scholarly journals A phase I/II trial to treat massive Africanized honeybee (Apis mellifera) stings using the new apilic antivenom

2021 ◽  
Author(s):  
Alexandre Naime Barbosa ◽  
Rui Seabra Ferreira ◽  
Francilene Capel Tavares de Carvalho ◽  
Fabiana Schuelter-Trevisol ◽  
Mônica Bannwart Mendes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Apis Mellifera ◽  
Adverse Events ◽  
Phase I ◽  
Adverse Reactions ◽  
Median Number ◽  
Treatment Schedule ◽  
Africanized Honeybee ◽  
Hospitalization Period ◽  
Safety Endpoint

ABSTRACTSafety, optimal minimum dose, and, preliminary effectiveness of a new generation Africanized honeybees (Apis mellifera) antivenom (AAV) were evaluated. A phase I/II, multicenter, non- randomized, single-arm clinical trial involving 20 participants showing multiple stings were studied. Participants have received either 2 to 10 vials of AAV based on the stings number together with a predefined adjuvant, symptomatic, and complementary treatment schedule. The primary safety endpoint was the presence of early adverse reactions within the first 24 hours after treatment. Preliminary efficacy through clinical evolution, including laboratory tests, was assessed at baseline and over the following four weeks. ELISA assays and mass spectrometry estimated the venom pharmacokinetics before, during, and after treatment. Twenty adult participants, 13 (65%) males, and 7 (35%) females, with a median age of 44 years and a mean body surface of 1.92 m2 (median = 1.93 m2) were recruited. The median number of stings was 52.5 ranging from 7 to more than 2,000. Envenoming severity was classified as 80% mild, 15% moderate, and 5% severe. According to the protocol, 16 (80%) participants received two AAV vials, 3 (15%) six vials, and one (5%) 10 vials. There was no discontinuation of the treatment due to acute adverse events and there were no late adverse reactions. Two patients showed mild adverse events with only transient itchy skin and erythroderma. All participants completed the infusion within two hours and there was no loss of follow-up after discharge. ELISA assays showed venom concentrations varying between 0.25 ng/mL and 1.479 ng/mL prior to treatment. Venom levels decreased in all cases during the hospitalization period. Surprisingly, in nine cases (45%), despite clinical recovery and without symptoms, the venom levels increased again during outpatient care 10 days after discharge. Mass spectrometry showed melittin in eight participants 30 days after the treatment. Considering the promising safety results of the investigational product for the treatment of massive Africanized honeybee attacks, added to efficacy in clinical improvement and immediate decrease in blood venom level, the AAV has shown to be safe for human use.Trial registrationUniversal Trial Number (UTN): U1111-1160-7011, Register Number: RBR-3fthf8 (http://www.ensaiosclinicos.gov.br/rg/RBR-3fthf8/).

scholarly journals Single-Arm, Multicenter Phase I/II Clinical Trial for the Treatment of Envenomings by Massive Africanized Honey Bee Stings Using the Unique Apilic Antivenom

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexandre Naime Barbosa ◽  
Rui Seabra Ferreira ◽  
Francilene Capel Tavares de Carvalho ◽  
Fabiana Schuelter-Trevisol ◽  
Mônica Bannwart Mendes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Clinical Trial ◽  
Adverse Events ◽  
Phase I ◽  
Serious Adverse Events ◽  
Clinical Trial Registration ◽  
Laboratory Findings ◽  
Africanized Honey Bee ◽  
Africanized Honeybee ◽  
Hospitalization Period

