Pharmacokinetic and Pharmacodynamic Characterization of Graspa Versus Native L-Asparaginase in Combination with Cooprall Chemotherapy in a Phase 3 Randomized Trial for the Treatment of Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2492-2492 ◽  
Author(s):  
Xavier Thomas ◽  
Yves Bertrand ◽  
Andre Baruchel ◽  
Nicolas Blin ◽  
Emmanuelle Tavernier ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Signs ◽  
Phase Iii ◽  
Disease Rate ◽  
P Value ◽  
Induction Phase ◽  
Phase 3 ◽  
Logrank Test ◽  
Asparaginase Activity

Abstract Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, pharmacokinetic (PK), pharmacodynamics (PD) and anti-ASPA antibodies at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C, GRASPA-s). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the report the PK of asparaginase activity, and PD effects. Results A total of 80 pts enrolled into the trial. A total 100% and 96% of patients had at least one day with asparaginase level >100 IU/L during induction, with GRASPA and L-ASP, respectively. Only one patient in L-Asp group did not reach this threshold. All patients in Arm C have also achieved total blood asparaginase level > 100 IU/L during induction. Prolonged ASPA activity was maintained across several key subpopulations as follows: Table 1. GRASPA L-ASP GRASPA L-ASP Age group Children Adults  N 21 21 5 7  Mean (SD) 20.8 (5.3) 11.4 (7.3) 19.3 (5.5) 3.2 (2.8)  Median 22.0 8.3 22.1 2.3 Risk Score S1/S2 S3/S4  N 16 15 10 13  Mean (SD) 20.2 (6.0) 12.0 (8.6) 20.9 (3.9) 6.3 (4.4)  Median 22.4 9.0 22.0 6.2 F1-F2/VANDA F1-F2 VANDA  N 16 15 10 13  Mean (SD) 19.5 ± 6.5 11.5 (9.0) 22.0 (0.2) 6.9 (4.2)  Median 22.9 8.8 22.0 6.9 The total ASPA activity >100 IU/L until the loss of that activity demonstrated that the activity was retained in the majority of pts in the GRASPA arm (89%) compared to only 26% in the L-ASP arm. The median times from first assessment of activity > 100 IU/L to loss of activity was not reached in the GRASPA arm by Day 28, but was 15 days in the L-ASP arm. The difference was statistically significant (table below). Similar trend was also observed with GRASPA-s. Table 2. Time from first assessment showing ASPA activity > 100 IU/L until loss of ASPA activity > 100 IU/L Number (%) of events Median [95% CI] Hazard ratio 95% CI Logrank test: p-value for superiority L-ASPN= 28 27 (96.4) 15[11; 21] 0.14 0.07, 0.28 <0.001 GRASPAN= 26 26 (100) NR* NR: not reached Additional information correlating ASPA with asparagine depletion and other amino acid changes (aspartate, glutamic acid, and glutamate) will be provided at the meeting. Conclusion GRASPA consistently demonstrated activity compared to L-ASP for the treatment of pts with relapsed ALL, and is therefore a suitable option for patients with relapsed ALL. Disclosures Thomas: ERYTECH Pharma: Consultancy. Bertrand:ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Bonin:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

scholarly journals Updated Clinical Activity of Graspa Versus Native l-Asparaginase in Combination with Cooprall Regimen in Phase 3 Randomized Trial in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3723-3723 ◽  
Author(s):  
Andre Baruchel ◽  
Yves Bertrand ◽  
Xavier Thomas ◽  
Nicolas Blin ◽  
Emmanuelle Tavernier ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Signs ◽  
Phase Iii ◽  
Induction Treatment ◽  
Clinical Activity ◽  
P Value ◽  
Phase 3 ◽  
Alternative Treatment Option

