Expanded Access Program Of Ponatinib (AP24534) For Patients (Pts) With Refractory Chronic Myeloid Leukemia (CML) Or Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4044-4044
Author(s):  
Ghayathri Jeyakumar ◽  
Hagop M. Kantarjian ◽  
Kendra L. Sweet ◽  
Cecilia Y Arana Yi ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Philadelphia Chromosome ◽  
Disease Stage ◽  
Clinical Activity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
T315i Mutation ◽  
Access Program

Abstract Background Ponatinib is a pan-BCR-ABL inhibitor with activity against BCR-ABL, including the TKI resistant T315I and all other clinically relevant mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with CML in chronic (CP-CML), accelerated (AP-CML), or blastic (BP-CML) phase, or Ph+ ALL were evaluated in an expanded access program. Methods 49 pts, including 24 CP-CML, 5 AP-CML, 8 BP-CML (100% Myeloid Blasts), and 12 Ph+ ALL were registered at 2 institutions. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. For this analysis, pts were grouped in cohorts according to the disease stage and presence or not of T315I. Results The median age for CP-CML, AP-CML, BP-CML, and Ph+ ALL pts was 44, 36, 56, and 57 yrs, respectively. Median yrs from diagnosis to start of ponatinib were 7, 1, 3 and 2, respectively. 94% had received imatinib, 80% dasatinib, 59% nilotinib, 2% bosutinib, and 24% had undergone prior SCT. Among 37 pts evaluable for response to prior dasatinib or nilotinib, 84% had history of resistance to these agents, 16% were intolerant. 92% pts had received at least 2 prior TKI, and 45% had received at least 3. Reported response rates with the most recent TKI were 63% (15/24) MCyR for CP-CML, and CHR 60% AP-CML, 0% BP-CML, 33% Ph+ ALL. After a follow-up of 9 months on therapy, 49% of CP-CML, 60% of AP-CML, 25% of BP-CML, and 9% of Ph+ ALL pts remain on study. The reasons for discontinuation were progressive disease (38%, 40%, 75%, and 83%, respectively) and adverse events (13%, 0%, 0% and 8%, respectively). Among the 49 pts, 58% (14/24) pts in CP-CML have achieved MCyR (46% CCyR). 60% (3/5) AP-CML achieved MCyR (2 of them CCyR), and 35% (7/20) BP/Ph+ALL achieved MCyR (5 of them CCyR). MMR is available by IS only for 40 pts and 26% achieved MMR, and at 9 mos. MMR was achieved by 21% CP, 0% in AP, 0% in BP-CML and 38% Ph+ ALL. The median PFS for all pts was 5.8 mos. Estimated PFS at 9 mos. was 50% overall, and 71% in CP, and 75% in AP, 25% in BP-CML and 17% in Ph+ ALL. In CP-CML, AP- CML, BP-CML and Ph+ALL the median PFS was estimated as 12.5 mos., 13.3 mos., 3.5 mos. and 1.4 mos. respectively. Overall median OS was not reached. The probability of OS at 9 mos. for all pts was 80%.; in CP-CML it was 100%, in AP-CML was 75%, in BP-CML 58% and in Ph+ ALL was 53% at 9 mos. The most common AEs were thrombocytopenia (18%), G1-2 rash (14%), and neutropenia (12%) and the G3-4 AEs were thrombocytopenia (4%) and pancreatitis (6%) with G3-4 lipase elevation 8% and G3 amylase 8%. Conclusions Ponatinib has clinical activity in refractory CML and pretreated Ph+ leukemia patients who have limited treatment options. The results of this expanded access study match those of the pivotal PACE trial confirming the clinical benefit with ponatinib in this setting. Disclosures: Kantarjian: ARIAD: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. O'Brien:ARIAD: Research Funding. Pinilla:Ariad: Advisory Board Other, Research Funding, Speakers Bureau. Cortes:Ariad, Pfizer and Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

