritis/rash or erythema, decreased appetite. One infusion-related reaction (Grade 2) was reported in 1 subject and event resolved. Conclusions: Intravenous administration of RGI-2001 resulted in quantifiable levels of RGI-7000 in all patients. Plasma levels of RGI-7000 were similar after the first dose and multiple doses. Its plasma half-life was approximately 36 hours. Disclosures Chen: AbbVie: Other: Data and Safety Monitoring Board Member; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member. Lane:Nanoscope Therapeutics: Consultancy; Regimmune Corporation: Consultancy; Revolution Medicines: Consultancy; Star Therapeutics: Consultancy; Valitor: Consultancy; Viewpoint Therapeutics: Ended employment in the past 24 months; Cleave Therapeutics: Consultancy.

scholarly journals Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Makoto Nakamura ◽  
Yusuke Meguri ◽  
Shuntaro Ikegawa ◽  
Takumi Kondo ◽  
Yuichi Sumii ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell Subsets ◽  
Inkt Cells ◽  
Early Recovery ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Reduced Dose ◽  
Graft Versus Leukemia ◽  
Novel Strategy

AbstractPosttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

scholarly journals Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

2015 ◽  
Vol 59 (7) ◽  
pp. 3718-3725 ◽  
Author(s):  
Amy E. Caruso Brown ◽  
Mindy N. Cohen ◽  
Suhong Tong ◽  
Rebecca S. Braverman ◽  
James F. Rooney ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Half Life ◽  
Viral Infections ◽  
Multiorgan Failure ◽  
Kidney Injury ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Life Threatening

ABSTRACTChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.

Antifungal Prophylaxis in Cancer Patients After Chemotherapy or Hematopoietic Stem-Cell Transplantation: Systematic Review and Meta-Analysis

2007 ◽  
Vol 25 (34) ◽  
pp. 5471-5489 ◽  
Author(s):  
Eyal Robenshtok ◽  
Anat Gafter-Gvili ◽  
Elad Goldberg ◽  
Miriam Weinberger ◽  
Moshe Yeshurun ◽  
...  
Keyword(s):  
Systematic Review ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Adverse Events ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Antifungal Prophylaxis ◽  
Hematopoietic Stem ◽  
All Cause Mortality ◽  
Related Mortality

Purpose To evaluate the effect of antifungal prophylaxis on all-cause mortality as primary outcome, invasive fungal infections (IFIs), and adverse events. Many studies have evaluated the role of antifungal prophylaxis in cancer patients, with inconsistent conclusions. Methods We performed a systematic review and meta-analysis of randomized, controlled trials comparing systemic antifungals with placebo, no intervention, or other antifungal agents for prophylaxis in cancer patients after chemotherapy. The Cochrane Library, MEDLINE, conference proceedings, and references were searched. Two reviewers independently appraised the quality of trials and extracted data. Results Sixty-four trials met inclusion criteria. Antifungal prophylaxis decreased all-cause mortality significantly at end of follow-up compared with placebo, no treatment, or nonsystemic antifungals (relative risk [RR], 0.84; 95% CI, 0.74 to 0.95). In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFI. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFI, whereas the difference in mortality was only borderline significant (RR, 0.88; 95% CI, 0.74 to 1.06). Prophylaxis with itraconazole suspension reduced documented IFI when compared with fluconazole, with no difference in survival, and at the cost of more adverse events. On the basis of two studies, posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFI when compared with fluconazole. Conclusion Antifungal prophylaxis decreases all-cause mortality significantly in patients after chemotherapy. Antifungal prophylaxis should be administered to patients undergoing allogeneic HSCT, and should probably be administered to high-risk acute leukemia patients.

scholarly journals Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

2010 ◽  
Vol 54 (10) ◽  
pp. 4143-4149 ◽  
Author(s):  
Andreas H. Groll ◽  
Gerda Silling ◽  
Charlotte Young ◽  
Rainer Schwerdtfeger ◽  
Helmut Ostermann ◽  
...  
Keyword(s):  
Stem Cell ◽  
Combination Therapy ◽  
Adverse Events ◽  
Amphotericin B ◽  
Hematopoietic Stem Cell ◽  
Liposomal Amphotericin ◽  
Fungal Infections ◽  
Study Drug ◽  
Invasive Fungal Infections ◽  
Hematopoietic Stem

ABSTRACT The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.