Abstract Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (proposed eryaspase, E-Coli L-Asparaginase encapsulated into red blood cells) improves pharmacokinetics, tolerability and maintain circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. In the non-allergic pts, GRASPA significantly reduced the incidence of hypersensitivity (0% vs 46%; p<0.001). ASPA activity >100 IU/l was 21 ± 5 vs 9 ± 7 days in GRASPA and L-ASP, respectively (p<0.001). Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the duration of ASPA activity > 100IU/L and the incidence of hypersensitivity during induction. Key secondary endpoints were complete remission, minimal residual disease, relapse rate, event free survival (EFS) and overall survival (OS). Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Results A total of 80 pts with relapsed and or refractory ALL were enrolled into the trial. There were a greater proportion of pts who completed the induction treatment in GRASPA arm (65%) than in the L-ASP arm (46%). The main reasons for treatment discontinuation were: target levels of asparagine depletion not reached (64%) in GRASPA arm, and adverse events (58%) in the L-ASP arm. In addition, in the L-ASP arm, 5 (19%) pts prematurely discontinued treatment due to disease progression. As of the cut-off date (28th August 2014), the majority of pts (63%) still continued in the study and followed-up for survival. The relapse rate at 6 and 12 mo was low, and accounted for 3 (13%; 95% CI: 2.6; 32.4) and 5 (26%; 95% CI: 9.1; 51.2) in the GRASPA arm, compared to 1 pt (5%) and 3 (17%; 95% CI: 3.6; 41.4) in the L-ASP arm, respectively. Except for L-ASP, and adult patients, the median EFS and OS were not reached for GRASPA in the entire set or in children, either at 12 months. Overall, there was a trend across all groups with lower EFS and OS event rates with GRASPA compared to L-ASP, as presented in table below. The 2-year follow up will be additionally provided at the meeting Table 1. GRASPA vs L-ASP All patients GRASPA = 26 L-ASP = 28 Children GRASPA = 21 L-ASP = 21 Adults GRASPA = 5 L-ASP = 7 12 mo EFS Median (mo) NR vs 11.6 NR 4.6 vs 1.6 Events 30.8% vs 50.0% 19.1% vs 38.1% 80% vs 85.7% HR 0.54 0.47 0.69 95% CI 0.23; 1.26 0.15; 1.47 0.20; 2.44 P Value* 0.153 0.196 0.569 12 mo OS Median (mo) NR NR 10 vs 8.2 Events 23.1% vs 32.1% 4.8% vs 14.3% 20% vs 42.8% HR 0.63 0.34 0.39 95% CI 023; 1.74 0.05; 2.42 0.05; 2.81 P Value* 0.377 0.424 0.705 *P value in all subsets is not statistically significant Conclusion GRASPA has demonstrated both safety and activity in pts with relapsed ALL, and provides an alternative treatment option for those patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy. Thomas:ERYTECH Pharma: Consultancy. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Bonin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3734-3734 ◽  
Author(s):  
Yves Bertrand ◽  
Andre Baruchel ◽  
Xavier Thomas ◽  
Nicolas Blin ◽  
Emmanuelle Tavernier ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Clinical Signs ◽  
Phase Iii ◽  
Disease Rate ◽  
Clinical Activity ◽  
Induction Phase ◽  
Hypersensitivity Reactions ◽  
Phase 3 ◽  
The Mean ◽  
The Impact