scholarly journals Expanded Access Program of Graspa for Treatment of Patients with Acute Lymphoblastic Leukemia Unable to Receive Other Form of L-Asparaginase - a Status Update (NCT02197650)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4877-4877 ◽  
Author(s):  
Yves Bertrand ◽  
Hervé Dombret ◽  
Bruno Quesnel ◽  
Jean-Louis Stephan ◽  
Claudine Schmitt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Allergic Reactions ◽  
Advisory Committees ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Background L-asparaginase (L-ASP) is a key drug in the treatment of acute lymphoblastic leukemia (ALL). However the toxicity profile, especially hypersensitivities up to acute allergic reactions is a major drawback. GRASPA (eryaspase (proposed INN) or E-Coli L-Asparaginase encapsulated into red blood cells) is a new product under development with the aim of improving the tolerance of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as "bioreactors". The RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Recently, a Phase III pivotal study of GRASPA in combination with COOPRALL chemotherapy protocols in patients with relapsed ALL demonstrated highly significant safety profile and clinical activity compared to control. However, there is an unmet medical need for patients who cannot receive current formulations of L-ASP. An expanded access program has recently been initiated in France to provide access for treatment with GRASPA in patients who are unable to receive other forms of L-ASP. Methods: This is a non randomized multicenter open label study, currently initiated in France. The primary objective of the EAP is to evaluate the tolerability of GRASPA. Patients under 55y of age presenting with de novo, relapsed or refractory ALL who are at risk to receive any other available L-ASP formulation are enrolled into this program. Patients with known allergic reactions to E.Coli L-ASP are also eligible. GRASPA is administrated every 2 to 3 weeks at a dose equivalent to 150 IU/kg of L-ASP during all chemotherapy courses intended to contain an asparaginase. Chemotherapy protocols are given according to the Investigator's choice. Patients are assessed regularly for safety and tolerability. The primary endpoint is tolerability; Key secondary endpoints include asparaginase activity, asparagine depletion, and clinical remission rates. An independent Safety Monitoring Board (DSMB) is set up, which will assess toxicities on yearly basis. Results As of time of June 2015, 13 patients were enrolled into the program. The first DSMB meeting reviewed the outcome of the first 7 patients enrolled into the program. Of the 7 pts (range 3 - 49 years), 5 males and 2 females were enrolled. Four pts presented with refractory disease and 3 with relapse, with all patients had evidence of allergies to 2 prior asparaginases (double allergies). There were 2 pts presenting with limiting toxicities, in the form of myelosupression, and streptococcal infection. There was no modification to the protocol recommended by the first DSMB An updated safety and clinical activity information on all patients will be provided. Conclusion: The EAP provides a potential treatment alternative for ALL patients, who are unable, or at risk of developing hypersensitivity reactions to prior asparaginases. The initial results from this program suggests that GRASPA is well tolerated, and may have a potential benefit in patients with double allergies. The program will be expanded to other European countries Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salako:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Pooled Treatment Analysis of Pediatric Patients with Defibrotide for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Multi-Organ Dysfunction Following Hematopoietic Stem Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4330-4330
Author(s):  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
Kamalika Banerjee ◽  
Alison L. Hannah ◽  
Robin L. Hume ◽  
...  
Keyword(s):  
Research Funding ◽  
Pediatric Patients ◽  
Occlusive Disease ◽  
Dose Finding ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Equity Ownership ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Defibrotide (DF) is approved for treatment of severe hepatic VOD/SOS in the European Union. In the United States, DF is available through an ongoing expanded-access protocol. Methods DF treatment for hepatic VOD/SOS with MOD is being assessed in a clinical program in pediatric and adult patients, including a phase 2 dose-finding trial, a pivotal phase 3 study of DF compared to historical controls (HC), and a single-arm expanded-access program. In the phase 2 dose-finding study, patients were randomized to receive 25 or 40 mg/kg/day. In the other 2 studies, treated patients received DF 25 mg/kg/d. DF was given in 4 divided doses for a recommended ≥14 days (dose-finding trial) or ≥21 days (pivotal and expanded-access studies). VOD/SOS was defined in each study by Baltimore and/or modified Seattle criteria. Here, we report results for treatment with DF 25 mg/kg/day in pediatric patients (aged ≤16y) with VOD/SOS plus MOD post-HSCT across these 3 studies. Results A pooled efficacy analysis included 255 pediatric patients with VOD/SOS and MOD post-HSCT who received DF 25 mg/kg/d in the dose-finding trial (n=22), pivotal trial (n=44), and expanded-access program (n=189). Among patients, 29.8% (n=76) were aged 0-23 mo, 48.6% (n=124) aged 2-11y, and 21.6% (n=55) aged 12-16y. 83.9% received allogeneic transplants (98.7% of patients aged 0-23 mo; 66.7% of patients aged 2-11y; 100% of patients aged 12-16y) and 16.1% received autologous transplants (1.3%, 0-23 mo; 32.3%, 2-11y; none, 12-16y). Acute leukemia (41.2%) was the most common primary disease (23.7%, 0-23 mo; 40.3%, 2-11y; 67.3%, 12-16y). At day +100 following HSCT, the survival rate in the overall pediatric population was 51.4% (95% CI, 45.2%-57.5%; n=131/255). Day +100 survival by age subgroup was 52.6% (95% CI, 41.4%-63.9%; n=40/76) in patients aged 0-23 mo, 53.2% (95% CI, 44.4%-62.0%; n=66/124) in those aged 2-11y, and 45.5% (95% CI, 32.3%-58.6%; n=25/55) in patients aged 12-16y. A safety analysis pooled data from the dose-finding and the pivotal trials, which incorporated on-site data monitoring, included 65 children who received DF at a dose of 25 mg/kg/day and 14 children in the HC group. At least 1 AE was reported for 93.8% (61/65) of DF-treated patients from these trials (95.5%, 0-23 mo; 89.7%, 2-11y; 100%, 12-16y), and for all HC patients. Overall AE profiles were generally similar between treated and HC patients. In these 2 trials, 67.7% of pediatric patients receiving 25 mg/kg/day DF had ≥1 serious AE (77.3%, 0-23 mo; 58.6%, 2-11y; 71.4%, 12-16y). Treatment-related AEs (TR-AEs) were reported in 44.6% of patients (31.8%, 0-23 mo; 44.8%, 2-11y; 64.3%, 12-16y). The most common TR-AE overall was pulmonary alveolar hemorrhage (2 patients per age group: 9.1%, 0-23 mo; 6.9%, 2-11y; 14.3%, 12-16y). AEs leading to death were reported for 49.2% (32/65) of patients from these 2 trials (72.7%, 0-23 mo; 31.0%, 2-11y; 50.0%, 12-16y) and 57.1% of HC patients (8/14; 40.0%, 0-23 mo; 85.7%, 2-11y; none, 12-16y). In the expanded-access program, ≥1 serious AE occurred in 98 (51.9%) patients ≤16y old; TR-AEs occurred in 41 (21.7%) of patients ≤16y old, most commonly pulmonary hemorrhage (6.9%), gastrointestinal hemorrhage (3.7%), and hypotension (3.7%). Conclusions In this pooled analysis of data from pediatric patients with VOD/SOS and MOD enrolled in 3 DF studies, day +100 survival was generally consistent across pediatric age subgroups. The safety profile in pediatric patients with VOD/SOS and MOD was generally consistent with what would be expected for this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Grupp:Novartis: Consultancy, Research Funding. Banerjee:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Safety analysis from an expanded access study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4532-4532
Author(s):  
Joaquim Bellmunt ◽  
Sumanta K. Pal ◽  
Hanzhe Zheng ◽  
Darren Tayama ◽  
Dannis Chang ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Clinical Activity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Fda Approval ◽  
The Us ◽  
Metastatic Urothelial Carcinoma ◽  
Access Program ◽  
Clinical Trial Information ◽  
Efficacy Population

