Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA8512-LBA8512 ◽  
Author(s):  
Sagar Lonial ◽  
Brendan M. Weiss ◽  
Saad Zafar Usmani ◽  
Seema Singhal ◽  
Ajai Chari ◽  
...  
Keyword(s):  
Median Time ◽  
Alkylating Agents ◽  
Single Agent ◽  
Open Label ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Grade 3 ◽  
International Multicenter Study ◽  
Line Of Therapy ◽  
Favorable Safety

LBA8512 Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.

Durable Responses with Bortezomib in Patients with Relapsed or Refractory Mantle Cell Lymphoma (MCL): Updated Time-to-Event Analyses of the Multicenter PINNACLE Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 125-125 ◽  
Author(s):  
Andre Goy ◽  
Steven Bernstein ◽  
Brad Kahl ◽  
Benjamin Djulbegovic ◽  
Michael Robertson ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Median Time ◽  
International Workshop ◽  
Single Agent ◽  
Stage Iv ◽  
Time To Event ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Grade 3

Abstract Background: We previously reported substantial activity with single-agent bortezomib (VELCADE®; Vc) in patients (pts) with relapsed or refractory MCL in the PINNACLE study (JCO2006;24:4867–74), which resulted in approval of Vc for MCL pts following ≥1 prior therapy. All pts have now completed treatment. Here we report updated time-to-event data in all pts, and by response category, with extended follow-up. Methods: 155 pts (median age 65 yrs; 55%/41%/4% with 1/2/≥3 prior therapies; 77% Stage IV MCL; 55% positive bone marrow) received Vc 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles; of these, 141 were response-evaluable. Response and progression were determined by modified International Workshop Response Criteria using independent radiology review. Results: After a median follow-up of 26.4 mo, 55 pts (35%) remained in follow-up; 93 (60%) had died, 2 (1%) had withdrawn consent, and 5 (3%) were lost to follow-up. Pts received a median of 4 treatment cycles (range 1–21; 8 in responding pts). Median time to first response was 1.3 months. Median duration of response (DOR) was 9.2 mo in all responders and has not been reached in pts achieving CR/CRu. Median time to progression (TTP), time to next therapy (TTNT; first Vc dose to start of next therapy), and overall survival (OS) are shown in the table for all pts and by response. Survival rate at 12-mo was 69% overall and 91% in responding pts. In pts refractory to their last therapy (no response or response with TTP <6 mo; n=58), median DOR was 5.9 mo, median TTP was 3.9 mo, median TTNT was 4.6 mo, and median survival was 17.3 mo. Safety profile was similar to previously reported; most common grade ≥3 AEs were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). The most common AE resulting in Vc discontinuation was peripheral neuropathy (10%). Twelve (8%) pts died on-study, including 5 (3%) considered related to Vc. Conclusions: Vc provides durable responses plus prolonged time off-therapy and survival in responding pts, suggesting substantial clinical benefit in relapsed/refractory MCL. Median TTP, TTNT, and OS (months) in all pts and by response All pts (N=155) Responders (N=45) CR/CRu (N=11) PR (N=34) SD (N=52) PD (N=34) NE, not estimable TTP 6.7 12.4 NE 9.1 6.9 1.2 TTNT 7.4 14.3 23.9 13.3 7.0 2.3 OS 23.5 35.4 36.0 35.1 27.8 13.7

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2128-2128
Author(s):  
Jean-Francois Rossi ◽  
A. Van Hoof ◽  
K. De Boeck ◽  
S. A. Johnson ◽  
D. Bron ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Response Rate ◽  
Time To Progression ◽  
Open Label ◽  
Overall Response ◽  
Fludarabine Phosphate ◽  
Duration Of Response ◽  
Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

scholarly journals Promising Clinical Efficacy and Toxicity Profile of Isatuximab Based Regimens for Treatment of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1949-1949
Author(s):  
Zunairah Shah ◽  
Madeeha Shafqat ◽  
Faiza Jamil ◽  
Mustafa Nadeem Malik ◽  
Abdul Rafae ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Overall Response Rate ◽  
Single Agent ◽  
Phase Ib ◽  
First Response ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Combination Regimens

Abstract Introduction: Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts). Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included. Results: A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%). Conclusion: In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. Disclosures No relevant conflicts of interest to declare.

Lenalidomide Is Safe and Active in Waldenstrom Macroglobulinemia (WM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4478-4478 ◽  
Author(s):  
Xavier Leleu ◽  
Steven Legouill ◽  
Chanaz Louni ◽  
Karlin Lionel ◽  
Anne Banos ◽  
...  
Keyword(s):  
Adverse Event ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Alkylating Agents ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
M Spike ◽  
Grade 3

