scholarly journals Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2754-2754
Author(s):  
Morie A Gertz ◽  
Radhika Tripuraneni ◽  
Gene G. Kinney
Keyword(s):  
Stock Options ◽  
Cardiac Involvement ◽  
Stage Iv ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
6Mwt Distance ◽  
Stage Iv Disease ◽  
Secondary Endpoints ◽  
Post Hoc

Abstract Background: Light chain (AL) amyloidosis is a rare, progressive, and typically fatal hematologic disorder caused by plasma cells that produce misfolded AL protein, resulting in deposits of amyloid in tissues and organs that cause organ dysfunction and failure. Birtamimab is an investigational monoclonal antibody designed to neutralize circulating soluble amyloid and deposited insoluble amyloid, thus promoting the phagocytic clearance of amyloid deposits. In 2018, the global phase 3 VITAL study in newly diagnosed, treatment-naïve patients was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835, 95% CI 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR=0.413, 95% CI 0.191, 0.895; p=0.025; Figure) in a subgroup of patients at high risk for early mortality (Mayo stage IV). At 9 months, the proportions of surviving patients were 74% and 49% in the birtamimab + SOC and placebo + SOC groups, respectively. Post hoc analyses of secondary endpoints in this subgroup also supported clinical and functional benefits of birtamimab + SOC, with clinically meaningful improvements observed in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance (both nominal p<0.05) at 9 months. Across all birtamimab clinical trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Aims: To evaluate the efficacy and safety of birtamimab + SOC versus placebo + SOC in Mayo stage IV patients with AL amyloidosis by assessing time to ACM over 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will receive either 24 mg/kg intravenous birtamimab or placebo every 28 days (both arms will also receive SOC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Patients will be randomly assigned 2:1 to birtamimab or placebo and will be stratified at randomization based on their 6MWT distance (<300 meters vs ≥300 meters). The primary efficacy endpoint of AFFIRM-AL is time to ACM using a log-rank test. Secondary endpoints are change from baseline to month 9 in SF-36v2 and 6MWT distance. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. An interim efficacy analysis is planned when ~50% of the events have occurred. Results: Given the >50% relative risk reduction for ACM observed in the post hoc analysis of VITAL for the AL amyloidosis subpopulation of patients with Mayo stage IV disease, the phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. Conclusion/Summary: Effective treatments to improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo stage IV disease is approximately 6-9 months. Birtamimab is the only investigational therapeutic in which a survival benefit has been observed, in a post hoc subgroup analysis of VITAL in patients with AL amyloidosis with advanced cardiac involvement. AFFIRM-AL is expected to initiate in mid-2021. (NCT04973137) Figure 1 Figure 1. Disclosures Gertz: Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis/Akcea, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice: Other: personal fees; Spectrum: Other: personal fees, Research Funding; AbbVie: Other: personal fees for Data Safety Monitoring board; Teva, Johnson and Johnson, Medscape, DAVA oncology: Other: speaker fees; Pharmacyclics, Proclara: Other: Advisory Board; i3Health: Other: development of educational materials; Springer Publishing: Patents & Royalties. Tripuraneni: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001). Kinney: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001).

Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1867-1867 ◽  
Author(s):  
Veerpal Singh ◽  
Ayman Saad ◽  
Jeanne Palmer ◽  
Jasleen K Randhawa ◽  
Parameswaran N. Hari
Keyword(s):  
Light Chain ◽  
Liver Dysfunction ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Initial Therapy ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Organ Response

Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

Weekly Combination Chemotherapy with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for Newly Diagnosed Patients with Advanced Cardiac Disease Due to Systemic AL Amyloidosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5139-5139
Author(s):  
Furha I. Cossor ◽  
Adam Boruchov ◽  
Michael Danso ◽  
Michael Edward Lee ◽  
Ayan Patel ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Single Agent ◽  
Left Ventricular ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Hematologic Response