4532 Background: A majority of mUC pts progress on standard platinum-based chemo regimens. Atezo (anti–PD-L1) was approved in the US for mUC in the post-platinum setting. Here we report the preliminary safety results from an expanded access program conducted to grant access to atezo, prior to commercial availability, to a broader range of mUC pts than are typically eligible for Phase I-III studies. Methods: From Nov 2015-Aug 2016, this study (NCT02589717) enrolled mUC pts who progressed during or following platinum. Atezo was given 1200 mg IV q3w, and pts could be treated post RECIST v1.1 PD until lack of clinical benefit (per investigator). Safety and clinical activity were key endpoints. PD-L1 expression on immune cells (IC) was assessed with the VENTANA SP142 IHC assay on the first 73 pts prior to protocol amendment omitting this requirement. This study was ended early following FDA approval of atezo. Results: 218 pts were enrolled at 36 sites in the US, with 214 treated pts comprising the safety/efficacy population (Table). Median treatment duration was 9 wks (range 3-26), corresponding to a median of 3 doses of atezo (range 1-8). Overall, 89% of pts had an AE. Treatment-related AEs (TRAEs) occurred in 46% (any Gr) and 7% (Gr3-4) of pts; 2 treatment-related Gr 5 AEs were seen (ileus; acute respiratory failure). TRAEs ≥ 5% were fatigue, decreased appetite and anemia. TRAEs leading to dose interruption or discontinuation occurred in 11% and 6% of pts, respectively. Investigator-assessed RECIST v1.1 ORR was 15% (95% CI: 9, 23), and disease control rate (ORR + SD) was 49% (95% CI: 40, 59). Additional clinical data will be reported. Conclusions: In this expanded access study, atezo was administered to > 200 mUC pts. Overall, atezo was safe and tolerable, supporting its use in a wider platinum-based population. Clinical trial information: NCT02589717. [Table: see text]