Abstract Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, PK, and anti-ASPA antibodies (A-Abs) at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n=28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the impact of A-Abs on safety and efficacy of GRASPA. Assessments were performed at Day 4, 13, 18, and 27 (F1/F2 block), Day 6, 15, and 27 (VANDA block), and Day 6, 12 (R2/R1 block). Results At baseline, 23%, 25%, and 58% of pts had +ve A-Abs status in Arms A, B, and C, respectively. The mean duration of total ASPA activity (Days) adjusted for baseline antibody status is presented below, and shows that activity slightly differed with positive status; however, GRASPA maintained higher activity compared to L-ASP: Table 1. GRASPA L-ASP GRASPA L-ASP GRASPA (Arm C) Antibody status Negative Positive Negative Positive N 20 21 6 7 11 15 Mean (SD) 22.4 (3.6) 10.31 (8.1) 14.17 (5.1) 6.5 (4.0) 18.9 (6.8) 18.4 (6.2) Median 22.4 8.3 12.2 7.0 21.8 21.7 Min; Max 10.2; 30.7 0.0; 25.0 9.8; 21.8 1.9; 14.0 9.1; 27.9 6.9; 25.0 The incidence of hypersensitivity reactions were 0%, 7/21 (33%), and 2/11 (18%) in pts with negative A-Abs, compared to 0%, 6/7 (85.7%), and 1/15 (7%) in pts with positive A-Abs, in arms A, B and C, respectively. The CR rate during induction was 75%, 48%, and 64% in pts with negative A-Abs, compared to 33%, 14% and 48% in pts with positive A-Abs, in arms A, B and C, respectively. Conclusion These results show that about one third of pts without evidence of prior hypersensitivity have silent A-Abs activation. Positive A-Abs appeared to attenuate the clinical activity in all treatments arms. GRASPA consistently demonstrated activity and improved hypersensitivity regardless of A-Abs status, and therefore, GRASPA is a suitable option for patients with relapsed ALL. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thomas:ERYTECH Pharma: Consultancy. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Bonin:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Reverse Phase Protein Assay (RPPA) Defines Specific Patterns in Childhood Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2510-2510
Author(s):  
Manuela Tumino ◽  
Benedetta Accordi ◽  
Manuela Sciro ◽  
Marco Giordan ◽  
Geertruy te Kronnie ◽  
...  
Keyword(s):  
Western Blot ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Wilcoxon Test ◽  
P Value ◽  
Induction Phase ◽  
Reverse Phase ◽  
Caspase 7 ◽  
Apoptotic Proteins

Abstract Background. ALL is the most frequent cancer in childhood. Although current chemotherapy protocols reach an event free survival (EFS) greater than 70%, the remaining cases relapse and ALL is still the first cause of death in children with cancer. Several efforts have been made to better understand the underlying mechanism involved in ALL. Current chemotherapy protocols have reached a plateau of effectiveness. The detection of minimal residual disease (MRD) during the course of treatment will definitively allows us to stratify children with ALL in standard (SR), intermediate (MR) and high (HR) risk, respectively. In the latter group we included patients with a prednisone poor response, with t(9;22) and t(4;11) (HR by default). Despite of this better definition of therapeutic response, the majority of relapses are included in the MR group, suggesting that we are treating different forms of ALL in this subset. For this reason new biomarkers and molecular targets are highly mandatory. The objective of functional proteome analyses of ALL is to bridge clinical applications with new biomarker discoveries that will be useful for determining prognosis and response to therapy and to identify potential new more selective treatments. Materials and Methods. We analyzed 81 diagnostic samples (peripheral blood and/or bone marrow) with B precursor ALL, that were diagnosed and treated at our centers (Catania and Padova) and enrolled in the AIEOP-LLA 2000 protocol. Reverse phase proteomic assay (RPPA) was used to interrogate the expression of 81 phosphorylated or native protein endpoints in our patients’ samples. We evaluated Pro- and Anti-Apoptotic, Protein Kinase, and Growth factor receptor cell signaling pathways. For statistical purposes, we considered the following characteristics: age at diagnosis, gender, immunophenotype, karyotype, white blood cell count and percentage of blast at diagnosis, response to prednisone, level of MRD at day 33 (TP1) and day 78 (TP2) during the induction phase. We distributed patients in 4 groups, based on risk (SR 21, MR 31, HR 10) and occurrence of relapse (19). We also studied patient specimens both at diagnosis and relapse only in those samples with a blast rate greater than 50% (10 cases out of 19). All findings obtained with RPPA were confirmed by Western blot analyses. We applied the Wilcoxon Test and the t-Test, using the ‘R’ software. Both univariate and multivariate analyses were performed. Results. Comparing subgroups for gender, WBC count (higher vs less than 50.000/ml), immunophenotype (Common vs others), karyotype (t(12;21) positive vs negative), prednisone good (PGR) vs poor (PPR) responders, analysis of MRD (SR vs MR, MR vs HR, SR vs HR, MR vs MR relapsed) and diagnoses vs relapses, we did not find any statistically significant data. Conversely, we found a statistically significant higher expression of FosB and Annexin II in the group of children with WBC &gt;50.000/ml (p value &lt;0,05); and of Zap70 (Y319)/Syk (Y352) in the subgroup of MR cases who did not suffer from relapse (p value &lt;0,05). Our study showed that in the apoptotic pathway, we detected a higher expression of all the pro-apoptotic proteins [Bax, SMAC/DIABLO, Caspase 7 total and cleaved (D198)], a low expression of anti-apoptotic proteins (Bcl-xL, XIAP) associated with a reduction or a lack of PARP total or cleaved (D214). We also found that a specific pattern of expression (higher PTEN (S380), PARP cleaved, Caspase 7 cleaved, PDK (S241), PKAc (T197), p90RSK (S380), MEK ½ (S217–221), IKBA (S32), GRB2; lower Beta Catenine) selected a subgroup of children (n°9) with a better survival when compared with other cases (p value &lt;0,05). Conclusions. Our preliminary data showed that RPPA in association with Western blot analysis, is a reliable strategy for the identification of biomarkers and/or molecules for targeted therapy. Application of this methodology on specific subgroups of children with ALL will allow us to identify new therapeutic strategies.