We evaluated the safety, optimal dose, and preliminary effectiveness of a new-approach Africanized honeybee (Apis mellifera) Antivenom (AAV) in a phase I/II, multicenter, non-randomized, single-arm clinical trial involving 20 participants with multiple stings. Participants received 2 to 10 vials of AAV depending on the number of stings they suffered, or a predefined adjuvant, symptomatic, and complementary treatment. The primary safety endpoint was the occurrence of early adverse reactions within the first 24 h of treatment. Preliminary efficacy based on clinical evolution, including laboratory findings, was assessed at baseline and at various time points over the four following weeks. ELISA assays and mass spectrometry were used to estimate venom pharmacokinetics before, during, and after treatment. Twenty adult participants, i.e., 13 (65%) men and 7 (35%) women, with a median age of 44 years and a mean body surface area of 1.92 m2 (median = 1.93 m2) were recruited. The number of stings ranged from 7 to > 2,000, with a median of 52.5. Symptoms of envenoming were classified as mild, moderate, or severe in 80% (16), 15% (3), and 5% (1) of patients, respectively; patients with mild, moderate, or severe envenoming received 2, 6, and 10 vials of AAV as per the protocol. None of the patients had late reactions (serum sickness) within 30 d of treatment. There was no discontinuation of the protocol due to adverse events, and there were no serious adverse events. One patient had a moderate adverse event, transient itchy skin, and erythroderma. All participants completed the intravenous antivenom infusion within 2 h, and there was no loss to follow-up after discharge. ELISA assays showed venom (melittin and PLA2) concentrations varying between 0.25 and 1.479 ng/mL prior to treatment. Venom levels decreased in all patients during the hospitalization period. Surprisingly, in nine cases (45%), despite clinical recovery and the absence of symptoms, venom levels increased again during outpatient care 10 d after discharge. Mass spectrometry showed melittin in eight participants, 30 d after treatment. Considering the promising safety results for this investigational product in the treatment of massive Africanized honeybee attack, and its efficacy, reflected in the clinical improvements and corresponding immediate decrease in blood venom levels, the AAV has shown to be safe for human use. Clinical Trial Registration: UTN: U1111-1160-7011, identifier [RBR-3fthf8].

Fludarabine, Rituximab, and Lenalidomide in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): A Phase I/II Trial of the Sarah Cannon Research Institute

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 715-715 ◽  
Author(s):  
Ian W. Flinn ◽  
R. Seth Cooper ◽  
Dana S. Thompson ◽  
Jamie K. Waselenko ◽  
James Reeves ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Risk Indicators ◽  
Combination Regimen ◽  
Treatment Schedule ◽  
Off Label ◽  
Poor Risk ◽  
Potential Alternative