scholarly journals Expanded Access Program: Evaluating Safety of Erythrocytes Encapsulating L-Asparaginase in Combination with Polychemotherapy in Patients Under 55 Years Old with Acute Lymphoblastic Leukaemia (ALL) at Risk to Receive Other Formulations of Asparaginase

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1214-1214
Author(s):  
Yves Bertrand ◽  
Nicolas Boissel ◽  
Claudine Schmitt ◽  
Alban Villate ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
At Risk ◽  
Board Of Directors ◽  
Whole Blood ◽  
Research Funding ◽  
Advisory Committees ◽  
E Coli ◽  
Expanded Access ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Introduction Asparaginase is an important part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity is found in 16.8% of patients treated with pegylated asparaginase (PEG-asp). Hypersensitivity is the most common cause of truncated asparaginase therapy which has been associated with decreased event free survival. Asparaginase (ASNase) encapsulated in erythrocytes (eryaspase) is an alternative formulation of ASNase aiming to prolong the half-life of ASNase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane protects asparaginase against elimination and prevents activation of the immune system. In the NOR-GRASPALL 2016 trial eryaspase consistently demonstrated prolonged ASNase activity in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated when combined with multiagent chemotherapy. The objective of this expanded access program was to explore the tolerability of eryaspase (150 U/Kg) combined with polychemotherapy in patients under 55 years of age with ALL, unable or at risk to receive any other available ASNase formulation. Patients in this study had developed hypersensitivities to prior E-Coli- and Erwinia-derived asparaginase therapies. Methods This was a non-randomized, multicentre, open label, Phase 1 study to assess the limiting toxicities, global safety and biological efficacy of eryaspase in combination with chemotherapy regimens. Patients were under 55 years of age with ALL de novo or in relapse or refractory; eligible for a chemotherapy treatment including ASNase; known contraindication and/or at risk of toxicity from other ASNase formulations. Eryaspase (150 U/Kg) was given as a replacement therapy for the remaining intended courses of asparaginase therapy. The number of courses was not defined and depended on therapeutic treatment chosen by the Investigator and the patient's response and tolerance. The primary endpoint was the exploration of the toxicity of eryaspase defined as the number and percent of patients presenting at least one limiting toxicity (LT) of eryaspase in combination with chemotherapy. Major secondary endpoints included: adverse events (AEs), pharmacokinetics (PK), pharmacodynamics (PD) and complete remission (CR) status at end of induction and survival status up to 12 months after inclusion. Results Eighteen patients enrolled of which seven (38.8%) patients experienced a total of 24 AE limiting toxicities, which were primarily bone marrow failure, and were indicative of the underlying ALL disease process and of the concomitant chemotherapy-related myelosuppression. All patients experienced at least one AE and Treatment Emergent (TEAE) and most (11 [61.1%] patients) experienced at least one SAE. A total of 17 (94.4%) patients experienced a TEAE of Grade 3 or above. No TEAEs led to withdrawal or dose reduction of eryaspase. Sparse whole blood ASNase concentrations following 150 U/Kg were within the range of concentrations expected for this dose level. At 14 days following the first infusion, the range of whole blood ASNase was 111 to 1160 U/Kg, which would be equivalent to the trough (nadir) for infusions every 2 weeks. Mean and median plasma asparagine (ASN) concentrations over time demonstrated a reduction by approximately 50% at 3 days post eryaspase infusion, followed by a slow return toward baseline before the next infusion of eryaspase. Seventeen (94.4%) patients achieved CR at least once overall. Fourteen (77.8%) patients were alive at the end of the study. Survival rate was 88.9% at 6 months and 77.8% at 12 and 18 months. Conclusion The AE profile of eryaspase was consistent with other studies and was as expected for this cohort of patients. Serious AEs were generally consistent with those that would be expected in this study population. A total of 17 patients in the study achieved a CR at least once overall and 14 were still alive at the end of the study. This study evaluated additional asparaginase therapy in double (and even triple) allergic patient population, who have received prior E-Coli- or Erwinia-derived asparaginase therapy. All patients achieved target asparaginase activity. Therefore, eryaspase provides an additional option for patients for whom further ASNase treatment is contraindicated due to toxicity and/or immunization. Disclosures Boissel: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; CELGENE: Honoraria. Recher: Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Incyte: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. El-Hariry: Erytech: Current Employment, Current holder of stock options in a privately-held company.