Abstract Abstract 5139 The treatment of systemic AL amyloidosis (AL) with advanced cardiac involvement (cardiac biomarker stage III) at diagnosis remains challenging and unsatisfactory. Median survival with melphalan and dexamethasone (MDex) in stage III patients is about 10 months from diagnosis with one quarter of patients dying within 3 months of starting therapy (BJH 2008;143:369; Blood 2010;116:522). Bortezomib has been shown to be the most active single agent in the treatment of AL (Blood 2011;118:865) and, when incorporated into CyBorD, clinical studies have shown a > 90% hematologic response rate in both myeloma and in AL (Blood 2010;115:3416; Leukemia 2009;23:1337; Amyloid 2010;17(S1):171a). In addition, bortezomib has been shown to have limited cardiac toxicity and no arrhythmogenicity in patients with AL and cardiac involvement (QJM 2011 published online July 13, 2011). Based on these data we have used CyBorD as initial standard therapy in patients with newly diagnosed systemic AL amyloidosis with advanced (stage III) cardiac involvement who are ineligible for stem cell transplant or clinical trials. We now retrospectively report the outcomes in the 11 consecutive stage III patients who have been treated thus far with CyBorD as initial standard therapy (6F, 5M). Patients were a median of 57 years old (range, 44–74) with median brain natriuretic peptide (BNP) of 709 (145–1490), troponin I of 0.29 (0.11–0.77), involved free light chains of 322mg/L (101–4325) and marrow plasma cells of 20% (4–41%). Median left ventricular (LV) ejection fraction and LV wall thickness (average of IVSd+LVPWd) by echocardiogram were 52% (35–70%) and 1.7cm (1.2–2.1) respectively. Patients received CyBorD on a 35-day cycle on days 1, 8, 15 and 22 with cyclophosphamide (300mg/m2) and dexamethasone (20 or 40mg flat dose) given orally or IV and bortezomib (1.3mg/m2) given IV or subcutaneously. Routine prophylactics included acyclovir, fluconazole and omeprazole. Patients have received a median of 4 cycles (1–8). Of the 11 patients, 2 died suddenly at 1 and 5 months, and 9 are alive with a median follow up of 8 months (3–15). Three patients experienced worsening congestive heart failure requiring hospitalization, medication adjustments and in 1 case pericardiocentesis. The gastrointestinal (GI) side-effects of bloating and constipation were common and usually manageable although 1 patient stopped therapy after 2 cycles because of lower GI bleeding. Of 10 patients evaluable for hematologic response, 8 responded (1 CR, 4 VGPR, 3 PR) (response criteria from Blood 2010;116:586a) and 2 had no response. Median time to response was 1 cycle (1–3). Thus far, there have been 4 patients (2 VGPR, 2 PR) who within months of starting therapy have had BNP reductions of 40% to 76% of baseline (median BNP reduction of 434pg/ml (282–712)). In conclusion, these retrospective data are encouraging and hopefully will spur the development of phase II and III trials in newly diagnosed patients with advanced cardiac involvement due to AL. Disclosures: Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant.

scholarly journals Phase II Trial of Cyclophosphamide, Lenalidomide and Dexamethasone (CYCLO-LEN-DEX) for Previously Untreated Patients with Light-Chain Amyloidosis (AL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2135-2135
Author(s):  
Joan Blade ◽  
Albert Oriol ◽  
Juan José Lahuerta ◽  
Maria-Victoria Mateos ◽  
Javier de la Rubia ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Cardiac Involvement ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Organ Response ◽  
New Treatment ◽  
Good Partial Response

