Subcutaneous alemtuzumab in patients with refractory/relapsed B-CLL after a fludarabine-based regimen

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6600-6600
Author(s):  
R. Bezares ◽  
G. Stemmelin ◽  
D. Argentieri ◽  
E. Lanari ◽  
E. Guy-Garay ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Duration Of Treatment ◽  
Barr Virus ◽  
Epstein Barr ◽  
Grade 3 ◽  
Cmv Disease

6600 Background: Alemtuzumab is the only immunotherapy that is effective as a single agent in patients with B-CLL who are refractory to, or who have relapsed after, fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. We report the first interim analysis of a new, less intensive schedule of alemtuzumab SC to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg bid during the second and third weeks, and 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg tid. Results: Patients (N = 36) with refractory (19%) or relapsed (81%) B-CLL had a median age of 67 years (range, 43–86 years), 28 were male, 61%/39% had Binet stage B/C disease, and 2 had B-cell prolymphocytic transformation. The median number of prior therapies was 1 (range, 1–4). The median duration of treatment was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 412 mg (range, 150–1,080 mg). Thirty-two patients were evaluable for response. The overall response rate of 93%: complete response (CR), 34%; unconfirmed CR, 6%; partial response (PR), 53%. Two patients (7%) did not respond to therapy. Of the 7 refractory patients, 5 had a PR, 1 did not respond, and 1 was not yet evaluable. Median overall survival was 10 months, which correlated with response and pretreatment status. Minimal residual disease (MRD) was measured by flow cytometry in 5 patients who achieved a CR: 3 patients had <0.5% of CD5/CD19/CD23+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, 5 patients experienced grade 3/4 infection; 2 patients had grade 3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusions: Results of this interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy. No significant financial relationships to disclose.

Subcutaneous Alemtuzumab in Patients with Refractory/Relapsed B-Cell CLL after a Fludarabine-Based Regimen. An Interim Analysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2843-2843
Author(s):  
R. Fernando Bezares ◽  
German Stemmelin ◽  
Daniel Argentieri ◽  
Emilio Lanari ◽  
Efrain Guy-Garay ◽  
...  
Keyword(s):  
B Cell ◽  
Interim Analysis ◽  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Prior Therapy ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background: Alemtuzumab is the only single agent immunotherapy to demonstrate a survival benefit in patients with B-cell chronic lymphocytic leukemia (B-CLL), who have relapsed from or are refractory to Fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. Here, we report the second interim analysis of a new, less intensive schedule of alemtuzumab administered subcutaneously (SC) to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg twice week during the second and third weeks, and 30 mg once weekly during Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg three-times daily. Results: Of the 38 patients who were recruited to participate in the trial, 12 (31.6%)were refractory and 26 (68.4%) had relapsed from prior therapy. Patients had a median age of 66.5 years (range, 43–86 years), 30 were male (79%), 45%/53% had Binet stage B/C disease. The median number of prior therapies was 1 (range: 1–4). The median duration of therapy was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 457 mg (range, 120–1,080 mg). Among the 35 patients who were evaluable for response, the overall response rate was 88.6%: 45.8%complete response (CR), 2.9% unconfirmed CR, 42.8% partial response (PR). Four patients ( 11.5%) did not respond to therapy. Of the 9 patients with refractory disease, 1 achieved a CR, 6 a PR and 2 did not respond. Median follow up was 13 months and median overall survival was not achieved. Minimal residual disease (MRD) was measured by flow cytometry in 6 patients who achieved a CR: 4 patients had <0.5% of CD5/CD19+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, over 38 evaluable patients, 4 (10,6%) experienced grade 3/4 infection; 2 patients had grade 2/3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusion: Results of this second interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy.