scholarly journals Impact on Outcomes of Baseline Bilirubin in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Receiving Defibrotide Treatment: A Post-Hoc Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2213-2213
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Weight Gain ◽  
Board Of Directors ◽  
Bilirubin Level ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Advisory Committees ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a difficult to predict, and potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). VOD/SOS develops via a pathophysiologic cascade, and VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with >80% mortality. Defibrotide was recently approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and is approved in the European Union to treat severe hepatic VOD/SOS post-HSCT. In the United States, defibrotide had been available through an expanded-access program. Methods Patients in the expanded-access program were diagnosed with VOD/SOS by investigators using Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of the following: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of the following: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy; elevated bilirubin was not required for patients with biopsy or who met modified Seattle criteria by presence of hepatomegaly with ascites/weight gain. This program included patients with or without MOD/MOF (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT is explored post hoc based on 4 bilirubin-level categories at time of study entry; together these categories have been defined as 1 of the criteria in the proposed VOD/SOS grading scale for adults from the European Society for Blood and Marrow Transplantation (EBMT; ≥2 mg/dL to <3 mg/dL, ≥3 mg/dL to <5 mg/dL, ≥5 mg/dL to <8 mg/dL, and ≥8 mg/dL [Mohty M et al. Bone Marrow Transplant. 2016;51:906-912]). It is important to note that bilirubin <2 mg/dL is not part of the proposed EBMT criteria for VOD/SOS in adults. Results Among 756 post-HSCT patients enrolled through April 18, 2015, who received ≥1 dose of defibrotide, 427 also had MOD/MOF. Median age was lowest in patients with bilirubin <2 mg/dL (5 years). By comparison, median age in patients with bilirubin ≥2 to <3 mg/dL (56% of all patients) was 16 years; for bilirubin ≥3 to <5 mg/dL, median age was 13 years; and for the 2 small groups with bilirubin ≥5 to <8 or ≥8 mg/dL, median ages were 15 and 16.5 years, respectively. Day +100 survival in the overall HSCT population of the expanded-access program was 55.4% by Kaplan-Meier estimate. The survival rate was 81.4% in patients with bilirubin <2 mg/dL; for patients with bilirubin levels ≥2 mg/dL, who tended to be older, survival estimates decreased (Table). Day +100 survival patterns by bilirubin level were generally similar in the subgroups of patients with and without MOD/MOF (Table). Overall, 515 post-HSCT patients (67%) reported ≥1 adverse event (AE). Serious AEs were reported by 386 patients (50%), and AEs leading to death occurred in 250 patients (33%). Among all AEs, 158 patients (21%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Conclusions Overall, higher bilirubin levels were associated with worse Day +100 outcomes (with the exception of the ≥5 to <8 mg/dL group, which represented only 5% of patients, and so has limited validity). However, interpretation of these results has to be treated with caution because only a single criterion from the EBMT guidelines was analyzed and because potentially confounding interactions (eg, age) were not assessed. Across all bilirubin-level categories, VOD/SOS with MOD/MOF was consistently associated with worse outcomes than VOD/SOS without MOD/MOF. These results further support the importance of identifying VOD/SOS earlier and suggest that diagnosis and treatment of VOD/SOS, before bilirubin becomes markedly elevated, may be associated with improved outcomes. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Pembrolizumab expanded access program (EAP) in Spain: clinical activity.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e21029-e21029
Author(s):  
Ana Arance ◽  
Josep M. Piulats ◽  
Ivan Marquez Rodas ◽  
Jose Luis Manzano ◽  
Alfonso Berrocal ◽  
...  
Keyword(s):  
Clinical Activity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

scholarly journals Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias

2008 ◽  
Vol 19 (7) ◽  
pp. 1320-1326 ◽  
Author(s):  
R. Capdeville ◽  
T. Krahnke ◽  
A. Hatfield ◽  
J.M. Ford ◽  
I. Van Hoomissen ◽  
...  
Keyword(s):  
Philadelphia Chromosome ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program ◽  
Philadelphia Chromosome Positive

scholarly journals Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Acute Leukemias: A Subgroup Analysis from the Defibrotide Expanded-Access Program