Abstract Abstract 715 Background: Fludarabine, rituximab, and cyclophosphamide (FCR) combinations have shown high CR rates in CLL, but toxicity-related concerns remain. Lenalidomide has been shown to have clinical activity in patients (pts) with CLL and is a potential alternative addition to the fludarabine, rituximab backbone. This is a nonrandomized, open label phase I/II dose-finding study of lenalidomide combined with fixed doses fludarabine and rituximab in a minimally or untreated population of patients with CLL. The Phase I portion will examine this combination regimen in pts who are untreated or have received minimal treatment comprised of single agent rituximab while the Phase II portion will enroll untreated CLL patients. Both Phases I and II of the study will consist of a screening, treatment, and a post-treatment period. Methods: Patients had untreated Rai stage III/IV or symptomatic stage 0-II CLL with no CNS involvement, ECOG PS 0–2, & adequate organ function. The phase I portion of this trial explored fixed doses of rituximab. The treatment schedule described is an alternative to the original schedule that had concurrent lenalidomide and chemotherapy dosing. Four pts were enrolled and the schedule was found to be toxic and discontinued. The protocol was amended to the following dosing schedule: rituximab(375 mg/m2 Cycle (C) 1, split over days (D)1 & 2), 500 mg/m2 D1 of C 2–6) and fludarabine (25 mg/m2on D1, 2, and 3) with one of two dose levels (DL) of lenalidomide, DL1 - 2.5mg PO on D8-28 of C1-6 (n=6), DL2 - 2.5mg PO D8-28 of C 1 & 5.0mg on D8-28 of C2-6 (n=45). Patients were restaged post-C3, 2 months after completion of treatment (≤6C), and every 6 months until disease progression. Study endpoints included response rate, progression free survival (PFS) and overall survival (OS). Results: Between 11/2008 & 5/2012, 64 pts enrolled; results are reported on 51. Pts were 55% male, with a median age of 62 yrs (range: 44–82 yrs). Rai stage at study entry was 8%/41%/20%/14%/17% for Rai stages 0/1/2/3/4 respectively. At the time of this analysis, 59% of pts had completed treatment. Treatment discontinuation due to toxicity occurred in 10% of pts; rash was the most common reason for participants to come off study prior to completing planned therapy. Grade 3/4 hematologic adverse events observed regardless of cause were: anemia (G3 12% and G4 2%), neutropenia (G3 25% and G4 22%), febrile neutropenia (G3 2% and G4 2%) and thrombocytopenia (G3 2% and G4 4%). The most frequently occurring treatment related non-hematologic adverse events were: rash (G3 12% and G4 2%), infection (G3 8%) and fatigue (G3 5%). Responses were reviewed by FISH risk profile and IWCLL 2008 criteria. Six patients were poor risk displaying 11q and/or 17p deletion. All pts with good risk indicators and those pts who did not meet criteria for good/poor risk were grouped and responses are shown below in table 1. Median FU was 21 months (range 0.03–45). Kaplan-Meier estimates of PFS and OS at 24 months is 71% and 88% respectively. At 24 months the estimated PFS and OS rates for the poor risk group were 60% and 66% respectively. Conclusion: Lenalidomide in combination with fludarabine and rituximab is a potential alternative to FCR. While response rates appear lower than studies with FCR so does toxicity. The toxicity of lenalidomide in this combination is schedule dependent. A unique side effect is rash which can occur at even the lowest doses of lenalidomide. Further follow-up is necessary to determine median PFS and OS Disclosures: Off Label Use: Off-label lenalidomide, investigational use in CLL. Reeves:Celgene: Equity Ownership.

A phase I/II study of docetaxel /S-1 with radiation for esophageal cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15061-15061
Author(s):  
T. Hirai ◽  
H. Matsumoto ◽  
Y. Hirabayashi ◽  
A. Urakami ◽  
K. Yamashita ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Cancer Patients ◽  
Response Rate ◽  
Combined Therapy ◽  
Treatment Schedule ◽  
Clinical Phase ◽  
Number Of Patients ◽  
Grade 3

15061 Background: The combined therapy of CDDP/5-FU with radiation is the standard therapy for esophageal cancer patients. However, this therapy is associated with a comparatively high incidence of gastrointestinal disorders resulting in therapy interruptions and long hospital stays. Herein, we propose a new regimen of Docetaxel / S-1 combined with radiation to improve the success rate and outcome. The clinical phase Istudy was conducted from May, 2004 until June, 2006. and we report on the results in this paper. Methods: Patients were given S-1 (60mg/m2/day) orally from days 1 to 14, and Docetaxel (20mg/m2 in level 1, 25mg/m2 in level 2, and 30 mg/m2 in level 3) intravenously on days 1 and 8. Patients received radiation in 2.0 Gy daily fractions from days 1 to 21, for a total of 30 Gy. Patients were given a seven-day rest after the first course, and then treated with the same regimen from days 28 to 49.P The phase I study was completed for 10 cases. Results: All patients completed the treatment schedule, with no treatment-related deaths and no grade 4 adverse events were observed. As for hematotoxicity, one case revealed leucopenia of grade 3 and neutropenia of grade 2. A non-hematotoxic adverse event (grade 3 anorexia) was observed in one patient. The response rate evaluated by RECIST was 66 % (CR in 2 cases, PR in 4 cases). We assumed that the recommended dosage of TXT and S-1 was 30mg/m2 and 60mg/m2, respectively, combined with a radiotherapy dose of 60Gy. Conclusions: This combination therapy may be superior to other treatments because of its lower rate of adverse events and higher response rates. We continue this study to Phase II in order to generate data on the response rate and adverse effect rate in a greater number of patients with esophageal cancer. No significant financial relationships to disclose.

