Stage I findings of a two-stage phase II study to assess the efficacy, safety, and tolerability of barasertib (AZD1152) compared with low-dose cytosine arabinoside (LDAC) in elderly patients (pts) with acute myeloid leukemia (AML).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6527-6527
Author(s):  
Giovanni Martinelli ◽  
Hagop Kantarjian ◽  
Elias Jabbour ◽  
Alfonso Quintas-Cardama ◽  
Kiyoshi Ando ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Risk Groups ◽  
Complete Response ◽  
Partial Recovery ◽  
Open Label ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Grade 3

6527 Background: Barasertib is the pro-drug to barasertib-hQPA, a selective Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II study (Löwenberg et al. Blood 2011;118:6030). Methods: AML pts aged ≥60 y considered unsuitable for intensive chemotherapy were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary endpoint was improved objective complete response rate (OCRR: CR + CRi [Cheson criteria, but requiring CRi confirmation ≥21 days after first appearance, with partial recovery of platelets and neutrophils]). Secondary endpoints included duration of response (DoR), overall survival (OS) and safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and all completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% [17/48] vs 11.5% [3/26]; difference, 23.9% [95% CI, 2.7-39.9]; P<0.05); barasertib responses were seen in all cytogenetic risk groups and appeared to be durable (median DoR [range], 82 [28-321] days; vs LDAC 30-85 days). Although not formally sized to compare OS data, a trend favoring barasertib was observed (HR=0.88, 95% CI, 0.49-1.58; P=0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile neutropenia were the most common adverse events (AEs) in the barasertib arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%, respectively). Grade ≥3 AEs with a greater incidence in the barasertib arm were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and pneumonia (25% vs 8%); grade ≥3 infection rates were also higher with barasertib (40% vs 23%). For both arms, there were similar discontinuation rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs (12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative toxicities were not observed with barasertib treatment. Conclusions: In this population with poor prognosis using standard chemotherapy, barasertib showed a significant improvement in OCRR vs LDAC, and a safety profile that was manageable and consistent with previous studies.

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.

Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9074-9074 ◽  
Author(s):  
Vivek Subbiah ◽  
Radj Gervais ◽  
Gregory J. Riely ◽  
Antoine Hollebecque ◽  
Jean-Yves Blay ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Braf Mutations ◽  
Open Label ◽  
Braf Inhibition ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Prior Systemic Therapy ◽  
Grade 3

9074 Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]

Anlotinib in chemotherapy-refractory metastatic esophageal squamous cell carcinoma (ESCC): A randomized, double-blind, multicenter phase II trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 95-95 ◽  
Author(s):  
Jing Huang ◽  
Juxiang Xiao ◽  
Wentao Fang ◽  
Ping Lu ◽  
Qingxia Fan ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Complete Response ◽  
Double Blind ◽  
Duration Of Response ◽  
Grade 3 ◽  
Vegfr Inhibitor ◽  
Loss Of Appetite

95 Background: The treatment option for ESCC patients (pts) progressing after chemotherapy is still uncertain. Anlotinib is a multi-target tyrosine kinase inhibitor involved in tumor angiogenesis and growth, such as vascular endothelia growth factor receptor (VEGFR) 2/3, etc. Methods: Eligible pts were advanced ESCC who had progressed after platinum or taxane containing chemotherapy. Between January 6, 2016 and May 22, 2018, a total of 165 pts from 13 centers in China were randomly assigned (in a 2:1 ratio) to anlotinib arm (n=110), and placebo arm (n=55). Pts were given anlotinib (12 mg/day) or placebo orally from day 1 to day 14 in a 21-day cycle until disease progression or had unacceptable toxic effects. The primary end point was progression-free survival (PFS). Results: Median PFS was 3.0 months with anlotinib and 1.4 months with placebo (HR 0.5, 95% CI, 0.3-0.7; P<0.0001). Complete response occured in 2 pts with anlotinib and 0 pt with placebo. The objective response rates were 7% in the anlotinib group and 4% in the placebo group (P=0.498), and the disease control rates (DCR) were 64% and 18%, respectively (P<0.0001). In anlotinib arm, median duration of response was 5.8 months (range, 3.1-19.7+). Grade 3/4 treatment-related adverse events (TRAE) were reported in 36.7% and 11.0% of the two group pts, and grade 5 TRAE were 2.8% and 0%, respectively. The most common grade 3/4 TRAE (>5%) in anlotinib arm were hypertension (15.6%) and loss of appetite (5.5%). Median overall survival were similar between the groups (6.1 months vs 7.2 months; HR 1.2, 95%CI 0.8-1.8, P=0.4261). The ratio of pts received post study treatments was 41.2% (40/97) in anlotinib arm and 72.7% (40/55) in placebo arm (P=0.0002), including chemotherapy (23.7% vs 54.6%), PD-1 inhibitors (4.1% vs 11.0%), and Apatinib, a VEGFR inhibitor, (10.3% vs 20.0%), etc. Conclusions: In pretreated advanced ESCC pts, anlotinib significantly improved PFS and DCR compared with placebo, with a manageable safety profile. Clinical trial information: NCT02649361.