Abstract Background: Treatment with oral melphalan and dexamethasone has been adopted as the standard of care for newly diagnosed patients with immunoglobulin light chain (AL) amyloidosis not eligible for high-dose melphalan and stem cell transplantation (HDM/SCT). However, new treatment options are still needed for this patient population. Aim: Based on the activity of IMiDs® immunomodulatory drugs in relapsed/refractory AL amyloidosis, we designed a multicenter prospective, phase II trial with lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients not eligible for autologous transplant. Patients and methods: The main inclusion criteria were newly diagnosed AL amyloidosis confirmed by biopsy, significant organ involvement, cardiac ejection fraction over 50%, serum creatinine below 3 mg/dL, and not being eligible for autologous transplant. Treatment schedule consisted of 6 cycles of lenalidomide at 15 mg orally (po) on days 1 to 21, dexamethasone at 20 mg po on days 1 to 4 and 9 to 12, and cyclophosphamide at 300 mg/m2 intravenously (iv) on days 1 and 8 every 28 days, followed by 6 more cycles of lenalidomide at the same dose, dexamethasone at 20 mg po on days 1 to 4 and cyclophosphamide 300 mg/m2 iv on day 1. After these 12 cycles, maintenance with lenalidomide (10 mg po on days 1 to 21) and dexamethasone (20 mg po on days 1 to 4) was planned for three additional years or until discontinuation due to intolerance or disease progression. All patients received prophylaxis of thromboembolic events with oral aspirin (100 mg po daily) or subcutaneous low-molecular-weight heparin. The primary endpoint was hematologic response. Diagnosis of AL amyloidosis, definition of organ involvement and response criteria followed the Consensus Opinion from the Xth International Symposium on Amyloid and Amyloidosis (Gertz et al, Am J Hematol 2005), adding the very good partial response category included in the recently reported criteria (Palladini et al, J Clin Oncol 2012). Assessments of response were performed at the beginning of each cycle during the treatment period and every 3 months during the maintenance phase. Results: From September 2010 to December 2012, 28 patients were enrolled in the study. Twenty-three patients had cardiac involvement, with cardiac stage 3 in 14 of them. The overall hematologic response rate was 46%, including 7 patients (25%) with complete response, 5 patients (18%) with very good partial response and 1 patient (3%) with partial response. The organ response rate was 46% and was only observed among patients who achieved hematologic response. The organ response was reached in 10 (43%) of the 23 patients with renal involvement and 6 (26%) of the 23 patients with cardiac involvement. In 4 patients lenalidomide was reduced or discontinued due to toxicity. A therapy-related serious adverse event was reported in 6 patients. No significant cytopenias and no second primary malignancies (SPM) were observed. So far, 11 patients remain on the study. Seventeen (60%) have been discontinued mostly due to death secondary to cardiac or renal AL-related late events (8 patients), progression or lack of response (4), and toxicity (3). After a median follow up of 24 months, the median PFS and OS have not been reached, being significantly longer in responders. The estimated probability of PFS and OS for responders was 92% at 34 months. In contrast, the median PFS and OS for non-responders were only 1.9 and 2.4 months, respectively. Finally, according to Mayo Clinic risk stratification based on cardiac biomarkers, median OS for patients with stage I-II has not been reached (the 2-year estimate was 100%), and was 2.2 months for stage III (p <0.001; Figure 1). Conclusions: Our results support the efficacy and safety of the combination lenalidomide, dexamethasone and cyclophosphamide as a new treatment option for patients with AL amyloidosis not eligible for ASCT, without the risk of neuropathy associated with bortezomib-based therapies. However, this regimen should be preferably used when the organ function is still preserved since patients with advanced stage disease, particularly those with severe cardiac involvement, are unlikely to benefit. Figure 1. Figure 1. Disclosures Blade: Janssen, Celgene and Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide. First-line therapy in combination for AL amyloidosis.. Oriol:Janssen and Celgene: Honoraria. Lahuerta:Celgene: Honoraria; Janssen: Honoraria. Mateos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Janssen and Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fernandez de Larrea:Janssen and Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. San Miguel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cibeira:Janssen and Celgene: Honoraria.

Outcomes with CPX-351 versus 7+3 by baseline bone marrow (BM) blast percentage in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (sAML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7042-7042
Author(s):  
Ellen K. Ritchie ◽  
Tara L. Lin ◽  
Laura F. Newell ◽  
Robert K. Stuart ◽  
Scott R. Solomon ◽  
...  
Keyword(s):  
Older Adults ◽  
High Risk ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Secondary Acute Myeloid Leukemia ◽  
Improved Outcomes ◽  
The Us ◽  
Remission Rates ◽  
Grade 3 ◽  
Post Hoc

7042 Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved as Vyxeos in the US and EU for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved OS and remission rates vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML. This post hoc analysis of phase 3 data assessed outcomes by baseline BM blast percentage. Methods: Pts diagnosed with AML per 2008 WHO criteria (≥20% blasts in peripheral blood or BM) were randomized 1:1 to receive ≤2 inductions of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive ≤2 consolidations. Results: CPX-351 had longer median OS and higher remission rates vs 7+3 irrespective of baseline BM blast percentage; median OS was worse in higher blast groups for both treatments (Table). The incidence of grade ≥3 TEAEs was >80% for both arms; febrile neutropenia was the most common. Conclusions: Improved outcomes were observed with CPX-351 vs 7+3 irrespective of baseline BM blast percentage in older adults with newly diagnosed high-risk/sAML. Clinical trial information: NCT01696084. [Table: see text]

Maintained Hematologic and Organ Responses at Two Years Following Stem Cell Transplant In Systemic Light-Chain Amyloidosis (AL) Using Short-Course Bortezomib and Dexamethasone Consolidation Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2391-2391 ◽  
Author(s):  
Heather Landau ◽  
Hani Hassoun ◽  
Michael A. Rosenzweig ◽  
Christina Bello ◽  
Elizabeth Hoover ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Cell Disease ◽  
Advisory Committees ◽  
Hematologic Response

