scholarly journals Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2292-2292 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Adult Patients ◽  
Off Label Use ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Off Label ◽  
Equity Ownership ◽  
Label Use

Abstract Introduction: Blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct, has been shown to induce remission in adult patients with relapsed/refractory BCP-ALL. Medically important adverse events (AEs) related to blinatumomab treatment in adults are cytokine release syndrome (CRS) and neurological events. We report the primary analysis of the phase 1 portion of a multicenter phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods: In this continuing study, eligible patients are <18 years old and must have BCP-ALL that is in second or later bone marrow relapse, in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or refractory to induction or reinduction therapy. Patients receive blinatumomab for 28 days by continuous intravenous infusion followed by a 14-day treatment-free period (for up to five cycles). Escalating dosing levels of 5, 15, and 30 μg/m²/day and stepwise dosing of 5–15 or 15–30 μg/m²/day were evaluated. The primary endpoint of the phase 1 portion of the study was maximum tolerated dose (MTD). Secondary endpoints included toxicity, complete remission (CR) rate, overall survival (OS), relapse-free survival (RFS), pharmacokinetics evaluation, and cytokine measurement. Results: In the phase 1 portion, 41 patients received a total of 73 cycles (median of 2 cycles received, range of 1 to 5). Eight (20%) patients had refractory disease and seven (17%) had experienced at least two bone marrow relapses. Twenty-six (63%) patients had relapsed following HSCT. Dose-limiting toxicities (DLTs) are listed in Table 1. The MTD was established at 15 µg/m²/day. To decrease the risk of CRS, a stepwise dose of 5–15 μg/m²/day was recommended for the phase 2 part of the study (5 µg/m²/day for 7 days, then 15 µg/m²/day). This dose was subsequently assessed in two age groups (2–6 and 7–17 years) in the phase 1 expansion part with one of 18 patients developing grade 3 CRS. No patient in the expansion cohort developed grade 4 or 5 CRS. Across all dosing levels, 13 (32%) patients had CR with 10 (77%) achieving minimal residual disease (MRD) negativity. Of these 13 patients, nine (69%) underwent HSCT. Among patients who achieved CR, median RFS was 8.3 months (95% CI: 3.0–16.0 months). Median OS was 5.7 months (95% CI: 3.3–9.7 months; Figure 1) with a median follow-up time of 12.4 months. Across all dosing levels, the most common AEs regardless of causality were pyrexia (78%), headache (37%), hypertension (32%), nausea (29%), abdominal pain (27%), pain in the extremity (27%), and anemia (27%). Pharmacokinetic parameters, including steady-state concentration (Css), clearance, and half-life were similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mostly within the first two days after starting blinatumomab, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions: In the phase 1 portion of this study in pediatric patients with relapsed/refractory BCP-ALL, the MTD was 15 µg/m²/day. CRS was dose-limiting, but stepwise dosing of 5–15 μg/m²/day has been effective in ameliorating CRS. Thirty-two percent of patients achieved CR and more than half were able to proceed to allogeneic HSCT. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Rheingold:Novartis: Consultancy. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhu:Amgen Inc.: Employment, Equity Ownership. Hijazi:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Gore:Amgen Inc.: Travel Support Other.