scholarly journals POS0928 NETAKIMAB EFFICACY IN ANTI-TNF-NAIVE AND ANTI-TNF-EXPERIENCED PATIENTS WITH ACTIVE ANKYLOSING SPONDYLITIS: RESULTS OF SUBANALYSIS OF PHASE 3 ASTERA TRIAL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 726.2-727
Author(s):  
S. Erdes ◽  
V. Mazurov ◽  
T. Dubinina ◽  
I. Gaydukova ◽  
A. Kundzer ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Phase Iii ◽  
P Value ◽  
Interleukin 17 ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
Asas Criteria

Background:According to previous studies, the effectiveness of interleukin-17 (IL-17) inhibitors was higher in anti-TNF-naïve patients with ankylosing spondylitis (AS) [1,2]. Netakimab (NTK) is a humanized anti-IL-17A antibody approved for the treatment of AS, psoriatic arthritis, moderate-to-severe plaque psoriasis in Russia and Belarus.Objectives:To compare the efficacy of NTK in anti-TNF-naïve patients with anti-TNF-experienced patients with active AS at week 16 of therapy.Methods:ASTERA (NCT03447704) is an ongoing phase 3 placebo (PBO)-controlled clinical study, aimed at evaluating NTK efficacy in AS [3]. 228 adult patients with active AS (BASDAI ≥ 4) were randomly assigned (1:1) to receive 120 mg NTK or PBO subcutaneously at week 0,1,2 and then q2w. This analysis includes 112 patients in NTK group. Efficacy endpoints included ASAS20/40, ASAS5/6 and ASAS partial remission (PR) at week 16 of therapy.Results:28 (25.0%) of 112 patients in NTK group had previous inadequate response/intolerance to anti-TNF (anti-TNF-IR): 24 (21.4%) – one anti-TNF, and 4 (3.6%) – two anti-TNF. 84 (75.0%) patients were TNF-naive. Achievement of ASAS criteria response at week 16 was similar in both groups (Table 1).Table 1.Efficacy of NTK at week 16ParameterTNF-naïve (n = 84)anti-TNF-IR (n = 28)p-value*ASAS20, n (%)52 (61.9%)17 (60.7%)0.91ASAS40, n (%)35 (41.7%)11 (39.3%)0.82ASAS5/6, n (%)39 (46.4%)11 (39.3%)0.51ASAS(PR), n (%)15 (17.9%) 4 (14.3%)0.78*- Fisher’s exact testConclusion:NTK 120 mg provided sustained improvements in signs and symptoms of AS in anti-TNF-naive and anti-TNF-IR patients at 16 weeks of therapy.References:[1]Blair HA, Dhillon S. Secukinumab: A Review in Ankylosing Spondylitis. Drugs. 2016;76(10):1023-30.[2]Dougados M, et al. Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020;79(2):176-185.[3]Mazurov VI, et al. Efficacy and safety of Netakimab, anti-IL-17A monoclonal antibody, in patients with ankylosing spondylitis. Results of phase III international, multicenter, randomized double-blind clinical trial BCD-085-5/ASTERA. Nauchno-Practicheskaya Revmatologia=Rheumatology Science and Practice. 2020;58 (4):376–386 (In Russ).Acknowledgements:This study was sponsored by JSC BIOCAD.Disclosure of Interests:Shandor Erdes: None declared, V Mazurov: None declared, Tatiana Dubinina: None declared, Inna Gaydukova Speakers bureau: Abbvie, Biocad, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, Alena Kundzer: None declared, Nikolaj Soroka: None declared, Anna Eremeeva Employee of: Biocad