Abstract Abstract 2391 Background: We report two-year follow up results from a phase II trial in which we use bortezomib and dexamethasone (BD) as consolidation following risk-adapted SCT for patients with AL (Blood 2009;114:533a). Methods: Patients with newly diagnosed AL involving <=2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Responses were assessed at 2–3 mos, 12 mos and 24 mos post-SCT. Patients with persistent clonal plasma cell disease at 2–3 mos post-SCT received consolidation with BD for up to 6 cycles (two 21-day, four 35-day cycles). Organ responses and overall survival (OS) were assessed at 12 and 24 mos post-SCT. Results: Thirty-seven patients were enrolled with kidney (68%), heart (43%), liver/GI (14%) and peripheral nervous system (16%) involvement. Forty-one percent had two organ-involvement. Three patients were removed from study prior to SCT due to ineligibility (N=2) or co-morbid illness (N=1); 1 patient is within 100 days of SCT. Four patients with advanced cardiac disease died within 100 days of SCT, resulting in a TRM of 12% (4/33). With a median follow-up of 29 mos, the OS at 12 mos post-SCT was 86%. At 12 and 24 mos, OS in patients with cardiac involvement was 69% and 49% respectively, versus 100% at both timepoints in those without (P = 0.001). Elevations of brain natruretic peptide (BNP) and troponin-I were significantly associated with worse OS, HR 1.2 (95% CI 1.1–1.4; P = 0.001) and HR 4.2 (95% CI 1.8–9.2; P = 0.001), respectively. Post-SCT, the hematologic response rate was 55% with 24% sCR. Sixty-eight percent (19/28) received consolidation with BD for persistent clonal plasma cell disease. At 12 mos post-SCT, the hematologic response rate in evaluable patients was 95% (20/21) with 62% achieving sCR and 60% having organ improvement. At 24 mos post-SCT, the overall response rate was 82% (14/17) including 53% who maintained a sCR and 88% (15/17) who had organ improvement. Interestingly, 92% (11/12) of patients with kidney involvement had organ responses at 24 mos versus 50% (7/14) at 12 mos. Overall, 87% of patients who received BD improved their hematologic response and all patients responded after 1 cycle. There was no correlation between the number of cycles received (median 6; range 1.25–6) and response. Of the 19 patients who received post-SCT BD, 79% experienced grade III-IV toxicity, which was most often hematologic toxicity with thrombocytopenia in 41%. Grade 2 or greater peripheral neuropathy was seen in 32%. Conclusions: In newly diagnosed patients with systemic AL amyloidosis, consolidation with BD following risk-adapted SCT is safe and effective for eradicating persistent clonal plasma cell disease. Hematologic responses are rapid resulting in high overall and unprecedented sCR rates. Organ function improves in the majority of patients and continues to occur over time. Cardiac involvement is associated with inferior survival and cardiac biomarkers are useful for assigning risk. Relapses are seen following completion of therapy, suggesting that a maintenance regimen following post-SCT consolidation may be worthy of further study. Disclosures: Landau: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The presentation will discuss bortezomib for consolidation in AL amyloidosis. Comenzo: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Gastrectomy for stage IV gastric cancer: a comparison of different treatment strategies from the SEER database

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacopo Desiderio ◽  
Andrea Sagnotta ◽  
Irene Terrenato ◽  
Bruno Annibale ◽  
Stefano Trastulli ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Strategies ◽  
Stage Iv ◽  
Multimodality Treatment ◽  
Timing Of Surgery ◽  
Seer Database ◽  
Newly Diagnosed ◽  
The West ◽  
Stage Iv Gastric Cancer ◽  
Stage Iv Disease

AbstractIn the West, more than one third of newly diagnosed subjects show metastatic disease in gastric cancer (mGC) with few care options available. Gastrectomy has recently become a subject of debate, with some evidence showing advantages in survival beyond the sole purpose of treatment tumor-related complications. We investigated the survival benefit of different strategies in mGC patients, focusing on the role and timing of gastrectomy. Data were extracted from the SEER database. Groups were determined according to whether patients received gastrectomy, chemotherapy, supportive care. Patients receiving a multimodality treatment were further divided according to timing of surgery, whether performed before (primary gastrectomy, PG) or after chemotherapy (secondary gastrectomy, SG). 16,596 patients were included. Median OS was significantly higher (p < 0.001) in the SG (15 months) than in the PG (13 months), gastrectomy alone (6 months), and chemotherapy (7 months) groups. In the multivariate analysis, SG showed better OS (HR = 0.22, 95%CI = 0.18–0.26, p < 0.001) than PG (HR = 0.25, 95%CI = 0.23–0.28, p < 0.001), gastrectomy (HR = 0.40, 95%CI = 0.36–0.44, p < 0.001), and chemotherapy (HR = 0.42, 95%CI = 0.4–0.44, p < 0.001). The survival benefits persisted even after the PSM analysis. This study shows survival advantages of gastrectomy as multimodality strategy after chemotherapy. In selected patients, SG can be proposed to improve the management of stage IV disease.