scholarly journals Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 963-963 ◽  
Author(s):  
Amir T Fathi ◽  
Robert Chen ◽  
Tanya M. Trippett ◽  
Maureen M. O'Brien ◽  
Daniel J DeAngelo ◽  
...  
Keyword(s):  
B Cell ◽  
Interim Analysis ◽  
Research Funding ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Adult Patients ◽  
Aggressive Lymphoma ◽  
Weekly Schedule ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background CD19, a B cell-specific marker, is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma. SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This first-in-human, phase 1, open-label, dose-escalation study is investigating the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in adult and pediatric patients with relapsed or refractory B-cell leukemia or highly aggressive lymphoma (NCT 01786096). Eligible patients must have B-cell acute lymphoblastic leukemia (B-ALL) or lymphoma (B-LBL), Burkitt leukemia or lymphoma, and be relapsed or refractory to at least 1 prior systemic regimen. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation for both pediatric and adult patients. The study is evaluating 2 schedules of IV SGN-CD19A administration: weekly (Days 1 and 8 of 21-day cycles; 0.3-4.5 mg/kg) or every 3weeks (q3week; 0.5-6 mg/kg). Results To date, 49 patients with relapsed or refractory leukemia (n=40) or lymphoma (n=9) have been treated. Median age of adult (n=38) and pediatric patients (n=11) was 37 and 11 years (range, 18-74 and 1-16), respectively. Patients received a median of 2 prior therapies (range 1-9); 14 patients (29%) previously received an allogeneic stem cell transplant. On the weekly schedule, 39 patients (28 adult, 11 pediatric) have been treated, and the median number of cycles is 2.5 (adults; range, 1-12) or 1 (pediatric; range, 1-4). On the q3week schedule, 10 adult patients have been treated, and the median number of cycles is 2.5 (range, 1-4) to date. Six patients remain on study treatment (3 on each schedule), and enrollment is ongoing. The toxicity profiles were similar across both dosing schedules (0.3-2.3 mg/kg weekly and 4-5 mg/kg q3week) and across adult and pediatric patients. The most frequently reported drug-related AEs included pyrexia, nausea, chills, vomiting, blurred vision, and dry eye. Frequent infusion-related reactions were observed early in the study, and recommendation for premedication was instituted. Ocular events were also observed and treated with ophthalmic steroids; steroid eye drop prophylaxis was instituted with each dose. Corneal findings consistent with superficial microcystic keratopathy were observed in 13 adult patients (34%) and in 1 pediatric patient (9%). Grade 3/4 corneal AEs have been observed in 4 adult patients; the majority of these events have resolved or improved to Grade 1 or 2. Steroid eye drop prophylaxis has reduced the incidence of Grade 3/4 events at this interim analysis. Three DLTs were observed: acidosis in a pediatric patient at 1 mg/kg weekly, cytokine release syndrome in an adult patient at 2 mg/kg weekly, and asymptomatic Grade 4 AST elevation in an adult patient at 5 mg/kg q3week. MTD has not yet been determined. SGN-CD19A ADC pharmacokinetic profiles indicate target-mediated drug disposition in patients with leukemia. Plasma ADC exposures generally increased with doses and were lower than those in patients with lymphoma. To date, no objective responses were observed in 9 efficacy-evaluable pediatric patients or in 3 adult patients with Burkitt lymphoma/leukemia. However, in efficacy-evaluable adult patients with B-ALL/B-LBL, objective responses were observed in 6 of 25 patients treated on the weekly schedule (3 CR, 2 CRp, 1 PR), and in 4 of 8 patients treated on the q3week schedule (2 CR, 2 CRp). Of 8 B-ALL patients with CR/CRp, 6 were MRD negative. Conclusions MTDs have not yet been identified, and dose escalation continues on weekly and q3week schedules. SGN-CD19A has been generally well tolerated. At this interim analysis, objective responses were observed in 30% (10 of 33) of heavily pretreated adult B-ALL/B-LBL patients dosed weekly or q3week. Evidence of activity in relapsed/refractory patients and lack of overlapping toxicities suggest opportunities for combination with conventional anti-leukemic therapies in lymphoblastic malignancies. Disclosures Fathi: Ariad: Consultancy; Exelixis: Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. O'Brien:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. Shah:Pharmacyclics: Consultancy; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Consultancy. Cooper:Seattle Genetics, Inc.: Research Funding. Foran:Seattle Genetics, Inc.: Research Funding. Hale:Seattle Genetics, Inc.: Research Funding. Pressey:Seattle Genetics, Inc.: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Albertson:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Borate:Genoptix: Consultancy; Seattle Genetics, Inc.: Research Funding.