804 A phase II study of the anti-programmed cell death-1 (PD-1) antibody penpulimab in patients with metastatic nasopharyngeal carcinoma (NPC) who had progressed after two or more lines of chemotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A853-A853
Author(s):  
Xiaozhong Chen ◽  
Wei Wang ◽  
Qingfeng Zou ◽  
Jingao Li ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Receptor Occupancy ◽  
Complete Response ◽  
Hepatic Function ◽  
Open Label ◽  
Barr Virus ◽  
Duration Of Response ◽  
Epstein Barr ◽  
Grade 3 ◽  
Anti Tumor Activity

BackgroundNPC is rare but has a distinct geographic distribution, with a predominance in Southeast Asia. Favorable results with PD-1 inhibitors in NPC provide a strong rationale to investigate penpulimab in this disease. Penpulimab was engineered to eliminate FcγR binding and ADCC/ADCP completely,where ADCC/ADCP effects can induce T-cell apoptosis and clearance and then compromise anti-tumor activity. Penpulimab demonstrated a slower PD-1 antigen binding off-rate than marketed PD-1 antibodies, which result in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and may contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab.MethodsAK105-202 (NCT03866967) is a multicenter, single-arm, open-label study of penpulimab in metastatic NPC patients (pts) with disease progression after ≥2 prior lines of therapy including platinum-containing chemotherapy. All patients received penpulimab 200 mg q2w until progression or unacceptable toxicity. The primary endpoint was ORR based on RECIST v1.1 as assessed by an independent review committee (IRC). Key secondary endpoints included DCR, PFS, duration of response (DoR). Archived tissues were retrieved for the analysis of PD-L1 (Shuwen SAB-028). PD-L1 expression of tumor proportion score (TPS)≥50% was regarded as positive. Plasma Epstein-Barr virus DNA were obtained for biomarker correlative analysis.ResultsAs of 18 September 2020, the median follow-up was 7.9 months (range 0.9 to 16.9). The anti-tumor activity of penpulimab in the 111 pts with disease progression after ≥2 prior lines of therapy evaluable for efficacy (defined as pts who had an opportunity to be followed for at least 16 weeks and had measurable disease at baseline per RECIST v1.1) is shown in the table 1.Treatment-related adverse events (TRAEs, including unlikely related) occurred in 79.2% of pts (≥G3 in 14.6% [19/130], treatment discontinuation in 3.1% [4/130]). Treatment-related SAEs occurred in 10.0% [13/130]. Most frequent TRAEs (≥10%) were fever (24.5%), hypothyroidism (24.6%), anemia (23.1%), ALT increased (17.0%) and WBC decreased (10.8%). Grade ≥3 TRAEs (≥2%) were hepatic function abnormal (2.3%) and anemia (2.3%).Abstract 804 Table 1a. Including 1 complete response and 29 partial response. At data cutoff, 90% of responders remained ongoing.b.43 pts were PD-L1 positive (TPS≥50%) and 66 pts were PD-L1 negative (TPS<50%).c. Including 1 ongoing response awaiting confirmation classified under SD.ConclusionsPenpulimab demonstrated encouraging anti-tumor activity and favorable safety profile in pts with disease progression after ≥2 prior lines of therapy. A higher proportion of objective responses was observed in NPC pts with PD-L1–positive tumors receiving penpulimab than those with PD-L1–negative tumors.

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Chadi Nabhan ◽  
Anand Patel ◽  
Dana Villines ◽  
Kathy Tolzien ◽  
Susan K. Kelby ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Benefit ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Biochemical Responses ◽  
Grade 3 ◽  
Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Inotuzumab ozogamicin (IO) combined with mini-hyper-CVD as salvage therapy for patients (pts) with R/R acute lymphoblastic leukemia (ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7025-7025 ◽  
Author(s):  
Rita Assi ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Susan Mary O'Brien ◽  
Partow Kebriaei ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Intrathecal Chemotherapy ◽  
Free Survival ◽  
Low Intensity ◽  
Transplant Candidates ◽  
Grade 3