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions

2021 ◽  
pp. 106002802098841
Author(s):  
Zachery Halford ◽  
Carli Coalter ◽  
Vanessa Gresham ◽  
Tabitha Brown
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Bispecific T Cell Engager

Objective: To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL). Data Sources: We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion. Data Synthesis: Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively. Relevance to Patient Care and Clinical Practice: Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens. Conclusions: Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

CASPAR (Alliance A031902): A randomized, phase III trial of enzalutamide (ENZ) with rucaparib (RUCA)/placebo (PBO) as a novel therapy in first-line metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS181-TPS181
Author(s):  
Arpit Rao ◽  
Charles J. Ryan ◽  
David James VanderWeele ◽  
Glenn Heller ◽  
Lionel D Lewis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Synthetic Lethality ◽  
Short Form ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Dna Breaks ◽  
Phase 3 ◽  
Logrank Test

TPS181 Background: Treatment with novel antiandrogens (NAA) and androgen deprivation therapy prolongs life in men with mCRPC but approximately 40% patients (pts) have radiographic progression within the first year. Inhibition of androgen receptor signaling results in increased double-strand DNA breaks and genomic instability. NAA+PARP inhibitor (PARPi) combinations have shown induction of synthetic lethality by this mechanism in multiple preclinical studies. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy and an NAA+PARPi combination has shown improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with NAA alone. Methods: CASPAR (A031902) is a randomized phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. A PK substudy will precede the phase 3 portion and enroll 6-18 pts to various doses of ENZ plus RUCA to establish safety and evaluate any clinically-significant drug-drug interactions (S-DDI). Treatment will be continued until disease progression and cross-over is not allowed. Co-primary endpoints are rPFS and overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 mutations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the concordance between tissue and plasma ctDNA-based HRR testing. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). CASPAR is available for participation to all US-NCTN sites starting in October 2020 with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882; acknowledgments.alliancefound.org. Clinical trial information: NCT04455750.

scholarly journals Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Haematologica ◽  
2020 ◽  
Vol 106 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Glen Lew ◽  
Yichen Chen ◽  
Xiaomin Lu ◽  
Susan R. Rheingold ◽  
James A. Whitlock ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Central Nervous System Relapse ◽  
Oncology Group

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children’s Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% +/- 3.0% and 72.3% +/- 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 +/- 4.0% and 93.8 +/- 2.7% for patients with MRD <0.1%, vs. 53.7 +/- 7.8% and 60.6 +/- 7.8% for patients with MRD ≥0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 +/- 6.2% vs. 66.9 +/- 4.5%, p=0.03) but not OS (81.5 +/- 5.8% for HCT vs. 85.8 +/- 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% +/- 9.2% and 51.7% +/- 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

Line Treatment of Adult Ph+ Acute Lymphoblastic Leukemia (ALL) Patients. Final Results of the GIMEMA LAL1205 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 305-305 ◽  
Author(s):  
Robert Foà ◽  
Antonella Vitale ◽  
Anna Guarini ◽  
Maria Sefania De Propris ◽  
Loredana Elia ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Induction Treatment ◽  
Induction Phase ◽  
Significant Prognostic Factor ◽  
Rt Pcr ◽  
Active Inhibitor