scholarly journals A Novel High Dose Chemotherapy Strategy with Bendamustine In Adjunct to Etoposide, Cytarabine and Melphalan (BeEAM) Followed by Autologous Stem Cell Rescue Is Safe and Highly Effective for the Treatment of Resistant/Relapsed Lymphoma Patients: a Phase I-II Study on 44 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 31-31 ◽  
Author(s):  
Giuseppe Visani ◽  
Lara Malerba ◽  
Pietro Maria Stefani ◽  
Saveria Capria ◽  
Piero Galieni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Adverse Events ◽  
Phase I ◽  
Median Time ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
Stem Cell Rescue ◽  
Relapsed Lymphoma

Abstract Abstract 31 Background: BEAM (Carmustine, etoposide, cytarabine, and melphalan) regimen is the most used conditioning regimen before autologous stem cell transplant (ASCT) in lymphoma patients. However, patients receiving BEAM show a significant number of side effects, and relapse rate after transplant is still a matter of concern. Therefore, new regimens with a higher efficacy and a better toxicity profile in comparison to BEAM are highly needed. Aims: We designed a phase I-II study to evaluate the safety and the efficacy of increasing doses of Bendamustine for the conditioning regimen to ASCT for resistant/relapsed lymphoma patients. Methods: Forty-four patients (median age 47 years, range 18–70) with resistant/relapsed non-Hodgkin (29) or Hodgkin (15) lymphoma were consecutively enrolled in the study. The new conditioning regimen consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of 3 patients each were treated starting with Bendamustine 160 mg/m2/daily given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected MTD, but not higher than 200 mg/m2. Patients were carefully monitored for adverse events. The study was registered at EMEA with the EUDRACT no 2008–002736-15. Results: The administration of Bendamustine was safe in all the 3 cohorts of patients. The major side effect was a grade III-IV oral mucositis developed by 9 patients during neutropenia. We then fixed the dose of Bendamustine 200 mg/m2 as safe and effective for the Phase II study. A median number of 5.68×106CD34+/kg cells (range 2.4–15.5) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5×109/l of 10 days. Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 16 days respectively. Twenty-two out of 44 patients presented a fever of unknown origin (50%). The median number of days with fever was 2 (range: 0–7), with a median number of 9 days of intravenous antibiotics (range: 3–22). All patients received G-CSF after transplant for a median time of 9 days (range: 8–25). Two patients developed a viral infection (1 HSV-6, 1 CMV) early after transplant. Thirty-nine out of 44 patients are evaluable up to now for the response to treatment. All evaluable patients are alive. 32/39 are in complete remission whereas 4/39 are in partial response, after a median follow-up of 11 months from transplant. Three out of 39 patients relapsed after a median time of 3 months from transplant. It is of note that 4/39 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue. Conclusions: The new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Basing on this experience, future studies incorporating Bendamustine in conditioning regimens pre-ASCT in lymphoma patients should use Bendamustine 200 mg/m2/day over 2 days. Acknowledgments: supported in part by AIL Pesaro Onlus. Disclosures: Malerba: celgene, Janssen-Cilag: Honoraria.

Adherence to novel oral anticancer therapies in the phase I setting: The Royal Marsden experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2542-2542
Author(s):  
Maxime Chenard-Poirier ◽  
Joo Ern Ang ◽  
Samuel John Harris ◽  
Alvaro Henrique Ingles Garces ◽  
Satyanarayana Seeramreddi ◽  
...  
Keyword(s):  
Phase I ◽  
Univariate Analysis ◽  
Median Number ◽  
Continuous Treatment ◽  
Adherence Rate ◽  
Published Data ◽  
Pharmacokinetic Data ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Development Unit

2542 Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.