7025 Background: Outcome of pts with R/R ALL is poor. IO, a CD22 monoclonal antibody bound to a toxin, calicheamicin, has single-agent activity in R/R ALL with response rate of 80% and median survival of 7.7 months. Adding IO to low-intensity chemotherapy might further improve clinical outcomes. Methods: Pts ≥18 years with R/R ALL were eligible. Chemotherapy was of lower intensity than standard hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction (DR), no anthracycline, methotrexate at 75% DR, cytarabine at 0.5 g/m2 x 4 doses). Rituximab (if CD20+ blasts) and intrathecal chemotherapy were given for first 4 courses. IO was given on day 3 of each of the first 4 courses at a dose of 1.8 mg/m2 for cycle 1 then 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), IO was modified to 1.3 mg/m2 for cycle 1 followed by 1.0 mg/m2 for subsequent cycles. Results: Sixty pts with a median age of 35 years (range 18-87) were treated. Overall, 47 pts (80%) responded, 32 of them (54%) achieving complete response. The overall minimal residual disease negativity rate among responders was 82%. Grade 3-4 toxicities included prolonged thrombocytopenia (79%), infections during induction and consolidations (52%, and 73% respectively), and hyperbilirubinemia (13%). VOD of any grade occurred in 9 patients (15%). At a median follow-up of 19 months, the median relapse-free survival (RFS) and overall survival (OS) were 9 and 11 months, respectively. The 2-year RFS and OS rates were 33% and 38%. The 2-year OS rates for patients treated in salvage (S)1, S2, and S3 and beyond were 53%, 0%, and 34%, respectively (p = 0.005). When compared to IO monotherapy in a similar pts population, a significant improvement in OS was observed (11 and 6 months, respectively; p = 0.003). Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective in pts with R/R ALL. Results are encouraging and appear superior to those obtained with IO alone, particularly in pts treated in S1. The risk of VOD should be considered carefully for transplant candidates and pts with previous liver damage. Lower dose of weekly schedules of IO are being explored Clinical trial information: NCT01371630.

Venetoclax induces sustained complete responses in refractory/relapsed patients with cardiac AL amyloidosis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19538-e19538 ◽  
Author(s):  
Fabien Le Bras ◽  
Jehan Dupuis ◽  
François Lemonnier ◽  
Silvia Oghina ◽  
Diane Bodez ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Influenza Infection ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Al Amyloidosis ◽  
Duration Of Treatment ◽  
Systemic Involvement ◽  
Academic Center ◽  
Heavily Pretreated

e19538 Background: Venetoclax (VEN) is an orally bioavailable small molecule inhibitor of the anti-apoptotic protein BCL-2 and has been shown to have efficacy against myeloma (MM), particularly in patients that harbor t(11;14). Approximately, 50% of AL amyloidosis patients will exhibit t(11;14) making VEN an attractive therapeutic option. Methods: We here report the results of a retrospective analysis of a monocentric series of refractory/relapsed (R/R) patients (pts) heavily pretreated with cardiac AL amyloidosis treated in a french academic center. VEN was given daily alone or in association with dexamethasone (DEX), with or without bortezomib (BTZ). Treatment was planned to be administered until progression. Results: Between February 2017 and January 2019, 7 consecutive R/R pts have been treated. All had received previous BTZ and daratumumab (DARA) containing regimen. Baseline characteristics were: median age: 72.7 years (range 40-84), Mayo Clinic stage: stage I in 2 pts, stage II in 3 and stage IIIA in 2. All patients but one had in addition to cardiac deposit, systemic involvement including kidney, joint, neurologic, gastro-intestinal tract, lymph node and muscle. All but one pts were refractory to their last treatment consisting of DARA-DEX with or without IMID. The t(11;14) translocation was present in 5 pts, absent in 1 and undetermined in 1 pts. Two pts had concomitant MM at diagnosis. Median number of previous line treatments was 4 (3-5). Five patients received VEN- BTZ- DEX as described in MM (PMID: 28847998), 1 with DEX and 1 as monotherapy. Five pts received 400 mg/d, one 200 mg/d and one 100 mg/d. Median duration of treatment was 76 days (30-713). All patients but one are still on treatment. One patient treated with 400 mg/d had a dose reduction to 100 mg/d due to grade 2 diarrhea. Four patients received at least 2 cycles and were evaluable for response. One 84 y old patient in stable disease after 1 cycle died due to influenza infection. 2 patients received only one cycle of treatment. Hematological complete response occurred in 2/4 (50%) patients, after 63 and 27 days. Interestingly, responses were sustained as the 2 responders were still on therapy after 76 and 713 days. This later patient, refractory to 2 previous lines had a cardiac and neurologic response. The 2 responding patients had proven t(11:14). Conclusions: On this limited series of heavily pretreated patients with R/R AL cardiac amyloidosis VEN used as a single agent or in combination can induce prolonged response and seems a promising drug with an acceptable safety profile in patients with t(11;14).