Initial Results from a Phase 2 Study of Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3703-3703 ◽  
Author(s):  
Lia Gore ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Christian M. Zwaan ◽  
Deepa Bhojwani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Phase 2 ◽  
Off Label Use ◽  
Cell Precursor ◽  
Off Label ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Patients (pts) with relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) and/or multiple prior salvage therapies and/or refractory disease have a particularly poor prognosis. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects T cells to CD19+ B cells resulting in serial lysis. In phase 2 clinical studies, blinatumomab has demonstrated antitumor activity in adults with relapsed/refractory non-Hodgkin lymphoma and ALL. We evaluated efficacy and toxicity of blinatumomab in pediatric pts with relapsed/refractory ALL who have a particularly poor prognosis. Methods: Eligible pts were 2-18 years of age and had B-cell precursor ALL that was refractory, in ≥2nd bone marrow relapse, or in any marrow relapse after alloHSCT. This was a multicenter, open-label study using a Simon 2-stage design with a phase 1 and a phase 2 part. In the phase 1 part, a stepwise dose of 5→15 µg/m²/day was established as the recommended phase 2 dose (von Stackelberg et al. Blood. 2013;122:70). Blinatumomab was given by continuous intravenous infusion for 4 weeks (5 µg/m²/day for the first week and 15 µg/m²/day thereafter), followed by two treatment-free weeks (one cycle) for up to five cycles. The primary endpoint for the phase 2 part of the study was rate of complete remission (CR) within the first two cycles of treatment, including CR with incomplete hematologic recovery. Secondary endpoints included relapse-free survival (RFS), rate of advancement to alloHSCT, overall survival (OS), and incidence and severity of adverse events (AEs). Minimal residual disease (MRD) response (<10-4 leukemic cells by PCR or flow cytometry) was an exploratory endpoint. We present 39 pts who were treated at the phase 2 dose (5→15 µg/m²/day), including 18 pts from the dose expansion cohort of the phase 1 part and 21 pts from the phase 2 part of the study. Results: 39 pts received blinatumomab at a dose of 5→15 µg/m²/day. The median (range) age was 9 (2–16) years; 62% of pts were male. Sixteen (41%) pts had one and 16 (41%) pts had two or more prior salvage therapies, respectively; seven (18%) were either primary refractory or had refractory relapse. Twenty-five (64%) pts had received prior alloHSCT; of those, six (16%) had one relapse and 19 (50%) had two or more relapses. Of the 39 pts, 34 (87%) had relapsed within 6 months prior to study entry. The median (range) time from last prior relapse to the relapse at study entry was 2.1 (0–13.7) months. 69% of pts had bone marrow blast infiltration of ≥50%. 19 (49%) pts started and completed one cycle of blinatumomab treatment (two cycles, 4 [10%] pts; three cycles, 2 [5%] pts). During the first two treatment cycles, 12 pts achieved CR, (31%; 95% CI, 17%–48%), mainly during the first cycle. Two additional pts (5%) had blast-free hypoplastic or aplastic bone marrow. Among pts with CR in the first two cycles, five (42%) had complete MRD response. Median RFS for CR responders was 5.6 (95% CI, 2.6–12.1) months. Among all 39 pts, median OS was 4.3 (95% CI, 3.6–8.1) months with 6 months of study follow-up time. Six (50%) of the 12 pts with CR proceeded to alloHSCT. An additional five pts who did not respond to blinatumomab received alloHSCT after blinatumomab treatment was stopped. All pts experienced AEs, mostly flu-like symptoms consistent with the mechanism of action of blinatumomab. AEs regardless of causality occurring in >20% of pts were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%). The most common grade ≥3 AEs included anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%). Cytokine-release syndrome occurred in three (8%) pts, two of whom (5%) had grade 3 events. Conclusions: Blinatumomab showed promising antileukemia activity in heavily pretreated pediatric relapsed/refractory B-cell precursor ALL pts, with a median time from last relapse of 2.1 months. Half of the pts who responded within the first two cycles were able to receive alloHSCT following blinatumomab-induced remission, suggesting that blinatumomab may open a window for alloHSCT in those pts who are resistant to salvage chemotherapy. Disclosures Gore: Amgen Inc.: Travel Support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. von Stackelberg:Amgen Inc.: Consultancy, Honoraria.

