Interim analysis results of surufatinib in U.S. patients with neuroendocrine tumors (NETs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4114-4114
Author(s):  
Andrew Scott Paulson ◽  
Daneng Li ◽  
Max W. Sung ◽  
Christopher Tucci ◽  
John S. Kauh ◽  
...  
Keyword(s):  
Safety Profile ◽  
Tyrosine Kinases ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Phase 3 ◽  
Heavily Pretreated ◽  
Grade 3

4114 Background: Surufatinib (S) is a targeted inhibitor of tyrosine kinases VEGFR1, 2, and 3; FGFR1; and CSF-1R. A manageable safety profile and statistically significant efficacy of S have previously been demonstrated in patients (pts) with advanced NETs of extrapancreatic (epNET) and pancreatic (pNET) origin in 2 phase 3 randomized trials conducted in China (SANET-ep, NCT02588170; SANET-p, NCT02589821). Pts with epNETs achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p < 0.0001), and pts with pNETs achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p = 0.0011), with S v placebo, respectively. S has recently been approved for the treatment (tx) of pts with epNETs in China. Methods: A phase 1, dose escalation (ESC)/expansion (EXP) trial was conducted to evaluate and confirm the efficacy and safety of S in US pts. ESC was completed, and the maximum tolerated dose and recommend phase 2 dose were determined to be 300 mg, same as previous trials. The EXP completed enrollment of the epNET and pNET cohorts, and the primary endpoint was investigator-assessed PFS rate at 11 mo. Secondary objectives included assessment of safety and PK. Results: 32 pts with heavily pretreated progressive NETs (16 epNET and pNET each) were enrolled in the dose EXP. The median age was 62.2 years (44-75) and 64.4 years (39-72) for epNET and pNET pts, respectively. 65.6% of pts received ≥3 prior lines of tx (median lines of therapy: epNET: 2 [2-5]; pNET: 4 [1-8]), and all pts previously received everolimus and/or sunitinib. As of the data cutoff of 30-Jun-20, 7 pts remained on tx (4 epNET; 3 pNET). The median number of tx cycles was 8.0 (2, 15) for epNET and 8.5 (2, 23) for pNET pts. The PFS rate at 11 mo was 51.1% (95% confidence interval [CI]: 12.8, 80.3) for pts with epNETs and 57.4% (95% CI: 28.7, 78.2) for pts with pNETs. The observed mPFS was 11.50 mo (95% CI: 6.47, 11.50) and 15.18 mo (95% CI: 5.19, NR) for pts with epNETs and pNETs, respectively. An objective response rate (ORR) of 6.3% was observed for pts with epNETs and 18.8% for pts with pNETs. A disease control rate of 90.6% (95% CI: 75.0, 98.0) was observed for all NET pts (93.8% epNET; 87.5% pNET). The safety profile of S remains consistent with previously completed trials. All pts (n = 32) had reported at least 1 adverse event (AE), and 24 pts (75%) reported AEs ≥grade 3. The most common AEs of any grade reported were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%), vomiting (28.1%), and nausea (25.0%). The most commonly reported AEs ≥grade 3 ( > 5%) were hypertension (37.5%); diarrhea (9.4%); and proteinuria, dysphagia, and anemia (6.3% each). AEs leading to tx discontinuation occurred in 21.9% of pts. Conclusions: S has demonstrated antitumor activity in heavily pretreated US pts with progressive NETs with a manageable safety profile that is consistent with 2 completed phase 3 studies. S continues to be studied in other ongoing clinical trials globally. Clinical trial information: NCT02549937.