scholarly journals Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1731-1731
Author(s):  
Sara K. Silbert ◽  
Elizabeth M. Holland ◽  
Seth M. Steinberg ◽  
Lauren Little ◽  
Toni Foley ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Phase I ◽  
Median Number ◽  
Toxicity Profile ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: CAR T-cells have demonstrated remarkable ability to induce complete remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). This success, however, is tempered by the toxicities associated with CAR T-cell therapy. Much has been published on cytokine release syndrome (CRS), but, to date, a comprehensive profile of specific end organ toxicities secondary to CAR T-cell therapy in the pediatric and young adult population is lacking. Methods: This retrospective, single center study, was performed to characterize the specific adverse events (AEs) experienced by pediatric and young adult patients during the first 30 days following CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events (CTCAE) were collected from all patients with r/r ALL treated on one of three phase I CAR T-cell trials (CD19, CD22, and CD1922) at the Pediatric Oncology Branch of the National Cancer Institute at the National Institutes of Health from 2012-2020. The primary objective was to determine the incidence of all severe AEs, defined as > grade (Gr) 3 AEs, overall and by organ system, attributed to research or disease. Secondary objectives were to stratify severe AEs based on development of CRS and CRS grade (using ASTCT CRS grading criteria). Descriptive statistics were reported along with comparisons of continuous parameters using Mann-Whitney and binomial parameters using Fischer's exact tests. Results: We reviewed AE data from 134 patients with r/r ALL receiving one of 3 unique CAR T-cell constructs (Table). The median age was 15.2 years (Interquartile range (IQR) 9.5-21.2). The median number of prior therapies was 5 (IQR 3-6) and 57% had received a prior hematopoietic stem cell transplant (HSCT). Amongst the 134 patients, a total of 1747 individual > Gr 3 AEs were experienced by 133 patients (99%) during the first 30 days following CAR infusion (Figure 1A). The median number of > Gr 3 AEs per patient was 10 (IQR 4.8-19). Cytopenias (including neutropenia, thrombocytopenia and anemia) comprised the vast majority of total > Gr 3 AEs (n=983, 56.3%). The most common severe (> Gr 3) AEs were thrombocytopenia (n=433, 24.8%), metabolic abnormalities (i.e. electrolyte derangements) (n=333, 19.1%), neutropenia (n=332, 19%), and anemia (n=218, 12.5%). With exclusion of cytopenias, 764 > Gr 3 AEs were experienced by 111 patients (83%), with a median of 4 (IQR 1-8.3) > Gr 3 AEs per patient. One grade 5 pulmonary AE occurred in the setting of acute respiratory distress syndrome (ARDS). Focusing on non-cytopenia AEs (Figure 1B), metabolic AEs made up 43.6% of AEs; hepatic toxicities (n=115, 15%), febrile neutropenia (n=114, 14.9%), and cardiovascular toxicities (n=59, 7.7%) were the next most frequent. Of the 134 patients, 104 (77.6%) developed CRS. All 30 patients without CRS had at least 1 > Gr 3 AE (median 6, IQR 3-11.3). In contrast, the median number of > Gr 3 AEs in those with CRS was 11.5 (IQR, 6-21.5), (p=0.0021). When stratified by CRS Gr 1-2 versus CRS Gr 3-4 (Figure 2), patients with higher-grade CRS also had a higher median number of > Gr 3 AEs per patient (p= 0.0017). Conclusions: Among 134 children and young adults with r/r ALL receiving phase I CAR T-cells, we found a high incidence (99%) of severe AEs, with a per patient median of 10 (IQR 4.8-19) > Gr 3 AEs. While the majority of > Gr 3 AEs were cytopenias, 17 different categories of AEs were experienced. The development and severity of CRS associated with an increase in the median number of severe AEs per patient. As phase I trials of CAR T-cell therapy expand, it is imperative to understand the full toxicity profile of these therapies. While the definition and refined grading of CRS has helped advance the field, there is a gap in knowledge regarding patient specific end-organ toxicities beyond CRS. Our data help establish a foundation for the full toxicity profile experienced by patients enrolling on phase I CAR T-cell trials. With an emerging role for earlier intervention for CRS, we anticipate that the toxicity burden will decrease. Next steps include characterizing the specific toxicities within each AE category, evaluating duration and time to resolution, distinguishing attribution to research versus disease and studying the impact of earlier use of tocilizumab on toxicity profile. Future directions will incorporate assessment of baseline organ function pre-CAR and its impact on development of post CAR severe AEs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Phase I Study of Oral Melphalan Combined with LBH589 for Patients with Relapsed or Refractory Multiple Myeloma (MM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1855-1855 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Ralph V. Boccia ◽  
Youram Nassir ◽  
Shellie Rothstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Chemotherapeutic Agents ◽  
Treatment Schedule ◽  
Deacetylase Inhibitor ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1855 Poster Board I-881 We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized. Disclosures: Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.