scholarly journals Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade

2020 ◽  
Vol 38 (15) ◽  
pp. 1655-1663 ◽  
Author(s):  
Allison Betof Warner ◽  
Jessica S. Palmer ◽  
Alexander N. Shoushtari ◽  
Debra A. Goldman ◽  
Katherine S. Panageas ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Single Agent ◽  
Multivariable Analysis ◽  
Complete Response ◽  
Median Number ◽  
Long Term Outcomes ◽  
Duration Of Treatment ◽  
Unresectable Stage

PURPOSE To analyze long-term outcomes after treatment discontinuation of anti–programmed death-1 (anti–PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti–PD-1 therapy with or without ipilimumab in relapsing patients. METHODS We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti–PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death. RESULTS CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti–PD-1 therapy and 11 of 44 patients escalated to anti–PD-1 plus ipilimumab. CONCLUSION In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

Randomized Comparison of Cladribine with Cyclophosphamide and Fludarabine with Cyclophosphamide in Previously Untreated Progressive and Symptomatic Chronic Lymphocytic Leukemia: The Interim Analysis of PALG CLL3 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2121-2121 ◽  
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Joanna Gora-Tybor ◽  
Jacek Najda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Interim Analysis ◽  
Residual Disease ◽  
Complete Response ◽  
Similar Efficacy ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Grade 3 ◽  
Toxicity Criteria ◽  
Related Mortality

Abstract The efficacy and toxicity of cladribine (2-CdA) + cyclophsphamide (CY) - CC versus fludarabine (FA) + CY - FC were compared in previously untreated chronic lymphocytic leukemia (CLL) patients. The study was started in January 2004. Eligible patients were asigned to either 2-CdA 0,12mg/kg/d and CY 250mg/m2/d for 3 consecutive days or FA 25mg/m2/d and CY 250mg/m2/d also for 3 days. Courses were repeated at 28 days intervals or longer if myelosupression and/or infection developes for a maximum 6 courses. The response and toxicity criteria were those recommended by NCI SWG. Minimal residual disease (MRD) was evaluated by flow cytometry if complete response (CR) was achieved. As shown in the table, there were no significant differences in the rates of overall response (OR), CR, grade 3/4 thrombocytopenia, neutropenia and infections between the programmes. MRD negativity was obtained in 4 patients in CC arm and in 6 patients in FC arm (p=0.69). The death rate was similar in both groups, 2 (3.2%) and 6 (8.2%), respectively (p=0.19). The therapy related mortality was not observed. In conclusion, CC and FC programmes seem to have similar efficacy and toxicity in previously untreated CLL patients. The results of the interim analysis of PALG CLL3 trial justify continuation of this study. Treatment Pts enrolled Pts evaluated OR (%) CR (%) Thrombocytopenia Neutropenia Infections CC 96 63 57 (90.5) 20 (31.7) 8 (12.7) 15 (23.8) 26 (41.3) FC 100 73 62 (84.9) 25 (34.3) 6 (8.2) 17 (23.3) 20 (27.4) p value 0.24 0.45 0.27 0.53 0.06

Fotemustine IN COMBINATION with BORTEZOMIB and DEXAMETHASONE: Encouraging PRELIMINARY RESULTS FROM A PHASE II STUDY On Relapsed REFRACTORY MYELOMA PATIENTS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3037-3037
Author(s):  
Alessandro Corso ◽  
Silvia Mangiacavalli ◽  
Federica Cocito ◽  
Cristiana Pascutto ◽  
Cesare Astori ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dose Reduction ◽  
Phase Ii ◽  
Preliminary Data ◽  
Interim Analysis ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Median Number ◽  
Before And After ◽  
Grade 3