Efficacy and safety of surufatinib in United States (US) patients (pts) with neuroendocrine tumors (NETs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4610-4610
Author(s):  
Arvind Dasari ◽  
Daneng Li ◽  
Max W. Sung ◽  
Christopher Tucci ◽  
John S. Kauh ◽  
...  
Keyword(s):  
Adverse Event ◽  
Safety Profile ◽  
Tyrosine Kinases ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Scientific Conference ◽  
Phase 3 ◽  
Grade 3

4610 Background: Surufatinib (S) is a targeted inhibitor of tyrosine kinases VEGFR1, 2, & 3, FGFR1, and CSF-1R. Safety and efficacy of S has previously been studied in China in early phase development, and in 2 randomized phase 3 placebo controlled trials (NCT02588170 & NCT02589821). These trials enrolled pts with NETs of extrapancreatic (epNET) and pancreatic (panNET) origin, respectively. Both trials are completed, stopping at their pre-planned interim analysis after meeting the primary endpoint of improved PFS. S demonstrated significant efficacy in pts with advanced epNETs, achieving a median Progression Free Survival [mPFS] of 9.2 v 3.8 months when compared to placebo. The mPFS achieved in pts with advanced panNETs is currently pending future disclosure at an upcoming scientific conference. Methods: A dose escalation (ESC)/expansion (EXP) study was conducted to evaluate and confirm the effects of S in US pts. Dose ESC was completed and the maximum tolerated dose and recommend phase 2 dose was determined to be 300mg QD; the same as previous trials. The primary objective of EXP was to evaluate anticancer activity in pts with select indications including panNETs and epNETs. Results: As of 21-Jan-20, 32 pts with heavily pre-treated progressive NETs (median prior lines of treatment [Tx]: 3; range 1-8) were enrolled. The 32 pts included 16 pts with panNET and 16 with epNET. All previously received everolimus and/or sunitinib. The median duration of Tx at the time of the data cut-off was 19 wks for all pts; 30.9 wks for panNET and 11 for epNET. 19 pts remain on active Tx (13 epNET and 6 panNET pts), 9 pts discontinued due to progression of disease, 2 withdrew consent and 2 discontinued due to adverse event (AE) (grade 3 tricuspid valve insufficiency, and grade 3 GI bleed). An objective response rate of 9.4% was observed. 3 panNET pts achieved a confirmed partial response (PR) and 1 had an unconfirmed PR per RECIST 1.1; no epNET pts achieved a PR. The safety profile of S remains consistent with previously completed trials. 27 pts (84.4%) had reported at least one adverse event (AE), and 16 pts (50%) reported ≥ grade 3 AE’s. The most common AE’s reported were: hypertension, fatigue, diarrhea, proteinuria and nausea. Pharmacokinetics (PK) analyses has shown similar exposure in panNET and epNET pts as was observed in ESC, and pts from the collective pool of pts. Conclusions: S has demonstrated promising antitumor activity in US pts with progressive NETs with a manageable safety profile. Additionally, PK and dose exposure data is consistent with trial results from large randomized phase 3 trials. Clinical trial information: NCT02549937 .

First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8500-8500 ◽  
Author(s):  
Paul G. Richardson ◽  
Annette J. Vangsted ◽  
Karthik Ramasamy ◽  
Suzanne Trudel ◽  
Joaquín Martínez ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Phase 1 ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Tumoricidal Activity ◽  
Evaluable Population ◽  
Heavily Pretreated ◽  
Grade 3

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .

Camrelizumab versus placebo combined with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma: A randomized, double-blind, phase 3 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6000-6000
Author(s):  
Li Zhang ◽  
Yunpeng Yang ◽  
Song Qu ◽  
Jin-Gao Li ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
First Line ◽  
Phase 3 ◽  
Double Blind ◽  
Metastatic Nasopharyngeal Carcinoma ◽  
Grade 3 ◽  
Gemcitabine And Cisplatin