scholarly journals Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial

2020 ◽  
Vol 38 (34) ◽  
pp. 4095-4106
Author(s):  
Chunyan Lan ◽  
Jingxian Shen ◽  
Yin Wang ◽  
Jundong Li ◽  
Zhimin Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Advanced Cervical Cancer ◽  
Open Label ◽  
Duration Of Response ◽  
Grade 3

PURPOSE Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, in patients with advanced cervical cancer. METHODS This multicenter, open-label, single-arm, phase II study enrolled patients with advanced cervical cancer who progressed after at least one line of systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once per day. The primary end point was objective response rate (ORR) assessed by investigators per RECIST version 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, and safety. RESULTS Forty-five patients were enrolled and received treatment. Median age was 51.0 years (range, 33-67 years), and 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease. Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months (range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months to not estimable). Median duration of response and median OS were not reached. Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). The most common potential immune-related AEs included grade 1-2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%). CONCLUSION Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.

Nilotinib is associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7039-7039
Author(s):  
E. Jabbour ◽  
P. le Coutre ◽  
M. Baccarani ◽  
K. Bhalla ◽  
G. J. Ossenkoppele ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Open Label ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant ◽  
Secondary Endpoints ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Grade 3

7039 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib and is an important therapeutic option for patients (pts) who have either imatinib-resistant or -intolerant CML disease. Results of a subset of pts with Ph+ CML-CP who received nilotinib for imatinib-intolerance are reported Methods: Pts were part of a phase II open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP. Imatinib intolerance was defined as no MCyR and discontinuation of imatinib due to Grade 3/4 AEs or persistent (> 1 mo) or recurrent Grade 2 AE (recurred > 3 times) despite optimal supportive care. The proportion of pts achieving MCyR was the primary endpoint, and safety and toxicity were secondary endpoints. Planned starting dose was nilotinib 400mg BID. Results: Of the 316 pts with CML-CP enrolled, 95 (30%) pts had imatinib-intolerance for either non-hematologic and/or hematolgic AEs. Some pts had more then one AE satisfying the criteria for intolerance. The frequency of intolerant symptoms for imatinib and nilotinib is shown in the table below. Only 2/80 (3%) pts with non-hematologic imatinib-intolerance experienced a recurrence of similar symptoms during nilotinib therapy. 33 patients entered the study due to hematologic intolerance (neutropenia, thrombocytopenia) and only 7/33 (21%) developed similar problems. In 86 pts with intolerance and at least 6 mos of follow up, 55% of these patients achieved MCyR, similar to that previously reported for imatinib-resistant patients. Conclusions: These are the first reported results evaluating cross intolerance symptoms to TKIs. The results demonstrate that nilotinib is effective in imatinib-intolerant CML-CP and has a very low rate of cross- intolerance, further supporting the excellent tolerability of nilotinib No significant financial relationships to disclose. [Table: see text]

Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response and prolonged stable disease observed in adenocarcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 91-91
Author(s):  
Geoffrey Y. Ku ◽  
Yelena Yuriy Janjigian ◽  
Manish A. Shah ◽  
Jessica Herrera ◽  
Laura H. Tang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Secondary Endpoints ◽  
Grade 3

