A Clinical Study of Bortezomib in Combination with Dexamethasone and/or Doxorubibcin for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5216-5216
Author(s):  
Jie Jin ◽  
Jiejing Qian ◽  
Haitao Meng ◽  
Wenbin Qian ◽  
Hongyan Tong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Objective Response ◽  
Median Number ◽  
Refractory Multiple Myeloma ◽  
Mean Response Time ◽  
Best Response ◽  
Common Grade ◽  
Grade 3 ◽  
Lost To Follow Up

Abstract Purpose: This study assessed the safety, tolerability, and response rate of bortezomib in combination with dexamethasone and/or doxorubibcin in patients with relapsed or refractory multiple myeloma. Methods: Botezomib was administered 1.3mg/m2 on days 1, 4, 8, 11 of a 28-day cycle. Intravenous dexamethasone was administered 20–40mg/d on day 1–2, 4–5, 8–9,11–12, and 5 patients were also given 20mg/d doxorubibcin on day 1–4. Results: Thirty relapsed or refractory myeloma patients (table 1) were enrolled; two patients could not be evaluated because they were lost to follow-up. Of the remaining patients 19 are male, 9 are female. Median age of the patients were 61(49–78). Median number of prior therapies was 4 (1–11). 22 of 28 patients who had been evaluated were assessable for response according to the EBMT criteria (European Group for Blood and Marrow Transplantation criteria). One CR(3.6%), twelve immunofixation-positive CRs[nCR] (42.9%), six PRs(21.4%), and three MR (10.7%) were observed. All patients who had an objective response were alive as of this analysis. Nine patients died during follow-up. Mean response time (time to best response)for the 28 patients was 25 days. Most common Grade ≥3 toxicities (table 2) were peripheral neuropathy(3/28), thrombocytopenia (3/28), rash(one in 28 patients). Six patients(21.4%) suffered herpes after one or two cycles. Table 1. Patents and Disease Characteristics (N=28) No. % Abbreviations: Ig, immunoglobulin; Parameter 61 49–78 Age, years Median Range 19 Sex Male Female 9 Paraprotein type IgG IgA Light-chain only 18 β2..Cmicroglubulin, 3 64.3 10.7 Range 7 25.0 Prior treatments 1262–8691 Median 4 Range 1–11 Table 2. Treatment-emergent adverse events Total No. of patients with event(%) Adverse event 0 Hematologic Neutropenia No. with 3(10.7) grade ≥3 event Thrombocytopenia No. 0 with grade ≥3 event Anemia No. with 6(21.4) grade ≥3 event 5(17.8) Nonhematologic herpes Diarrhea 10(35.7) Fatigue Rash No. with 1(3.6) grade ≥3 event Tachycardia Peripheral 1(3.6) neuropathy Total No. No. 16(57.1) with grade ≥ 3 event 3(10.7) Conclusion: Bortezomib plus dexamethasone given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for multiple myeloma patients.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

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.

Prospective cohort study of Kaposi sarcoma treated under real-world conditions in Malawi.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11569-11569
Author(s):  
Edwards Kasonkanji ◽  
Yolanda Gondwe ◽  
Morgan Dewey ◽  
Joe Gumulira ◽  
Matthew Painschab ◽  
...  
Keyword(s):  
Cohort Study ◽  
Kaposi Sarcoma ◽  
Median Number ◽  
Sub Saharan Africa ◽  
Worst Case ◽  
Loss To Follow Up ◽  
Presenting Symptoms ◽  
Grade 3 ◽  
Lost To Follow Up