6000 Background: Camrelizumab plus gemcitabine and cisplatin (GP) showed promising preliminary anticancer activity as first line (1L) therapy in patients (pts) with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) in a phase 1 trial ( W Fang et al; Lancet Oncol 2018). Here, we compared the efficacy and safety of camrelizumab with placebo plus GP as 1L therapy for pts with R/M NPC in a phase 3 trial. Methods: Eligible pts with previously untreated R/M NPC were randomized (1:1) to receive either camrelizumab (200 mg on day 1) plus gemcitabine (1000 mg/m2 on days 1, 8) and cisplatin (80 mg/m2 on day 1) or placebo plus the same chemotherapy regimens intravenously Q3W for a maximum of 6 cycles, followed by maintenance therapy with camrelizumab or placebo. The primary end point was progression-free survival (PFS) per independent review committee (IRC). Secondary end points included investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS) and tolerability. This trial is registered with ClinicalTrials.gov, number NCT03707509. Results: From Nov 2018 to Nov 2019, 263 pts from 28 centers were randomized to camrelizumab plus GP (n = 134, camrelizumab arm) or placebo plus GP (n = 129, placebo arm). At data cutoff on Dec 31, 2020 (67.7% maturity), 178 IRC-assessed PFS events occurred, and the median follow-up was 15.6 months (range 1.3-25.5). The median PFS per IRC was 10.8 months (95% CI 8.5-13.6) in the camrelizumab arm and 6.9 (95% CI 5.9-7.9) in the placebo arm (HR 0.51 [95% CI 0.37-0.69]; one-sided P < 0.0001). Investigator-assessed PFS showed similar results. IRC-assessed ORR was 88.1% (95% CI 81.3-93.0) in the camrelizumab arm and 80.6% (95% CI 72.7-87.1) in the placebo arm, with a median DOR of 9.9 (95% CI 7.7-12.5) and 5.7 months (95% CI 5.2-6.9; HR 0.48 [95% CI 0.34-0.68]), respectively. The DCR was 96.3% (95% CI 91.5-98.8) in the camrelizumab arm and 94.6% (95% CI 89.1-97.8) in the placebo arm. 18-month PFS rate was 34.8% (95% CI 25.7-44.1) vs 12.7% (95% CI 6.8-20.5), respectively. OS benefit was observed in the camrelizumab arm vs placebo arm (median not reached vs 22.6 months; HR 0.67 [95% CI 0.41-1.11]). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 93% of pts in the camrelizumab arm and 90% in the placebo arm. The most common grade ≥3 TRAEs were decreased white blood cell count (66% vs 70%), decreased neutrophil count (64% vs 65%), decreased platelet count (40% vs 40%), and anemia (39% vs 43%). None of the differences were statistically significant. The safety profile was as expected, with no new signals observed. Conclusions: Addition of camrelizumab to GP significantly prolonged PFS as 1L therapy for R/M NPC, with a manageable safety profile. These data suggest that first line treatment with camrelizumab plus GP could be a standard of care for R/M NPC. Clinical trial information: NCT03707509.

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9515-9515
Author(s):  
Omid Hamid ◽  
Ding Wang ◽  
Tae Min Kim ◽  
Sang-We Kim ◽  
Nehal J. Lakhani ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adrenal Insufficiency ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Treatment Naïve ◽  
Grade 3

9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1077-1077
Author(s):  
Joyce O'Shaughnessy ◽  
Kevin Punie ◽  
Mafalda Oliveira ◽  
Filipa Lynce ◽  
Sara M. Tolaney ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Antibody Drug Conjugate ◽  
Phase 3 ◽  
Chemotherapy Agent ◽  
Recist 1.1 ◽  
Duration Of Response ◽  
Grade 3