Abstract Background: Dasatinib is a potent, oral inhibitor of the BCR-ABL, c-KIT and SRC kinase family, which has proven to be a more active inhibitor of BCR-ABL and c-KIT than imatinib in preclinical studies. Clinically, it has been shown to be effective in chronic myeloid leukemia and in Ph+ ALL patients resistant or intolerant to imatinib. Aims: The primary objective of the study was to assess the activity of dasatinib in de novo adult Ph+ ALL patients in terms of complete hematological remission (CHR); the secondary objectives were treatment toxicity, rate of immunophenotypic and molecular responses, disease-free survival (DFS), relapse rate and overall survival (OS). Methods: The GIMEMA LAL 1205 protocol was designed for patients ≥18 years (no upper age limit) who receive dasatinib po, 70 mg BID. A steroid pre-phase is started 7 days prior to dasatinib administration and continued up to day 31, and then tapered. The pre-phase allows identification of the BCR/ABL transcript. Dasatinib is given for 12 weeks. Two intrathecal methotrexates are administered at days +22 and +43. All cases are analyzed through a central handling of samples at presentation for morphology, immunophenotype, cytogenetics and molecular biology at the coordinating center in Rome. Minimal residual disease (MRD) is also centrally investigated by flow-cytometry and Q-RT-PCR at days +22, +43, +57 and +84. The protocol was designed for 48 patients. Results: Recruitment started in November 2006 and was completed in August 2008. The median age of the 48 enrolled BCR/ABL+ ALL patients was 54 years (range 24-76), 26 were females and 22 males. The median WBC count was 20.1 (range 2.2–133). The last analysis has been conducted on 36 patients. One patient stopped treatment after 14 days due to intestinal toxicity and 1 patient refused treatment. Thus, to date 34 patients are evaluable for response. Nineteen cases were p190+ and 15 p210+ (5 were p190/p210+). A &gt;75% response to the steroid pre-phase was recorded in 82.7% of patients. All 34 patients (100%) have witnessed a CHR: 32 (94.12%) at the 1st determination at day +22, 1 at the 2nd at day +43 and 1 at the 3rd at day +57. No fatalities have been observed. In 13 patients, at least 1 severe adverse event (SAE) has been recorded, for a total of 26 SAEs. Overall, the compliance has been good; only 1 patient stopped treatment at day 67 due to toxicity while in CHR. The median follow-up is so far 11.2 months. The OS at 10 months is 80.7%. Immunophenotypic and BCR/ABL Q-RT-PCR monitoring of MRD has shown a very marked clearance of leukemic cells by day +22, progressively strengthened at the subsequent timepoints. In p190+ cases the minimal MRD value was reached at day +43, while in p210+ cases this was observed at day +84, documenting a lower susceptibility to dasatinib by this molecular subgroup. So far, 9 patients have relapsed, at a median of 72 days from the end of induction; in agreement with the MRD data, 7/9 relapses occurred within the p210+ cases and 2/9 within the p190+ cases. The presence of mutations has been investigated in 8/9 relapsed samples: 5 showed a T315I mutation, 1 an E255K mutation and 2 were wt. Cloning experiments allowed to detect in 2 cases low levels of T315I mutations already at presentation and on MRD cells at the end of the induction treatment. The first multivariate analysis has been conducted for DFS and the degree of PCR reduction − ≤10−3 vs ≥10−3 - has so far emerged as the only significant prognostic factor. Conclusions: This study demonstrates that in adult Ph+ ALL dasatinib monotherapy is capable of inducing a CHR in virtually all patients, irrespective of age, without important toxicities and with no fatalities. The hematological response is associated with a very marked and rapid debulking of the neoplastic clone documented at the MRD level, particularly for p190+ cases. The degree of PCR response is of prognostic relevance. No relapses have been observed during the induction phase. The optimal post-induction treatment strategy, which was not part of the study, remains to be defined, particularly in light of the genetic instability of Ph+ ALL and of the selection/induction of mutations. These results, together with those previously reported by our group with imatinib alone for elderly patients, question the use of chemotherapy, with or without a TK inhibitor, for the remission induction of Ph+ ALL.