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3412-3412
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Kaplan Meier ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Reported mean incidence of VOD/SOS following HSCT is an estimated 13.7% (range 0%-62.3%). VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Endothelial cell (EC) damage, triggered by cytotoxic chemotherapeutic conditioning regimens and a prothrombotic-hypofibrinolytic state, is a critical factor in the pathophysiology of VOD/SOS. In the United States, defibrotide is approved for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT, and in the European Union, defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT. Prior to its approval, defibrotide had been available in the United States through an expanded-access program. Here, Day +100 post-HSCT survival and safety are analyzed for the 2 largest primary-disease subgroups in that study: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Methods Patients in the expanded-access program had VOD/SOS diagnosed by Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy, and this study included patients with or without MOD (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Results A total of 867 patients were enrolled in the safety population of the expanded-access program through April 18, 2015, including 476 patients with MOD. The primary diseases affecting 5% or more of the safety population at baseline were AML, 25.7% (222/867); ALL, 23.4% (202/867); neuroblastoma, 8.5% (73/867); and myelodysplastic syndrome, 5.7% (27/867). Data were available for 756 post-HSCT patients who received ≥1 dose of defibrotide. Of those patients, 207 (27.4%) patients had AML and 152 (20.1%) patients had ALL as their primary disease. Of the AML patients, 49.8% (103/207) were male, and 50.2% (104/207) were female; median age at HSCT was 23 years (range: 0.5, 74.0 years); and all had allogeneic HSCT. Among the ALL patients, 62.5% (95/152) were male, and 37.5% (57/152) were female; median age at HSCT was 16 years (range: 0.3, 68.0 years); and all had allogeneic HSCT. At Day +100 post-HSCT, observed survival was 45.4% (94/207) among AML patients and 42.8% (65/152) among ALL patients; 50.7% (105/207) and 52.0% (79/152), respectively, had died; and status was not available (ie, no HSCT date recorded, did not have sufficient follow-up, or their data were not available) for 3.9% (8/207) and 5.3% (8/152), respectively. For AML patients, Kaplan-Meier estimated survival rate was 47.8% (95% confidence interval [CI], 40.7%-54.5%; Figure 1); among ALL patients, Kaplan-Meier estimated survival rate was 46.0% (95% CI, 37.7%-53.9%; Figure 2). Adverse events (AEs) occurred in 76.8% (159/207) of AML patients and 64.5% (98/152) of ALL patients, with serious AEs in 57.5% (119/207) and 52.6% (80/152), respectively. Treatment-related AEs, as assessed by investigators, occurred in 21.7% (45/207) of AML patients and 17.1% (26/152) of ALL patients (>2% in either group [all <4%]: pulmonary hemorrhage, epistaxis, gastrointestinal hemorrhage, hypotension). Treatment-related AEs leading to discontinuation developed in 14.5% (30/207) of AML patients and 8.6% (13/152) of ALL patients (>2% in either group [all <3%]: pulmonary hemorrhage, gastrointestinal hemorrhage); treatment-related deaths occurred in 3.4% (7/207) of AML patients and 2.6% (4/152) of ALL patients, respectively, with none occurring in >1 patient in either subgroup. Conclusions The Day +100 survival rates and safety profile for the AML and ALL subgroups in the expanded-access program were consistent with prior defibrotide studies and analyses of the overall HSCT population in this study. Kaplan-Meier estimates of survival at Day +100 were similar between the AML (47.8%) and ALL (46.0%) subgroups. Taken together, these subgroup results affirm the overall efficacy and safety profile of defibrotide in post-HSCT patients with VOD/SOS and underlying acute leukemia. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:The National Cancer Institute of the National Institutes of Health: Research Funding; Gentium: Research Funding. Grupp:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

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