Survey on Off-Label Use of Antineoplastic Agents in Pediatric Patients using a Large-scale Medical Database in Japan

2020 ◽  
Vol 51 (6) ◽  
pp. 307-316
Author(s):  
Mayuko KURODA ◽  
Ayaka NAKAMURA ◽  
Nanae TANEMURA ◽  
Masayoshi NAKAKUNI ◽  
Junko SATO ◽  
...  
Keyword(s):  
Antineoplastic Agents ◽  
Large Scale ◽  
Pediatric Patients ◽  
Off Label Use ◽  
Medical Database ◽  
Off Label ◽  
Label Use

ATG Dose Correlates with Acute and Chronic GvHD In Patients Undergoing Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation: A Large Retrospective Monocenter Analysis on 301 Patients.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3485-3485
Author(s):  
Roberto Crocchiolo ◽  
Sabine Furst ◽  
Luca Castagna ◽  
Jean El Cheikh ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Adult Patients ◽  
Off Label Use ◽  
Off Label ◽  
Grade 3 ◽  
Label Use

Abstract Abstract 3485 Introduction: RIC associating Fludarabine-Busulfan-ATG (FBA) is quite popular as preparative for allogeneic hematopoietic stem cell transplantation (RIC-AlloSCT). However the best association us still a matter of debate. Busulfan is crucial for disease control but limited by a dose-dependent toxicity and ATG plays a pivotal role in the prevention of both acute and chronic GvHD but with a potential higher relapse rate. Here we retrospectively compared different FBA regimens among adult patients transplanted at our Institution for a hematological malignancy, with the aim of identifying whether some pre- or peri-transplant variables are predictive of outcome. Patients and methods: on 635 patients allografted between May 1998 and Feb 2010, a total of 301 patients affected by malignancy received FBA-based RIC-AlloSCT and were the object of the present analysis. Comparisons between baseline patient, donor and AlloSCT characteristics with transplant outcome were performed: univariate and multivariate Cox regression analysis were used to find any correlation between the above mentioned variables and OS, DFS, NRM, relapse incidence, acute (aGvHD) and chronic (cGvHD) GvHD. Variables with p<0.20 were included in multivariate analysis, and only variables with a p<0.05 were retained in the final model. Results: median (range) follow-up was 917 (71-4051) days. Two-year OS, DFS and NRM were 66%, 58% and 20% for the entire cohort. Relapse at two years was 26%. Cumulative incidence of grade 2–4, grade 3–4, overall and extensive cGvHD were: 29%, 12%, 58% and 40%. In multivariate analysis, patient's age was significantly associated with OS, NRM, grade 2–4 and 3–4 aGvHD; disease status at transplant significantly correlated with DFS and relapse incidence. ATG at a dose of 5 mg/kg compared to 2.5 mg/kg, was significantly associated with a reduced risk of developing grade 3–4 aGvHD (HR= 0.46, 95% CI: 0.22–0.99, p=0.05) and cGvHD (HR= 0.33, 95% CI: 0.20–0.54, p<0.0001), without affecting relapse (p=n.s.). Overtime we modified our standard RIC from F5B2A1 (Fludarabine over 5 d, oral Bu over 2 d and ATG for1d) (N=114) to F5BX2A2 (Fludarabine over 5 d, IV Bu over 2 d and ATG over 2 d) (N=84). Population was not similar and notably older (51 vs. 57 years, p<0.0001) in the latter group. Despite this we observed similar NRM (22% vs. 23%: p=n.s.) in patients older than 55 years; in patients younger than 55 F5BX2A2 was associated with better but not statistically significant OS (77% vs. 65% at two years, p=0.21) and reduced NRM (9% vs. 18% at two years, p=0.10). Conclusions: in this large monocenter series of adult patients undergoing FBA-based RIC-AlloSCT, the use of ATG at a dose of 5 mg/kg appeared to significantly reduce incidence and severity of cGvHD and grade 3–4 aGvHD compared to ATG 2.5 mg/kg without increasing disease relapse. Moreover, despite patients' disparity between the two cohorts, reduced NRM was observed in patients < 55 years old treated with F5BX2A2 regimen with respect to those receiving F5B2A1. Disclosures: Off Label Use: Zevalin is off-label use in conditioning regimen in France.