Acute Enterocolitis Incidence in Patients with Hematological Malignancies Receiving Myelotoxic Therapy Requiring Hematopoietic Stem Cell Support - Palifermin Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5461-5461
Author(s):  
Isabel Sousa ◽  
Catarina Geraldes
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Adverse Events ◽  
Stem Cell Transplantation ◽  
Parenteral Nutrition ◽  
Hematopoietic Stem Cell ◽  
Oral Mucositis ◽  
Hematological Malignancies ◽  
Control Group ◽  
Hematopoietic Stem

Abstract Background: Chemotherapeutic agents can cause severe oral and gastrointestinal mucositis, for which there is currently no treatment. Previous research demonstrates that palifermin - keratinocyte growth factor - is potentially antimucotoxic, reducing the duration and severity of oral mucositis after intense chemotherapy in hematological cancers. The primary aim of this study was to determine palifermin effectiveness in ameliorating chemotherapy-induced diarrhoea and oral mucositis incidence. Palifermin adverse events were also assessed. Methods: Retrospective observational study involving patients with hematological malignancies undergoing autologous hematopoietic stem-cell transplantation after myelotoxic therapy. All the patients received antibiotic, antifungal, and antiviral prophylaxis. Patients being treated with palifermin to decrease the incidence and duration of severe oral mucositis (Palifermin Group) were compared to a control group of patients who did not receive palifermin (Control Group). Palifermin was administered during 3 consecutive days, before and after myelotoxic therapy in a 60 μg/Kg daily intravenous dose. Results: Twenty-four patients were included, 8 in Palifermin Group and 16 in Control Group. Baseline malignancies were Hodgkin and non Hodgkin lymphoma, acute myeloid leukemia, and multiple myeloma. All patients underwent autologous hematopoietic stem-cell transplantation after the following conditioning regimes: BEAM, BuCy, and Mel200 respectively. In Palifermin Group, 62.5% were male, mean age 47.6±13.0 years, mean disease duration of 22.3±10.1 months (N=8). In Control Group 56.3% were male, mean age 45.8±12.1 years (N=16). Mean performance status (Karnofsky Index) was 80±14.1% and 71.3±15.1%, in each group, respectively. No statistically significant differences between Palifermin and Control Groups were found regarding the degree of diarrhoea, although in the Palifermin Group the majority of patients presented a grade 2 (N=3) and in the Control Group a grade 3 (N=6). In the Palifermin Group there was a tendency for a lower incidence of hypoalbuminemia [12.5% (Palifermin Group) vs. 50% (Control Group)], which corresponded to a significant lower difference in the needs for receiving parenteral nutrition (P=0.011). Nevertheless, these findings were not translated in less febrile episodes or less iv antibiotic therapy days. There were no significant differences between the two groups regarding the degree of oral mucositis, the number of days of analgesic opioids use, and the number of hospitalization days, most probably due to the small sample considered. The most common adverse events in the Palifermin Group were reversible erythema and edema of the face and upper trunk that have occurred only in 3 patients. Weight increase was mild and similar in both groups of patients [Median weight increase±SD: 1,0±1,7 Kg (Palifermin Group) vs 2,0±2,5 Kg (Control group)]. Conclusion: Gastrointestinal and oral mucositis are common consequences of cancer therapy with a direct and significant impact on the quality of life and care costs, also affecting patient’s survival. Our exploratory study shows that palifermin treatment is well tolerated, potentially reducing diarrhoea and the incidence of hypoalbuminemia, and significantly reducing the needs for parenteral nutrition. However further studies with an increased number of patients will be necessary to provide more evidence concerning palifermin efficacy in the management of these cancer therapy’s debilitating side-effects.

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