Abstract Abstract 3037 Fotemustine (Muphoran), a nitrosourea alkylating agent approved for use in the treatment of metastatic melanoma, has proven to be effective as single agent in relapsed/refractory multiple mieloma (MM). We report preliminary data of a phase II single centre study exploring the feasibility and the efficacy of the combination bortezomib (B) + fotemustine (Mu) + dexamethasone (D) (B-MuD) in relapsed/refractory MM patients. This study has been approved by local ethical committee; all patients (pts) signed written informed consent before the enrolment. MM pts relapsed or refractory after at least one therapy were eligible for the study. Pts who received prior bortezomib-containing regimen were included only if not considered bortezomib-refractory. Fotemustine at the escalating doses of 80 and 100 mg/m2 i.v. on day 1 was associated to Bortezomib 1,3 mg/m2 i.v. on days 1,4,8,11 + Dexamethasone 20 mg orally on days 1–2, 4–5, 8–9, 11–12 of 21-day cycle for a total of 6 cycles. Protocol was amended after the enrolment of the first five pts due to a considerable toxicity. We observed 3 grade 3–4 peripheral neuropathy, 1 grade 3 pneumonia, 4 grade 4 thrombocytopenia and two pts dropped-out (one for grade 3 pneumonia at 2° cycle, and one for grade 4 peripheral neuropathy at 3° cycles). Thus the schedule was modified as following: Fotemustine at escalating doses of 80 and 100 mg/m2 i.v. on day 1, Bortezomib 1,3 mg/m2 i.v. once weekly on days 1, 8, 15, 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, 22 for six 35-day cycles. An interim analysis of feasibility and efficacy was planned after the inclusion of the first two cohort of 6 pts each, treated with escalating dose of Fotemustine according to the amended schedule. Up to now, 18 pts have been enrolled (5 pts before and 13 after the amendment): M/F 10/8, median age 69 years (44-82), median number of previous therapies 2 (1-5). Previous treatments included autologous transplant in 10 pts (59%), bortezomib in 8 pts (44%), oral melphalan in 7 pts (41%) and thalidomide in 12 (71%). After the inclusion of 12 pts the MTD for Fotemustine was established to be 100 mg/m2. No drop-outs were registered after the amendment. Preliminary data on response are available in 10 pts. Nine pts (90%) obtained at least a PR, 8 pts (80%) registered ≥VGPR (CR 10%). At time of this analysis 79 cycles were delivered: 14 before, 65 after the amendment. Eighty-nine AE of any grade were observed, 43 hematological and 46 non-hematological. Thrombocytopenia was the most common AE either before and after the amendment. Need for dose reduction was significantly lower after the amendment. In detail fotemustine was reduced in 14% of cycles before and never after the amendment (p=0.0001), bortezomib dose reduction were performed in 36% of cycles before and 15% after the amendment (p=0.08), dexamethasone dose reduction occurred in 64% of cycles before and 13% after the amendment (p=0.0001). In conclusion, this interim analysis shows that fotemustine in combination with bortezomib and dexamethasone is safe and gives encouraging results in relapsed/refractory myeloma patients with 80% of ≥VGPR. Updated results will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Immunotherapy for Esophageal and Gastric Cancer

2017 ◽  
pp. 292-300 ◽  
Author(s):  
Ronan J. Kelly
Keyword(s):  
Gastric Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Single Agent ◽  
Phase Iii ◽  
Immune Checkpoints ◽  
Barr Virus ◽  
Mutation Burden ◽  
Heavily Pretreated ◽  
Epstein Barr

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%–27% for patients with PD-L1+ tumors and 10%–17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16184-e16184
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
Roland Ching-Yu Leung ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Refractory Ascites ◽  
Time To Progression ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Experienced Grade ◽  
Systemic Therapies

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

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