Treatment of a Patient with Refractory Non-Langerhans-Cell-Histiocytosis with the Tyrosine Kinase Inhibitor Sorafenib: Clinical and Genetic Implications

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4715-4715
Author(s):  
Andreas Viardot ◽  
Frank Stegelmann ◽  
Thorsten Zenz ◽  
Peter Möller ◽  
Konstanze Döhner
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Off Label Use ◽  
Off Label ◽  
Hands And Feet ◽  
Label Use

Abstract Abstract 4715 Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome. We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation. To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated. Disclosures: Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria.

Off-Label Antithrombin Use In Pediatrics: Evaluation Of Safety, Efficacy and Usage Patterns

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1137-1137 ◽  
Author(s):  
Rosa Diaz ◽  
Brady S Moffet ◽  
Donald Mahoney ◽  
Donald L Yee
Keyword(s):  
Pediatric Patients ◽  
Heparin Therapy ◽  
Activity Level ◽  
Ventricular Assist Devices ◽  
Bleeding Complications ◽  
Off Label Use ◽  
Bleeding Events ◽  
Off Label ◽  
Heparin Resistance ◽  
Label Use

Abstract Background Antithrombin (AT) is a naturally occurring anticoagulant, and occupies a critical role in regulating thrombin generation. AT concentrate (ATC) is indicated for patients with hereditary AT deficiency but off-label use for acquired heparin resistance in patients receiving anticoagulation for thrombotic disease is not uncommon. Use of ATC in children in this and other settings such as extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD) appears to be expanding. However, no guidelines exist with respect to proper indications and monitoring, and scant safety and efficacy data is available. The objective of this study was to review our substantial institutional experience with off-label pediatric use of ATC regarding indications for use, dosing practice, dosing effect, adverse events, and patient outcomes. Methods An institutional review board (IRB)-approved retrospective chart review is being performed on all pediatric patients who received human-plasma derived ATC at Texas Children’s Hospital from 2001 to 2013. Data collection includes demographic, clinical and laboratory data. We are currently reporting on the first 100 consecutive patients examined using descriptive statistics and ANOVA for group comparisons. Results One hundred patients with median age 5 months (range 0 to 216 months) received 536 doses of ATC (median 4 doses per patient, range 1 to 29) between February 2012 and May 2013. Clinical scenarios for ATC use included heparin (unfractionated (UFH) or low molecular weight (LMWH)) therapy for thrombosis in 47%, ECMO in 38%, VAD in 5% and other settings in 10% of the 100 consecutive patients analyzed. Neither dosing nor dose response (measured as AT activity level post- versus pre-ATC dose) differed significantly between these patient groups. For the group of patients who received AT for thrombosis and heparin therapy, only 57% had subtherapeutic levels (anti-Xa activity <0.3 units/mL for UFH or <0.5 units/mL for LMWH) at the time of ATC initiation. Of these, only 22% achieved therapeutic levels within 12 hours after the first ATC dose. Among all the groups, 33% of children had bleeding events within 72 hours after ATC administration, most commonly reported as oozing from line sites (n=15). There was no association between AT activity levels measured after ATC administration and bleeding events. The 2 patients that developed intracranial hemorrhage were on ECMO. There were no allergic reactions. End of hospitalization mortality was 28%. Conclusion In this high-risk cohort of pediatric patients, off-label ATC was most commonly given in the setting of heparin therapy for thrombosis and low AT levels, but often without apparent evidence for inadequate heparinization as measured by low anti-Xa activity. Although ATC administration led to a significant rise in AT activity for most patients, interindividual response to ATC varied greatly, with some patients demonstrating little to no response. Furthermore, among patients who exhibited clear signs of heparin resistance, the first administration of ATC potentiated an adequate heparin effect in only a small minority. Finally, ATC administration was associated with high rate of minor bleeding complications and rare major bleeding events. These findings raise significant questions about the safety, efficacy and appropriate use of ATC in pediatrics and highlight the need for its further prospective study. Disclosures: Off Label Use: Antithrombin concentrate.