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

Predictive Value of Minimal Residual Disease: Analysis By Flow-Cytometry in Children with Relapsed Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2494-2494
Author(s):  
Myriam Ruth Guitter ◽  
Jorge Gabriel Rossi ◽  
Elisa Sajaroff ◽  
Carolina Carrara ◽  
Pizzi Silvia ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Time Points ◽  
Group 3 ◽  
Group 2 ◽  
To Receive ◽  
Group 1

Abstract Introduction: Despite the advances observed in the outcome of pediatric acute lymphoblastic leukemia (ALL) treatment during the last 20 years, relapse remains the most common cause of treatment failure in childhood ALL. Several factors have been associated to the prognosis of these patients; however, minimal residual disease (MRD) emerges as a relevant predictor of outcome. Objectives: The aims of this study were to assess MRD by flow-cytometry in relapsed ALL and to evaluate its prognostic impact as a predictor factor of outcome at the end of the induction therapy and prior to hematopoietic stem cell transplantation (HSCT). Patients and Methods: From Aug'10 to Jun'15, 123 ALL patients were treated at our center. MRD determination at least at two time-points during relapse treatment was a requirement for considering a patient eligible for the present study. Sixty-six cases were excluded due to the following causes: 10 patients died during induction, 2 died early in complete remission (CR), 29 did not respond to chemotherapy, in 13 patients MRD determination was not performed: 4 did not have clinical data available, 4 patients were Down Syndrome and 4 children received treatment for relapse in other centers. Thus, fifty-seven patients achieved CR and were evaluated for MRD at two time points. Of them, 56 patients belonged to S4 and S3 and 1 patient to S1 group as defined by the Berlin-Frankfurt-Münster stratification for relapsed ALL. MRD was analyzed by multiparametric flow-cytometry following ALL-IC 2009 guidelines. Negative MRD was defined as disclosing less than 0.1% of blasts. For this analysis, patients were stratified based on MRD levels at two different time points: after end of induction, before HSCT or at any other time point during the follow-up for patients who did not undergo HSCT. Three groups were defined: Group-1: negative at both time points (n= 23), Group-2: positive at 1 time point (n= 13) and Group-3: positive at both time points (n= 21). Patients who relapsed before receiving HSCT were considered Group-3. Twenty-five patients underwent HSCT: 13 of them from Group-1, 9 from Group-2 (2 had positive MRD previous to receive HSCT) and 3 patients from Group-3. HSCT was performed with matched familiar donor in 16 cases and matched unrelated donor in 9 cases. Results: The distribution of events according to receiving or not HSCT was: 5 died due to transplant related mortality (TRM), 9 relapsed after receiving HSCT and 16 during treatment with chemotherapy. With a median follow-up of 16 (range: 6-67) months, overall 3-year EFS probability (EFSp) (SE) was 32 (8)%. The 3-year EFSp was 75 (11)% for Group-1, 24 (14)% for Group-2 and 0% for Group-3 (p-value <0.00001). Comparing patients who did not receive HSCT vs. patients who did, EFSp (SE) was 32 (12)% and 29 (11)% respectively (p-value: non-significant). The EFSp (SE) according to MRD groups in patients who underwent HSCT was: Group-1: 53 (19)%, Group-2: 14 (13)% and 0% for Group-3 (p-value: 0.06). Conclusions: MRD quantification by flow-cytometry demonstrated to be a significant prognostic factor for relapsed ALL. Both, TRM and death in CR rates, were high and should be decreased by improving supportive measures. MRD determination by flow-cytometry in patients who underwent HSCT showed a trend to achieve a better EFSp, thus representing a relevant tool for stratifying relapsed ALL patients in order to achieve a better selection of patients to receive HSCT. Disclosures No relevant conflicts of interest to declare.

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