91 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial of sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We performed a phase II trial of single-agent sorafenib with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response and toxicity. Methods: Patients (Pts) with measurable metastatic E and GEJ cancer with ≤3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Thirty-five patients have been accrued, with 34 evaluable; median age 62, 31 male, 4 female, median KPS 80%, E 25, GEJ 10, adenocarcinoma (AC) 30 squamous 5, median no. of prior therapies 2. Of 31 response-evaluable Pts, 1 (3%) ongoing complete response was noted (34+ months) in a Pt with E AC with biopsy-proven lymph node recurrence after chemoradiation and surgery; 23 Pts (74%) had stable disease. Median PFS is 3.7 months (95% CI 1.9 to 4 months), with median overall survival 8.9 months (95% CI 6.9 to 11.6 months). Four patients remain on treatment. Significant grade 3 toxicities included hand foot reaction (3 Pts), rash (1 Pt), dehydration (3 Pts) and fatigue (2 Pts). Twenty-seven of 33 tumors (82%) tested positive for phospho-ERK by immunohistochemistry. Conclusions: Encouraging activity in terms of PFS has been noted in this heavily pre-treated population. Updated data will be presented. Supported by a grant from Bayer. Clinical trial information: NCT00917462.

First-line durvalumab + monalizumab, mFOLFOX6, and bevacizumab or cetuximab for metastatic microsatellite-stable colorectal cancer (MSS-CRC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 128-128
Author(s):  
Zev A. Wainberg ◽  
Jennifer Robinson Diamond ◽  
Giuseppe Curigliano ◽  
Sanjeev Deva ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase 1 ◽  
Objective Response ◽  
Biologic Agent ◽  
First Line ◽  
Open Label ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps

128 Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC ( RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m2 QW (up to 500 mg/m2 Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435. [Table: see text]

Denosumab for the treatment of bisphosphonate-refractory hypercalcemia of malignancy (HCM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20512-e20512
Author(s):  
Mimi I-Nan Hu ◽  
Ilya Glezerman ◽  
Sophie Leboulleux ◽  
Karl L. Insogna ◽  
Rasim A. Gucalp ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Serum Calcium ◽  
Complete Response ◽  
Osteonecrosis Of The Jaw ◽  
Open Label ◽  
Serious Adverse Events ◽  
Duration Of Response ◽  
New Treatment ◽  
Grade 3

e20512 Background: HCM, caused primarily by tumor-induced bone resorption, is treated with intravenous (IV) bisphosphonates (BisP), but patients (pts) can relapse or become refractory. Denosumab binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods: In this single-arm, open-label, proof-of-concept study, pts with HCM (corrected serum calcium [CSC] >12.5 mg/dL [CTCAE grade ≥3]) despite IV BisP treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 28, then every 4 weeks. The primary endpoint was the proportion of pts with CSC ≤11.5 mg/dL (CTCAE grade ≤1) within 10 days of denosumab initiation. Results: The study enrolled33 pts (64% men; mean age 60 years; 76% with advanced solid tumors, 39% with bone metastases [BM]), with a median (25th, 75th percentile [Q1, Q3]) follow-up of 56 (18, 79) days. Median (Q1, Q3) baseline CSC was 13.7 (13.2, 14.2) mg/dL; 19 pts (58%) had HCM symptoms. Median (Q1, Q3) time from last BisP treatment to first dose was 17 (13, 22) days. At day 10, 21 pts (64%) reached CSC ≤11.5 mg/dL, including 54% of pts with BM and 70% without BM. Over the course of the study, 23 pts (70%) reached CSC ≤11.5 mg/dL, by a median (95% confidence interval [CI]) of 9 (5–19) days. A complete response (CSC ≤10.8 mg/dL, as defined by previous studies) occurred in 12 pts (36%) at day 10, and in 21 pts (64%) during the study, by a median (95% CI) of 23 (11–43) days. Among pts who reached CSC ≤11.5 mg/dL, the median (95% CI) duration of response was 104 (9–not estimable) days. The most frequently reported serious adverse events were worsening of HCM (5 pts, 15%) and dyspnea (3 pts, 9%). Two pts had isolated episodes of CSC levels ≤8.0 mg/dL (CTCAE grade 2); no pts had CSC <7.0 mg/dL (grade 3). No osteonecrosis of the jaw was reported. Conclusions: In this study of pts with HCM despite recent IV BisP treatment, denosumab effectively lowered serum calcium to grade ≤1 in 64% of pts within 10 days, and induced durable responses. These findings are particularly meaningful given that pts entered this study with grade ≥3 HCM within a median 17 days after receiving IV BisP. No unexpected safety findings were identified. Denosumab may offer a new treatment option for HCM in these pts. Clinical trial information: NCT00896454.

Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4012-4012 ◽  
Author(s):  
Thomas Yau ◽  
Yoon-Koo Kang ◽  
Tae-You Kim ◽  
Anthony B. El-Khoueiry ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Disease Progression ◽  
Objective Response ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Endpoints ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Clinical Trial Information

4012 Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]

Interim analysis of the AVETUXIRI Trial: Avelumab combined with cetuximab and irinotecan for treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC)—A proof of concept, open-label, nonrandomized phase IIa study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 80-80
Author(s):  
Marc Van Den Eynde ◽  
Nicolas Huyghe ◽  
Astrid De Cuyper ◽  
Isabelle Sinapi ◽  
Marie Ferrier ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Tumor Cell Death ◽  
Open Label ◽  
Stage Design ◽  
Primary Endpoints ◽  
Starting Dose ◽  
Immunogenic Tumor Cell ◽  
Secondary Endpoints ◽  
Grade 3

80 Background: Immune checkpoint inhibitors have demonstrated poor efficacy in MSS mCRC. Previous research indicate that cetuximab (anti-EGFR chimeric monoclonal antibody) could initiate, independently from RAS mutation, an immunogenic tumor cell death and mediate antitumor immune response. In this trial, we aim to explore the clinical efficacy and safety of anti-PDL1 avelumab (AVE) combined with cetuximab (CET) and irinotecan (IRI) for treatment refractory MSS mCRC. Methods: AVETUXIRI (NCT03608046) is a multicenter academic study recruiting MSS, BRAFV600E wt, mCRC patients (pts) refractory to standard treatment (fluoropyrimidine, oxaliplatin, irinotecan and anti-EGFR treatment if RAS wt tumor) in 2 cohorts (cohort A: RAS wt – cohort B: RAS mut). In both cohorts, patients receive CET (400 mg/m2 W1, 250 mg/m2 W2, 500 mg/m2/2 weeks from W3), IRI (180 - 150 mg/m2/2 weeks from W1) and AVE (10 mg/kg/2 weeks starting from W3). Primary endpoints are overall response rate (ORR), defined as partial or complete response (PR or CR) according (i)RECIST1.1, and safety. Secondary endpoints include disease control rate (DCR), PFS and OS. Based on a Simon 2-stage design for ORR in each cohort (cohort A: P0=0.15, P1=0.33 / cohort B: P0=0.09, P1=0.25 / α = 0.1, β = 0.2 in both cohorts), 10 and 13 patients are required in the first stage of cohort A and B respectively. At least 2 pts have to reach PR or CR in each cohort to allow the continuation of the trial in the 2nd stage. Results: Between Oct 2018 and Jan 2020, 23 patients (median age 62 y-old, 86.9% male 78.3% left-sided, 91.3% synchronous mCRC) have been included in the first stage of the trial. No major or unexpected safety events were observed. 21.7% (5/23) of pts presented grade 3 diarrhea, all related to IRI, with complete resolution after IRI dose reduction or interruption. A reduced starting dose of IRI (150 mg/m2) was amended (09/2019) for the last included 8 pts without any grade 3-4 diarrhea occurrence. Grade 1-2 hypothyroidism was the only immune-related side effect. 3 PR were observed in cohort A and none in cohort B. DCR was 60.0% (6/10) and 61.5% (8/13) in cohort A and B respectively. Median PFS and OS were respectively 4.2 and 12.7 months (cohort A) and 3.8 and 14.0 months (cohort B). 6 months-PFS rate was 40.0% and 38.5% in cohort A and B. 12 months-OS rate was 53.3% and 57.7% in cohort A and B. The median follow-up of patients was 9.2 months. Conclusions: The AVETUXIRI trial met its primary efficacy endpoint for RAS wt mCRC pts justifying the study continuation in cohort A (2nd stage). No PR was observed in RAS-mut cohort. Nevertheless, encouraging data of DCR, PFS and OS observed in RAS mut cohort allow the opening of a new cohort for RAS-mut mCRC (cohort C) with PFS as primary endpoint. Clinical trial information: NCT03608046.

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