1077 Background: In pts with pretreated mTNBC, standard-of-care chemotherapy is associated with low objective response rates (ORRs) and short median progression-free survival (PFS). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated FDA approval for treatment of pts with mTNBC who have received ≥2 prior therapies for metastatic disease. The confirmatory phase 3 ASCENT study (NCT02574455) in pts with relapsed/refractory mTNBC demonstrated a significant survival benefit of SG over TPC (median PFS: 5.6 vs 1.7 mo, HR 0.41, P< 0.0001; median overall survival [OS]: 12.1 vs 6.7 mo, HR 0.48, P< 0.0001) with a tolerable safety profile. Here we summarize efficacy results for SG vs each TPC agent in ASCENT to examine how each TPC agent performed individually. Methods: Pts had mTNBC refractory to or progressing after ≥2 prior standard chemotherapy regimens. Pts were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8, every 21 days) or single-agent TPC (eribulin, vinorelbine, capecitabine, or gemcitabine). Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Secondary endpoints were ORR per RECIST 1.1, duration of response, OS, and safety. Outcomes for each of the agents in the TPC arm were analyzed and compared with SG. Results: Of 529 pts enrolled, 468 were BMNeg. Among pts in the TPC cohort (n = 233), eribulin was the most commonly chosen chemotherapy (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29). Treatment with eribulin, vinorelbine, capecitabine, and gemcitabine resulted in shorter median PFS vs SG (2.1, 1.6, 1.6, and 2.7 vs 5.6 mo, respectively); similar results were observed for median OS (6.9, 5.9, 5.2, and 8.4 vs 12.1 mo), ORR (5%, 4%, 6%, and 3% vs 35%), and clinical benefit rate (CBR; 8%, 6%, 10%, and 14% vs 45%). Key grade ≥3 treatment-related adverse events (TRAEs) with TPC overall vs SG included neutropenia (33% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), and anemia (5% vs 8%). Key grade ≥3 TRAEs with eribulin vs SG included neutropenia (30% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), anemia (2% vs 8%), and peripheral neuropathy (2% vs none), respectively. The safety profiles of vinorelbine, capecitabine, and gemcitabine combined were consistent with that of TPC overall and with eribulin. One treatment-related death was reported for the TPC arm (eribulin) and none with SG. Conclusions: The efficacy benefit observed with SG vs TPC in pts with mTNBC was retained when evaluating each TPC chemotherapy agent individually. These results confirm that SG should be considered as a new standard of care in pts with pretreated mTNBC. Clinical trial information: NCT02574455 .

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9500-9500
Author(s):  
Alexander M. Eggermont ◽  
Andrey Meshcheryakov ◽  
Victoria Atkinson ◽  
Christian U. Blank ◽  
Mario Mandalà ◽  
...  
Keyword(s):  
Disease Progression ◽  
Objective Response ◽  
Stage Iv ◽  
Median Number ◽  
Complete Resection ◽  
Stage Iii ◽  
Phase 3 ◽  
Double Blind ◽  
Grade 3 ◽  
To Receive

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

scholarly journals TRLS-06. PHASE 1 EXPANSION STUDY OF IRINOTECAN LIPOSOME INJECTION (nal-IRI) IN PATIENTS WITH METASTATIC BREAST CANCER (mBC): FINDINGS FROM THE COHORT WITH ACTIVE BRAIN METASTASIS (BM)

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i9-i9 ◽  
Author(s):  
Carey Anders ◽  
Pamela Munster ◽  
Donald Northfelt ◽  
Hyo Sook Han ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Disease Control ◽  
Phase 1 ◽  
Objective Response ◽  
Metastatic Breast ◽  
Median Number ◽  
Cns Metastases ◽  
Cns Disease ◽  
Topoisomerase 1 ◽  
Metastatic Setting ◽  
Heavily Pretreated

Abstract BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
Bertrand Coiffier ◽  
Stéphane Lepretre ◽  
Lars Møller Pedersen ◽  
Ole Gadeberg ◽  
Henrik Fredriksen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Partial Remission ◽  
Phase 1 ◽  
Objective Response ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Safety And Efficacy ◽  
Anti Cd20

Abstract Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.