Assisted Administration Of  Subcutaneous 5-Azacytidine  to The Patient's Home. Significant Reduction Of Indirect Costs Incurred By Care Recipients and Unpaid Caregivers Together With a Total Adhesion To The Treatment Schedule and Same Safety

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5587-5587
Author(s):  
Francesco Iuliano ◽  
Eleonora Iuliano ◽  
Alessia Perricelli ◽  
Angelo Pomillo ◽  
Maria Luci ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site Reaction ◽  
Indirect Costs ◽  
Median Number ◽  
Treatment Schedule ◽  
Hospital Inpatient ◽  
Adherence To Treatment ◽  
Care Recipients ◽  
Grade 3 ◽  
Rbc Transfusion

Abstract Background and aim Administration of azacitidine is planned in-patient daily, there is no experience of its administration to the patient's home. The aim of this work was to evaluate the feasibility of a program of home administration of azacitidine able to reducing the cost-of-illness, to increase adherence to treatment while maintaining the same safety of the therapy given in hospital. Material and methods Between Jan 2008 and Dec 2012, 22 consecutive  patients, (MDSs, n = 15; CMML, n = 4; AML, n = 3), were enrolled in the study. The pharmacoeconomic analysis included assessment of direct costs ( hospital inpatient, physician inpatient, physician outpatient, emergency department nursing home care, specialists’ and other health professionals’ care, diagnostic tests, prescription drugs and drug sundries, and medical supplies),indirect costs incurred by care recipients and unpaid caregivers, including time, productivity and travel cost. Results Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days  every 4 weeks,  Median age of the patients was 71 years (range, 65–83). Median number of courses delivered to each patient was 9 (range, 3–31) Hematologic responses (CR/PR/mCR) were induced in 6 patients (27.0%)  Median number of treatment courses to achieve any response was 2 (range, 1–6) Adverse events were evaluated for the first 6 courses for all patients, for a total of 124 courses. Major adverse events were cytopenia and cytopenia-related infection. Grade 3 or higher neutropenia was 64.4%) but incidence of febrile episode requiring intravenous antibiotics was  8,4% slightly lower than reported from the pivotal clinical study. Grade 3 or higher non-hematologic toxicities were infrequent. Injection site reaction 0.4 and site pain 0% Median follow-up duration of surviving patients was 46.9 months (range, 11.8–55.5). Of the 14 patients  who were RBC transfusion dependent at baseline, 48.0% of these patients became RBC transfusion independent during the treatment period. Adherence to treatment was 100%. In our experience, despite the high percentage of elderly patients of whom 36% living in rural area, it was possible to give treatment to all patients with 100% adherence. There has been a reduction in direct medical costs due  to less use of hospitalization, a reduction of indirect costs by 63% due to the lower number of working days lost and a drastic reduction of travel costs, with the same efficacy and safety of administration. Disclosures: Off Label Use: drug administration at patient home instead of hospital.

scholarly journals Allogeneic human umbilical cord-derived mesenchymal stem/stromal cells for chronic obstructive pulmonary disease (COPD): study protocol for a matched case–control, phase I/II trial

