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).

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.

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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 ◽

10.1182/blood.v122.21.4044.4044 ◽

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.

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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 ◽

10.1182/blood.v126.23.4877.4877 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4877-4877 ◽

Cited By ~ 1

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.

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Treatment of Adults with Minimal Residual Disease (MRD) Positive Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Blood ◽

10.1182/blood-2019-122931 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2624-2624

Author(s):

Nicolas Boissel ◽

Renato Bassan ◽

Josep-Maria Ribera ◽

Sabina Chiaretti ◽

Robin Foà ◽

...

Keyword(s):

Board Of Directors ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Expanded Access ◽

Expanded Access Program ◽

Equity Ownership ◽

Access Program

Introduction: In November 2015, conditional approval of blinatumomab was granted for adults with relapsed and/or refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (R/R Ph- BCP-ALL). Prior to country-specific reimbursement, blinatumomab was made available to patients (pts) who met pre-specified criteria via an expanded access program in specific countries: this included both adults and pediatric pts with diagnosis of R/R Ph- BCP-ALL, R/R Ph+ BCP-ALL, or minimal residual disease (MRD)-positive Ph-/Ph+ ALL. Here, we report on adults with MRD+ BCP-ALL enrolled in this expanded access program with reference to their characteristics and both blinatumomab usage and effectiveness. Methods: The retrospective observational study (NEUF) recruited pts who initiated blinatumomab in the available expanded access setting between 2014 and 2016. Pts were followed from blinatumomab initiation until death, entry into a clinical trial, end of follow-up, or the end of the study period (30 June 2017), whichever occurred first. Efficacy analyses were undertaken on a MRD intention-to-treat basis. MRD response was defined as MRD level <10-4 within first cycle and within the first 2 cycles. MRD assessment was undertaken as per local clinical practice, including flow cytometry and polymerase chain reaction (PCR): MRD status was then extracted from the patient medical record. Median disease-free survival (DFS) was defined as time from initiation of blinatumomab until date of relapse (blasts in bone marrow >5% or extramedullary relapse after documented response) or death, whichever occurred first. Adverse events were reported separately, according to local regulations. Results: Out of 373 enrolled pts, 109 MRD positive adult ALLs (83 Ph-; 26 Ph+) were included in Italy (53), France (23), Spain (20), Russia (11), and the UK (2). Most patients (76%, n=83) were Ph-. Forty-one percent (n=45) were female and median age was 43 years (interquartile range [IQR]: 27, 55). In their medical history, 16% (n=17 out of 109 MRD positive patients) had a prior allogeneic hematopoietic stem cell transplant (HSCT). The median number of prior salvage therapies was 0 (IQR: 0.0, 1.0). Among blinatumomab co-medications, almost 90% were treated with dexamethasone, 35% (n=36) as pre-phase and 87% (n=92) as pre-medication. Of the 82 pts with evaluable MRD within two cycles of blinatumomab, 83% (n=66) had a MRD response (Table), including 48 with non-detectable MRD and 18 with MRD <10-4. Following blinatumomab initiation, 68% (n=74 out of 109) of pts proceeded to HSCT: 65 (88%) of these patients had documented complete remission with full/partial/incomplete recovery of peripheral blood counts before transplant. The median time from complete response (CR) to HSCT was 2.4 months (range: 1.6, 5.3), with median follow-up time being 18.5 months (IQR: 14.0, 27.7). The median DFS was 27.6 months (IQR: 7.4, not estimable [NE]). Censoring for HSCT increased DFS to 33.0 months (IQR: 8.9, NE). At 24 months following blinatumomab initiation, overall survival ((OS) was 65% (95% confidence interval [CI]: 52.8, 74.2): when censoring for HSCT, OS was 77.6% (95% CI: 52.8, 88.9); median follow-up time was 4.0 months (IQR: 2.6, 13.7). The Kaplan-Meier estimate of the non-relapse mortality following HSCT post-blinatumomab was 6% (95% CI: 1.9, 16.4) at 3 months and 10% (95% CI: 4.6, 22.3) at 12 months. Conclusions: In this large multi-country, multi-site study, blinatumomab was shown to induce molecular response within two cycles in the majority of patients with evaluable MRD. Furthermore, the median DFS was over two years, while two-thirds of pts were still alive 24 months after initiation. This study demonstrates the real-world effectiveness of blinatumomab and is consistent with results from clinical studies (BLAST). Disclosures Boissel: NOVARTIS: Consultancy. Bassan:Shire: Honoraria; Incyte: Honoraria; Amgen Inc.: Honoraria; Pfizer: Honoraria. Chiaretti:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Papayannidis:Novartis: Honoraria; Incyte: Honoraria; Teva: Honoraria; Shire: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Alam:Amgen: Employment, Equity Ownership. Brescianini:Amgen: Employment, Equity Ownership. Pezzani:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership. Rambaldi:Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

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Tazemetostat Expanded Access Program for Adults With Epitheliloid Sarcoma

Case Medical Research ◽

10.31525/ct1-nct04225429 ◽

2020 ◽

Author(s):

Keyword(s):

Expanded Access ◽

Expanded Access Program ◽

Access Program

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IPILIMUMAB IN PATIENTS WITH DISSEMINATED MELANOMA: THE N.N. PETROV NATIONAL MEDICAL RESEARCH CENTER OF ONCOLOGY EXPANDED ACCESS PROGRAM EXPERIENCE

Problems in oncology ◽

10.37469/0507-3758-2018-64-3-388-393 ◽

2018 ◽

Vol 64 (3) ◽

pp. 388-393

Author(s):

Yekaterina Anokhina ◽

V. Rubinchik ◽

Yekaterina Yaremenko ◽

Gulfiya Teletaeva ◽

Dilorom Latipova ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Medical Research ◽

Research Center ◽

Expanded Access ◽

Risk Of Death ◽

National Medical ◽

Expanded Access Program ◽

Access Program

Ipilimumab (IPI) provides a ten-year overall survival in almost 20 % of selected patients participated in several phase II-III trials. However, the expanded access program (EAP) looks more like routine practice than like clinical trials& This is why the results of such application could be different. Here we present the long-term follow-up data of single center EAP. Ninety-six patients with disseminated melanoma progressing after at least one lines of drug therapy were included at the N.N. Petrov National Medical Research Center of Oncology. Sixty-seven (70 %) patients had stage IV M1c, 35 patients (36 %) had elevated LDH before initiating IPI therapy. All patients received IPI 3 mg / kg IV every 3 weeks for a maximum of 4 cycles. Totally, 320 cycles (mean - 3.3 per patient) were conducted. Grade 3-4 immuno-mediated adverse events (imAE) observed in 18 (19 %) patients. Three patients died of adverse events, possibly associated with ongoing therapy. The median time to progression was 3 (95 % CI, 2.4 to 3.5) mo., the median overall survival was 13 (95 % CI, 8.3 to17.6) mo. Previous immunotherapy with dendritic cell vaccines decreased the risk of death by 48 % (Log-rank p = 0.049). The wild type BRAF status increased three-year overall survival from 29 to 68 % (p = 0.042). Our data confirms long-term safety and efficacy of IPI in patients with pretreated disseminated melanoma in the close to real practice setting.

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