The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 968-968 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Daniel J. DeAngelo ◽  
Dan Douer ◽  
Hervé Dombret ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Mutation Status ◽  
Response Data ◽  
Notch Receptors ◽  
Equity Ownership ◽  
Grade 3 ◽  
Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

Clinical Pharmacology Profile of Pacritinib (PAC), a Novel JAK2/FLT3 Inhibitor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5178-5178
Author(s):  
Suliman Al-Fayoumi ◽  
Mary S. Campbell ◽  
Sherri Amberg ◽  
Huafeng Zhou ◽  
Lindsey Millard ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Plasma Concentration ◽  
Systemic Exposure ◽  
Maximum Plasma ◽  
Cyp3a4 Inhibitor ◽  
Off Label Use ◽  
Cardiac Safety ◽  
Employment Equity ◽  
Off Label ◽  
Equity Ownership

Abstract Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC. Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [14 C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted. Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [14 C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean Cmax and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC Cmax and AUC by 51% and 87%, respectively vs PAC alone. Median Tmax was similar when co-administered with rifampin vs PAC alone (5-6 h), but t1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change <10 msec) and a small but non-clinically significant shortening in the placebo-corrected change in QTcF below 0 msec in the first 12 h post-dose. Across all clinical pharmacology studies, PAC was tolerable (primarily grade 1 gastrointestinal AEs), consistent with the PAC clinical safety profile to date. Conclusions: PAC exhibits moderate oral bioavailability and is eliminated primarily through metabolism and biliary excretion. Minimal excretion occurs via renal clearance, indicating dosage adjustment is unlikely to be warranted in renal impairment. Increase in PAC exposure is limited when co-administered with a strong CYP3A4 inhibitor, unlikely necessitating dosage adjustments. There is marked reduction in systemic exposure when co-administered with a strong CYP450 inducer and co-administration should therefore be avoided due to potential for negative impact on efficacy. PAC was not found to cause QT prolongation, suggesting favorable cardiac safety. Single 100-400 mg doses of PAC were well tolerated in healthy volunteers in these studies. Overall, PAC exhibited a favorable clinical pharmacology profile supportive of its safety and tolerability at clinical dose levels. Table. PK Parameter(Geometric Mean; n=12) PAC 400 mg Cmax, μg/mL 3.83 AUC0-t, μg∙h/mL 184 t1/2, h 37.5 Tmaxa, h 6.00 λz, L/h 0.0185 CL/F, L/h 2.08 Vz/F, L 112 Oral bioavailability, % 58.6 aMedian for Tmax. λz, terminal elimination rate constant; AUC0-t, area under the plasma concentration curve from time 0 to time t; CL/F, apparent oral clearance; Cmax, maximum plasma concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Vz/F apparent volume of distribution during terminal phase. Disclosures Al-Fayoumi: CTI Biopharma: Employment, Equity Ownership. Off Label Use: This abstract discusses off-label use of pacritinib. Campbell:CTI Biopharma: Equity Ownership. Amberg:BMS: Employment, Equity Ownership; Juno: Equity Ownership. Zhou:CTI Biopharma: Employment, Equity Ownership. Millard:CTI Biopharma Corp.: Employment. Dean:CTI Biopharma: Employment, Equity Ownership.

scholarly journals Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2427-2427 ◽  
Author(s):  
Troy E. Barger ◽  
Andy Boshier ◽  
Vibha Jawa ◽  
June Kim ◽  
Daniel T. Mytych ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Employment Equity ◽  
Lower Baseline ◽  
Increased Risk ◽  
Equity Ownership ◽  
Global Registry