11569 Background: Kaposi sarcoma (KS) is the leading cancer in Malawi (34% of cancers). Outside of clinical trials, prospective KS studies from sub-Saharan Africa (SSA) are few and limited by loss to follow up. We conducted a prospective KS cohort study of standard of care bleomycin/vincristine (BV) at Lighthouse HIV clinic, in Lilongwe, Malawi. Methods: We enrolled pathologically confirmed, newly diagnosed, HIV+ KS patients from Feb 2017 to Jun 2019. We collected clinical and treatment characteristics, toxicity, and outcomes of KS with follow-up censored Jun 2020. Patients were treated with bleomycin (25 mg/m2) and vincristine (0.4 mg/m2) every 14 days for a planned maximum of 16 cycles. STATA v13.0 was used to calculate descriptive statistics and Kaplan Meier survival analysis. Toxicity was graded using NCI CTCAE v5.0. Results: We enrolled 138 participants, median age 36 (IQR 32-44) and 110 (80%) male. By ACTG staging, 107 (78%) were T1 (tumour severity), 46 (33%) were S1 (illness severity) and 46 (33%) had Karnofsky performance status ≤70. Presenting symptoms included edema in 69 (53%), visceral disease in 9 (7%), and oral involvement in 43 (33%). Prior to KS diagnosis, 70 (51%) participants were aware of being HIV+ for median 17 months (IQR 6-60) and had been on ART for median 16 months (IQR 6-60). Median CD4 count was 197 (IQR 99-339), median HIV-viral load was 2.6 log copies/mL (IQR 1.6 – 4.8) and 57% were HIV-suppressed ( < 1000 HIV copies/ml). The median number of cycles was 16 (IQR 7-16). 62 (45%) participants missed at least one dose due to stock out. Amongst patients with missed doses, the median number was 3 (IQR 2-4) for bleomycin and 2 (IQR 1-3) for vincristine. 14 (10%) participants experienced at least one reduced dose due to toxicity. 5 (4%) participants suffered grade ≥3 anaemia, 13 (9%) grade ≥3 neutropenia, and one participant had grade 4 bleomycin-induced dermatitis. There was no reported grade ≥3 bleomycin lung toxicity or vincristine-induced neuropathy. Of 115 evaluable participants, responses at the end of therapy were: complete response in 52 (45%), partial response in 27 (23%) stable disease in 5 (4%), and progressive disease in 31 (28%). Median duration of follow-up was 20 months. At censoring, 69 (50%) were alive, 36 (26%) dead, and 33 (24%) lost to follow-up. Overall survival is shown Table as crude and worst-case scenario; worst-case assumes all participants lost to follow up died. Conclusions: Here, we present one of the most complete characterizations of KS presentation and treatment from SSA. As in other studies from the region, the majority of patients presented with advanced disease, chemotherapy stock-outs and loss to follow up were common, and mortality was high. Studies are planned to understand the virologic characteristics, improve therapies, and better implement existing therapies.[Table: see text]

Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9507-9507 ◽  
Author(s):  
Hussein Abdul-Hassan Tawbi ◽  
Peter A. J. Forsyth ◽  
Alain Patrick Algazi ◽  
Omid Hamid ◽  
F. Stephen Hodi ◽  
...  
Keyword(s):  
Objective Response ◽  
Complete Response ◽  
Median Number ◽  
Disease Assessment ◽  
Response Data ◽  
Grade 3 ◽  
Favorable Safety ◽  
The Brain ◽  
Clinical Trial Information

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]

SYNFRIZZ: A first-in-human (FIH) study of a radiolabeled monoclonal antibody (Mab) targeting frizzled homolog 10 (FZD10) in patients (pts) with advanced synovial sarcomas (SyS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11054-11054
Author(s):  
Philippe Alexandre Cassier ◽  
Anne Laure Giraudet ◽  
Chicaco Iwao-Fukukawa ◽  
Gwenaelle Garin ◽  
Jean-Noel Badel ◽  
...  
Keyword(s):  
Objective Response ◽  
Tumor Uptake ◽  
Best Response ◽  
Primary Endpoints ◽  
Clinical Investigations ◽  
Common Grade ◽  
Synovial Sarcomas ◽  
Grade 3 ◽  
To Receive ◽  
Clinical Trial Information

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.

3-weekly daratumumab-IMiD-dexamethasone is highly efficacious and cost-effective in relapsed/refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19521-e19521
Author(s):  
James Chim ◽  
Vincent Wong ◽  
Elaine AU ◽  
Yok-Lam Kwong
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Cost Effective ◽  
Median Number ◽  
Infusion Reaction ◽  
Immunomodulatory Agents ◽  
Asian Patients ◽  
Best Response ◽  
Rapid Responses ◽  
Grade 3

e19521 Background: Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2-weekly for 8 doses, and then every 4-weekly thereafter. Given the high cost and the long half-life as an antibody, a 3-weekly dosing of dara was used together with IMiD/dexamethasone. Methods: Dara at 16mg/kg was used every 3-weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression. Results: Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50-84 years) were studied. The median number of previous therapies was 2 (range: 1-5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara-lenalidomide-dex in six (46.2%), and dara-pomalidomide-dex in seven (53.8%). Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3-10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade ¾: 76.9%), infusion reaction (38.5%, all grade ½), neuropathy (38.5%, all grade ½), gastrointestinal (all grades: 38.5%, grade ¾: 7.7%), and sepsis (all grades: 30.8%; grade ¾: 23.1%). Neutropenia was effectively prevented with prophylactic G-CSF. Conclusions: In conclusion , a 3-weekly dara-IMiD-dex regimen is highly efficacious, inducing deep and rapid responses, hence cost-effective for less affluent countries. In view of prevalent grade 3/4 neutropenia despite less frequent dara, 3-weekly dara might be more suitable for Asian patients.

Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

2012 ◽  
Vol 30 (16) ◽  
pp. 1953-1959 ◽  
Author(s):  
Sagar Lonial ◽  
Ravi Vij ◽  
Jean-Luc Harousseau ◽  
Thierry Facon ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Low Dose ◽  
Infusion Reaction ◽  
Weekly Dose ◽  
Refractory Multiple Myeloma ◽  
Subsequent Cycle ◽  
Clinical Responses ◽  
Grade 3

Purpose This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Patients and Methods Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. Results Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. Conclusion The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.

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