scholarly journals Subcutaneous Daratumumab (DARA SC) + Bortezomib, Cyclophosphamide, and Dexamethasone (VCd) in Asian Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: Subgroup Analysis from the Phase 3 Andromeda Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Kenshi Suzuki ◽  
Ashutosh D. Wechalekar ◽  
Kihyun Kim ◽  
Chihiro Shimazaki ◽  
Jin Seok Kim ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Research Funding ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Publicly Traded ◽  
Duration Of Treatment ◽  
Phase 3 ◽  
Asian Patients ◽  
Kidney Involvement ◽  
Major Organ

Introduction: Systemic AL amyloidosis is a rare disorder of clonal CD38+ plasma cells characterized by deposition of insoluble amyloid fibrils leading to tissue damage and organ dysfunction. Currently, there are no health authority-approved treatments for AL amyloidosis, and standard of care (SoC) includes therapies developed for multiple myeloma (MM). DARA is a human CD38-targeting antibody for MM. Combining DARA with VCd improved outcomes for AL amyloidosis versus VCd alone in the phase 3 ANDROMEDA study. Here, we report a subgroup analysis of Asian patients (China, Japan, and Korea) from ANDROMEDA. Methods: Eligible patients had newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and no symptomatic MM. Patients were randomized 1:1 to receive DARA SC plus VCd (D-VCd) or VCd. All patients received bortezomib (1.3 mg/m2 SC QW), cyclophosphamide (300 mg/m2 PO or IV QW), and dexamethasone (40 mg PO or IV QW) for six 28-day cycles with or without DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) by injection QW in Cycles 1-2, Q2W in Cycles 3-6; after Cycle 6, patients continued DARA monotherapy as maintenance for up to 24 cycles (28-day cycles). Disease status was evaluated Q4W in Cycles 1-6 and Q8W after Cycle 7 until hematologic progression or major organ deterioration. The primary endpoint was overall hematologic complete response (CR) rate; key secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), survival, and safety. MOD-PFS was defined as the time from randomization to any of the following events (whichever occurred first): death, clinical manifestation of cardiac or renal failure, or hematologic progression. Results: Among 388 randomized patients (D-VCd, n=195; VCd, n=193), 60 were Asian (D-VCd, n=29; VCd, n=31). Baseline characteristics were well balanced between arms and consistent with the intent-to-treat population. The median age was 66 years, 70% and 58% had heart and kidney involvement, respectively, and 60% had ≥2 organs involved. Cardiac stage I, II and IIIA/B were 28%, 28%, and 43%, respectively. The median duration of treatment was 9.2 mo for D-VCd and 5.3 mo for VCd. Median follow-up was 9.4 mo. The overall hematologic CR rate was 59% for D-VCd and 10% for VCd (odds ratio, 13.2; 95% CI, 3.3-53.7; P&lt;0.0001). D-VCd vs VCd achieved higher rates of very good partial response or better (≥VGPR; 93% vs 61%). MOD-PFS favored D-VCd-treated patients (HR 0.21; 95% CI, 0.06-0.75, P=0.0079). A total of 12 deaths occurred (D-VCd, n=3; VCd, n=9). The most common (≥10%) grade 3/4 TEAEs were lymphopenia (D-VCd 35%/VCd 32%), neutropenia (10%/3%), diarrhea (10%/7%), pneumonia (7%/10%), cardiac failure (7%/10%), hypokalemia (7%/10%), anemia (3%/10%), thrombocytopenia (3%/10%), hypoalbuminemia (3%/10%), and syncope (3%/10%). TEAEs leading to treatment discontinuation occurred in 1 patient in each treatment arm. Conclusion: The addition of DARA SC to VCd was superior to VCd alone in Asian patients, resulting in deeper hematologic responses and improved clinical outcomes, including MOD-PFS, with a safety profile consistent with the overall study population. These data support the use of D-VCd in Asian patients with newly diagnosed AL amyloidosis. Disclosures Suzuki: Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Zhou:Peking University First Hospital: Current Employment. Iida:Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Janssen: Honoraria, Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Caleum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. OffLabel Disclosure: To evaluate the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with AL amyloidosis.

EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2004-2004
Author(s):  
Patrick Roth ◽  
Thierry Gorlia ◽  
Jaap C. Reijneveld ◽  
Filip Yves Francine Leon De Vos ◽  
Ahmed Idbaih ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Standard Treatment ◽  
Early Stage ◽  
Karnofsky Performance Status ◽  
Methylation Status ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Newly Diagnosed Glioblastoma ◽  
Secondary Endpoints

2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.

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