Abstract Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing. Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted. Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result. Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2). Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO. Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs. Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy. Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. Disclosures Barger: Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

scholarly journals Therapeutic Strategy for Elderly Patients with ACUTE Myeloid Leukemia (AML) Carrying the DNMT3A Mutation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5269-5269 ◽  
Author(s):  
Elena Rossetti ◽  
Monica Crugnola ◽  
Cecilia Caramatti ◽  
Luisa Craviotto ◽  
Elena Masselli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Septic Shock ◽  
Complete Remission ◽  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Off Label Use ◽  
Bone Marrow Blast ◽  
Off Label ◽  
Blast Count ◽  
Label Use

Abstract BACKGROUND: AML in the elderly is associated with low complete remission (CR) rates after induction therapy, poor survival and high treatment-related mortality. 5-Azacytidine (5-AZA) has emerged as a valid substitute of the Conventional Care Regimens (CCR) in a small subset of patient with a bone marrow blast count ranging from 20% to 30%. However, in a off-label use, 5-AZA may also be used in patients with bone marrow blast infiltration >30%. Furthermore, 5-AZA can be also used for the maintenance therapy after the bone marrow blast count has been reduced under the 5% cut-off. AIMS: to assess both safety and efficacy of in-label use of 5-AZA in elderly AML patients who have reached a bone marrow blast count between 5% and 30% after an induction conventional chemotherapy. METHODS: from 2010 to 2013, 13 patients (8 males; 5 females) with a median age of 74 (range 64-86) years and a newly diagnosed AML have been enrolled. At the diagnosis, the median bone marrow blast count was 45% (range 24%-95%). Cytogenetics showed: normal karyotype in 7 patients, chromosome 8 trisomy in 2, complex karyotype in 4. A DNMT3A mutation was documented in 5 cases. Neither FLT3-ITD mutations nor NPM1 mutations were present. According to age, performance status and comorbidities, all patients received a CCR induction chemotherapy. Low Dose Cytarabine, 100mg/sqm, was given subcutaneously for 5 days in 4 patients, Fludarabine (25mg/sqm intravenously for 5 days) and Cytarabine (2gr/m2 intravenously for 5 days) in 4 and the ICE schedule- Idarubicine (10mg/sqm intravenously for 3 days), Cytarabine (100mg/sqm intravenously for 5 days) and Etoposide (50mg/sqm intravenously for 3 days) in 5. At the day +31 bone marrow evaluation, no one obtained a Complete Remission, in 5 patients blast count ranged between 20% and 30%; in 4 between 15% and 20%; and in 4 between 5% and 10%. Then, all patients received 5-AZA at 75mg/sqm subcutaneously for 7 days every 28 days. The median number of cycles was 8 with a minimum of 1 cycle and a maximum of 15 cycles. Adverse hematological events were: grade III-IV neutropenia in 7 patients (54%) and thrombocytopenia in 9 patients (69%). Fever was the major non-hematological side effect during 5-AZA: fever was of unknown origin (FUO) in 4 patients, infection-related in 4 (2 pneumonias, 1 sepsis from Pseudomonas Aeruginosa and 1 from KPC). One patient died after the first cycle for septic shock due to KPC. RESULTS: Among the 12 evaluable patients the median survival was 16 months (range 2 – 44). Our data showed a longer median survival (17 months) in the 5 patients with DNMT3A mutation in comparison with those with wild-type DNMT3A (11 months). In consideration of the limited number of patients, the p-value was 0.47. In addition, a reduction of transfusion requirements as well as an improvement of quality of life were obtained. Therapy with 5-AZA was overall well tolerated as only one patient needed a long-term hospitalization and died from septic shock. In conclusion, we showed that a bone marrow blast reduction after conventional induction chemotherapy and a subsequently treatment with 5-AZA can be a valid option in elderly patients with AML and DNMT3A mutation. More patients and longer follow-up are required for confirming these encouraging preliminary results. Disclosures Off Label Use: Gemtuzumab Ozogamicin in AML.

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