Abstract Background. Lenalidomide has proved safe and effective in multiple myeloma (MM), particularly in elderly patients. Furthermore, it has been showed that lenalidomide enhanced rituximab-mediated antibody-dependent cell-mediated cytotoxicity. Unexpectedly, lenalidomide (25 mg/d on days 21/28) along with rituximab (375 mg/m²/wk) produced clinically significant acute anemia in patients with WM, most of them received 25mg/day with no improvement when the dose was reduced (Treon et al. CCR, 2009). No cause was attributable to the occurrence of this adverse event. Thus, we sought to perform a study with incremental concentrations of single agent lenalidomide to determine the maximum tolerated dose (MTD) of lenalidomide in WM, and possibly unravel the cause of anemia upon treatment with lenalidomide. Methods. RV-WM-0426 is a multicenter phase I/II dose escalation open label study of lenalidomide in relapse/refractory WM. Lenalidomide was given oral daily 21 / 28 days per cycles for 1 year, at escalated dose of 15 to 20 then 25mg across cohorts of 3 to 6 patients each during the phase 1 part, then followed by 9 patients to recruit in the phase 2 part at the maximum tolerated dose (MTD). The primary endpoint was the MTD, secondary endpoint included response rate (International WM Workshop) and response duration, safety, measurements of free light chain assays, and PFS and OS. Results. 17 patients were enrolled in the study, the median age was 69 (range 48-81), with 7 patients older than 75, 70% were male. 53% had adverse IPSS 3. The median hemoglobin level was 11.2 (95%CI 9.9-12.5), median M spike level 26.5 (95%CI 23-40), 23% had clearance creatinin below 60ml/min. The median number of prior lines was 1 (range 1-8), all patients but 2 exposed to alkylating agents, 30% to nucleoside analogues, 47% to the monoclonal antibody mabthera, none of the patients have had a transplantation. The median time from diagnosis to study entry was 3 years (range 2-15). At the highest dose tested, 20 mg, 2 patients had dose-limiting toxicity, septic syndrome during grade 4 neutropenia and severe fatigue, respectively. The MTD was thus established at the 15 mg/day 21 days out of 28. 7/17 (41%) patients completed one year of single agent lenalidomide at 15mg day 21/28. Single agent lenalidomide in WM provided an overall response (minimal response (MR) and better) on an intent-to-treat basis at 15mg/day of 36%, and an extra 2 patients had a prolonged stable disease (SD). A flare effect (transient initial increase of the M spike) was observed in 5 patients. With a median follow-up of 36 months, 14 have progressed with a median time to progression of 16 months (95%CI 5.5-26), with 35% of patients with a PFS greater than 24 months. One patient died with a 5-year overall survival (OS) of 91%. The most common adverse event (AE ≥ 10%) was fatigue of at least grade 2, reported in 50% of the patients. The incidence rate of grade 3 and greater hematological AE at 15mg was 14% for anemia, 43% for neutropenia, and no thrombopenia observed. 78% experienced a non hematological AE of at least grade 2, but only 2 patients had a grade 3 AE, nephrotic syndrome and cramps. No second primary malignancy (SPM) nor thromboembolic event were reported to date. Only 21% of patients had dose reduction with a median time of 7 months, and 35% had study drug interruption related to an AE with a median time of 4 months. Conclusion. The MTD of lenalidomide is 15mg/day given on days 21/28 in relapse and refractory WM. Lenalidomide is active in the treatment of RRWM and the safety profile appeared manageable, essentially of grade 2 AEs. Future studies may look into combinations to lenalidomide and continuous therapeutic effect in WM at the determined MTD. Disclosures Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Combination immunotherapy with ipilimumab and nivolumab in patients with rare gynaecological malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6091-6091
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Bo Gao ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Low Grade ◽  
Gynecological Cancers ◽  
Prior Therapy ◽  
Gynecological Malignancies ◽  
Duration Of Response ◽  
Radiological Response ◽  
Grade 3 ◽  
Tumor Types

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]

Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8536-8536 ◽  
Author(s):  
Sagar Lonial ◽  
Hans Chulhee Lee ◽  
Ashraf Badros ◽  
Suzanne Trudel ◽  
Ajay K. Nooka ◽  
...  
Keyword(s):  
Single Agent ◽  
Proteasome Inhibitors ◽  
Prior Therapy ◽  
Meaningful Activity ◽  
Common Grade ◽  
Duration Of Response ◽  
Independent Review ◽  
Grade 3 ◽  
Dose Modifications

8536 Background: Single-agent belantamab mafodotin (B-cell maturation antigen targeting immunoconjugate) showed clinically meaningful activity and manageable safety in patients with heavily pre-treated RRMM (DREAMM-2, NCT03525678, Lancet Oncol.2020). We report updated results (median follow-up 9 months). Methods: DREAMM-2 is an ongoing single-agent belantamab mafodotin (2.5 or 3.4 mg/kg) study in patients with RRMM after ≥3 prior therapy lines and refractory to an immunomodulatory agent, a PI, and refractory and/or intolerant to an anti-CD38 mAb. Primary endpoint: overall response rate (ORR; ≥partial response per independent review committee). Results: ORR was 31% in the 2.5 mg/kg (19% with ≥very good partial responses [VGPR]) and 35% (24% with ≥VGPR) in the 3.4 mg/kg groups (Table). Duration of response (DoR) was not reached (NR) in the 2.5 mg/kg and 6.2 months in the 3.4 mg/kg groups; 1-year overall survival (OS) estimate was 53%. Common Grade 3/4 AEs ( > 10% in either group) were keratopathy (2.5: 29%; 3.5: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). AEs were managed with dose delays (2.5: 54%; 3.4: 62%) and reductions (2.5: 34%; 3.4: 43%); discontinuations due to AEs were uncommon (2.5: 9%; 3.4: 12%). Conclusions: Single-agent belantamab mafodotin was well-tolerated, and clinically meaningful responses were sustained despite dose modifications with longer follow-up. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

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.

scholarly journals FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

2021 ◽  
Author(s):  
Jane E. Rogers ◽  
Michael Lam ◽  
Daniel M. Halperin ◽  
Cecile G. Dagohoy ◽  
James C. Yao ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Free Survival ◽  
Prior Therapy ◽  
Well Differentiated ◽  
Grade 3 ◽  
Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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