Phase III Trial of Pixantrone Dimaleate Compared with Other Agents as Third-Line, Single-Agent Treatment of Relapsed Aggressive Non-Hodgkin's Lymphoma (EXTEND): Results From the Treatment and Follow-up Periods.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1677-1677 ◽  
Author(s):  
Ruth Pettengell ◽  
Bertrand Coiffier ◽  
Geetha Narayanan ◽  
Fernando Hurtado de Mendoza ◽  
Raghunadharao Digumarti ◽  
...  
Keyword(s):  
Treatment Group ◽  
Primary Endpoint ◽  
Safety Profile ◽  
Single Agent ◽  
Median Number ◽  
Phase 3 ◽  
Comparator Group ◽  
Duration Of Response ◽  
Heavily Pretreated

Abstract Abstract 1677 Poster Board I-703 Introduction Nearly half of patients with aggressive non-Hodgkin's lymphoma (NHL) relapse or are refractory to initial therapy. With each subsequent therapy, the probability of response decreases and the responses are less durable. An agent currently in development, pixantrone dimaleate (pixantrone), is a novel aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. The clinical activity and safety profile of pixantrone are promising in patients heavily pretreated for relapsed aggressive NHL and who received prior treatment with up to 450 mg/m2 of doxorubicin. Patients and Methods This phase 3, randomized, multicenter, controlled, open-label study enrolled patients who had ≥1 prior anthracycline-containing regimen and failed 2 prior treatment regimens for relapsed aggressive (de novo or transformed) NHL. Seventy patients were randomized to a treatment group administered pixantrone 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles. Seventy patients were randomized to the investigator's choice of a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, or mitoxantrone; in the US only, gemcitabine and rituximab were permitted). Patients in both groups were followed up to 18 months after last treatment. The primary endpoint, CR/CRu rate, was assessed by an independent assessment panel (IAP). Other efficacy endpoints were overall response rate (ORR), responses lasting ≥4 months, progression-free survival (PFS), overall survival (OS), duration of response, and time to response. This report includes the results from the treatment period and updated results from the follow-up period, which is still ongoing. Results A total of 140 patients were randomized with 70 patients in each treatment group. Of the 140 patients, 96% received treatment (n=68 for pixantrone, n=67 for comparator). The median number of treatment cycles that patients in the pixantrone group received was 4 compared with 3 for the comparator group. The percentage of patients who received all 6 treatment cycles in the pixantrone group was 32.4% compared with 28.4% for the comparator. The primary endpoint, CR/CRu rate (assessed by IAP), in the ITT population was 20.0% for the pixantrone group compared with 5.7% for the comparator (P = 0.021). The ORR for the pixantrone group was 37.1% compared with 14.3% for the comparator (P = 0.003), and the percentage of patients with objective responses lasting at least 4 months for the pixantrone group was 25.7% compared with 8.6% for the comparator (P =0.012). The median number of months of PFS in the pixantrone group was 4.7 compared with 2.6 for the comparator (HR= 0.60, log rank P = 0.007). The median number of months of OS, while not fully mature, was 8.1 for the pixantrone group compared with 6.9 for the comparator (HR=0.88, log rank P = 0.554). Subgroup assessments of the CR/CRu rate and ORR, by risk factor, were consistently higher in the pixantrone group than in the comparator group. These subgroup assessments included prior exposure to anthracyclines ('300 mg/m2 or ≥300 mg/ m2) and rituximab (treated or not treated), IPI score ('1 or ≥2), and NHL diagnosis (refractory or relapsed), and age ('65 or ≥65). In the pixantrone group, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and the incidence of febrile neutropenia was 7.4%. The percentage of patients with cardiac disorder SAEs was 8.8% in the pixantrone group compared with 4.5% for the comparator. Conclusions In this phase 3, randomized, multicenter study, patients with relapsed aggressive NHL administered single-agent pixantrone achieved superior efficacy, compared with other single-agent chemotherapeutic agents, as measured by CR/CRu rate, ORR, responses lasting ≥4 months, and PFS. Positive trends were observed in OS and duration of response. Patients in the pixantrone group tended to reach CR sooner than patients in the comparator group. Pixantrone has a tolerable safety profile in heavily pretreated patients with relapsed aggressive NHL. Disclosures Cernohous: Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment.

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