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e045788
Author(s):  
Duc M Hoang ◽  
Kien T Nguyen ◽  
Anh H Nguyen ◽  
Bach N Nguyen ◽  
Liem Thanh Nguyen
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Adverse Events ◽  
Phase I ◽  
Pulmonary Disease ◽  
Stromal Cells ◽  
Case Control ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Control Phase ◽  
Matched Case

IntroductionThe global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and it has become a major public health burden worldwide, including in Vietnam. A large body of preclinical and clinical studies supports the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of lung injury, including COPD. The aim of this trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) as a supplementary intervention in combination with standard COPD medication treatments in patients with moderate-to-severe COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 and Vietnam Ministry of Health’s guidelines.Methods and analysisThis matched case–control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between June 2020 and December 2021. In this study, 40 patients will be enrolled and assigned into two age-matched, gender-matched and COPD condition-matched groups, including a UC-MSC group and a control group. Both groups will receive standard COPD medication treatment based on the GOLD 2019 guidelines and the Vietnam Ministry of Health protocol. The UC-MSC group will receive two doses of thawed UC-MSC product with an intervention interval of 3 months. The primary outcome measures will include the incidence of prespecified administration-associated adverse events and serious adverse events. The efficacy will be evaluated based on the absolute changes in the number of admissions, arterial blood gas analysis, lung function and lung fibrosis via CT scan and chest X-ray. The clinical evaluation will be conducted at baseline and 3, 6 and 12 months postintervention.Ethics and disseminationEthical approval was secured from the Ethical Committee of Vinmec International Hospital (number:166/2019/QĐ-VMEC) and Vietnam Ministry of Health (number:2002/QĐ-BYT). The results will be reported to trial collaborators, publication in peer-reviewed academic journals.Trial registration numberNCT04433104.

Efficacy of an Oxycodone-Propofol Combination versus a Fentanyl-Propofol Combination in Conscious Sedation during Therapeutic Endoscopic Retrograde Cholangiopancreatography in Elderly Patients

Gerontology ◽  
2020 ◽  
pp. 1-8
Author(s):  
Peipei Guo ◽  
Huisheng Wu ◽  
Lan Liu ◽  
Qiu Zhao ◽  
Zhao Jin
Keyword(s):  
Adverse Events ◽  
Elderly Patients ◽  
Endoscopic Retrograde Cholangiopancreatography ◽  
Postoperative Nausea ◽  
Recovery Time ◽  
Adverse Reactions ◽  
Conscious Sedation ◽  
Endoscopic Retrograde ◽  
Patients Satisfaction ◽  
Low Incidence

<b><i>Background:</i></b> With a rapidly aging population, the need for endoscopic retrograde cholangiopancreatography (ERCP) is increasing. The commonly used sedation anesthesia in ERCP is a combination of propofol and fentanyl, even though fentanyl may cause some adverse reactions such as respiratory depression. <b><i>Objectives:</i></b> This study aimed to evaluate the efficacy of oxycodone combined with propofol versus fentanyl combined with propofol for sedation anesthesia during ERCP. <b><i>Methods:</i></b> A total of 193 patients aged from 65 to 80 years undergoing ERCP were enrolled and randomized into two groups: an “oxycodone combined with propofol” group (group OP, <i>n</i> = 97) and a “fentanyl combined with propofol” group (group FP, <i>n</i> = 96). The rate of perioperative adverse events as well as the recovery time, patients’ satisfaction, and endoscopists’ satisfaction were noted. <b><i>Results:</i></b> There was no difference in the frequency of hypotension or bradycardia between the two groups, but there were more episodes of desaturation (SpO<sub>2</sub> &#x3c;90% for &#x3e;10 s in 8.3%), postoperative nausea (7.3%), and vomiting (5.2%) in group FP than in group OP. Patients’ satisfaction in group FP was lower than that in group OP. The recovery time was longer in group FP than in group OP. <b><i>Conclusions:</i></b> Oxycodone combined with propofol was effective in ERCP, with a low incidence of perioperative adverse events.

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