scholarly journals Intratumoral Combinatorial Administration of CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 670
Author(s):  
Julia Katharina Schwarze ◽  
Gil Awada ◽  
Louise Cras ◽  
Jens Tijtgat ◽  
Ramses Forsyth ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Solid Tumors ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Advanced Solid Tumors ◽  
Myeloid Dendritic Cells ◽  
Injection Site Reactions ◽  
Best Response ◽  
Induce Antibody

Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG1 monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)+ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 106 CD1c (BDCA-1)+ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumonitis (n = 2), colitis (n = 1), and bullous pemphigoid (n = 1). The best response was a durable partial response in a patient with stage IV melanoma who previously progressed on checkpoint inhibitors. Our combinatorial therapeutic approach, including IT injection of CD1c (BDCA-1)+ myDCs, is feasible and safe, and it resulted in encouraging signs of antitumor activity in patients with advanced solid tumors.

A phase Ib clinical trial on intratumoral administration of autologous CD1c (BDCA-1)+ myeloid dendritic cells (myDC) in combination with ipilimumab (IPI) and avelumab (AVE) plus intravenous low-dose nivolumab (NIVO) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14012-e14012 ◽  
Author(s):  
Julia Katharina Schwarze ◽  
Gil Awada ◽  
Louise Cras ◽  
Ramses Forsyth ◽  
Ivan Van Riet ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Total Dose ◽  
Solid Tumors ◽  
Low Dose ◽  
Tumor Antigens ◽  
Study Drug ◽  
Advanced Solid Tumors ◽  
Myeloid Dendritic Cells ◽  
Primary Endpoints ◽  
Anti Tumor Activity

e14012 Background: Intratumoral (IT) myDC play a pivotal role in initiating antitumor immune responses and "re-licensing” of antitumor cytotoxic T-lymphocytes within the tumor microenvironment. IT injection of anti-PD-L1 IgG1 mAb AVE and anti-CTLA-4 IgG1 mAb IPI may reduce the number of regulatory T cells and lyse PD-L1+ tumor cells, thereby releasing tumor antigens that can be captured and processed by IT co-administered CD1c (BDCA-1)+ myDC, reinvigorating the cancer immunity cycle. Methods: Patients (pts) with advanced solid tumors who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastasis with IPI (max total dose of 10 mg) and AVE (max total dose of 40 mg) plus IV NIVO (10 mg) on day 1 followed by IT injection of autologous, non-substantially manipulated CD1c (BDCA-1)+ myDC on day 2. Administration of AVE, IPI, and NIVO was repeated every 14 days thereafter. Primary endpoints were safety and feasibility. Repetitive FNA cytology/IHC of treated lesions was performed. Results: In this ongoing trial, 6 pts (3x melanoma, 1x epithelial ovarian carcinoma, 2x triple negative breast carcinoma) were treated with IT injection of a median of 27,2x106 (range 10-43x106) CD1c (BDCA-1)+ myDC and a median of 5 (range 2-10) study drug administrations. At time of this analysis 3 pts are evaluable for response: an ongoing PR ( > 8 months) was documented in a melanoma pt who previously progressed on PD-1 and CTLA-4 inhibitors. In 2 other melanoma pts regression of the injected metastases coincided with progression of non-injected metastases. Adverse events consisted of transient grade(G)2 local pain at injection site in 2 pts, G1 pruritus in 2 pts, G2 pneumonitis in 1 pt, G1 rash in 1 pt, and pruritus and redness of the skin overlaying the injected lesion in 1 pt. Analysis of cytology/IHC results is ongoing. Conclusions: IT injection of autologous CD1c (BDCA-1)+ myDC with IT co-injection of AVE and IPI plus IV low-dose NIVO is feasible and tolerable and resulted in encouraging early signs of anti-tumor activity in injected as well as non-injected lesions. Clinical trial information: NCT03707808.

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 318-318 ◽  
Author(s):  
T. Doi ◽  
N. Fuse ◽  
T. Yoshino ◽  
H. Murakami ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Best Response ◽  
Grade 3

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

The association of toxicities and outcomes with circulating endothelial cells (CEC) in non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (Bev).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19012-e19012
Author(s):  
Nooshin Hashemi Sadraei ◽  
Lingling Du ◽  
Ruchi Yadav ◽  
Ronald Grane ◽  
Barbara Jacobs ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Healthy Subjects ◽  
Proportional Hazards ◽  
Stage Iv ◽  
Stage I ◽  
Circulating Endothelial Cells ◽  
Advanced Solid Tumors ◽  
Chi Square ◽  
Disease Characteristics ◽  
Nsclc Patients

e19012 Background: Bev in combination with chemotherapy (CT) is a standard treatment for pts with stage IV NSCLC. However, there are no established biomarkers to improve benefit-to-risk profile of therapy. CEC are a marker of vascular turnover. We hypothesized CEC may be associated with treatment outcome/toxicity. Methods: Stage IV NSCLC pts were treated with Bev along with CT of choice per clinician. CEC were measured at baseline and after 2 cycles of Bev-containing therapy. CellSearch (Veridex, New Jersey) was used to capture and quantify CEC via immunomagnetic and immunofluorescence techniques. CEC were enumerated as nucleated, CD146+/CD105+/CD45- cells in 4 mL of blood. For comparison, baseline CEC were also collected in 3 other groups; healthy subjects, stage I-III NSCLC, and advanced solid tumor pts. Chi-square tests and non-parametric methods were used to assess associations between CEC and pt/disease characteristics, toxicity, and proportional hazards models were used for comparisons of progression free and overall survival (PFS and OS). Results: Evaluated were 62 individuals: 29 stage IV NSCLC, 10 stage I-III NSCLC, 13 advanced solid tumors (melanoma, sarcoma, renal and adrenal cancers), and 10 healthy subjects. The median of CEC/ml blood in healthy subjects was 6. Based on its distribution, CEC >13/ml was deemed elevated. Elevated CEC was seen in 48% of stage IV NSCLC (median 12/ml), in comparison to 20% of stage I-III NSCLC (8/ml) and 23% of advanced solid tumors (6/ml) Baseline CEC in stage IV NSCLC was independent of patient/ disease characteristics including site of disease and tumor size. CEC increased during treatment in most patients (61%). CEC doubling between baseline and cycle2 was associated with more cytopenia and hemorrhage. (75% vs 20%, p=0.05 and p=0.03 for absolute and relative CEC changes). Baseline CEC and changes during treatment did not correlate with response (p≥ 0.32) and pts with elevated baseline CEC had a trend towards worse PFS (p=0.09) and OS (p=0.10). Conclusions: CEC are commonly elevated in advanced NSCLC. CEC increases may be predictive of adverse events from Bev-CT and when elevated at baseline may suggest worse PFS.

High baseline lymphocyte count is a predictive biomarker of prolonged time to progression in patients with advanced solid tumors receiving checkpoint inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Mariangela Maltese ◽  
Stefano Panni ◽  
Silvia Lazzarelli ◽  
Matteo Brighenti ◽  
Federica Negri ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Lymphocyte Count ◽  
Checkpoint Inhibitors ◽  
Absolute Lymphocyte Count ◽  
Predictive Biomarker ◽  
Rank Test ◽  
Advanced Solid Tumors ◽  
Time To Progression ◽  
Neutrophil Lymphocyte Ratio ◽  
Kaplan Meier

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.

Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2554-2554 ◽  
Author(s):  
Jermaine Coward ◽  
Vinod Ganju ◽  
Ramin Behzadigohar ◽  
Kenneth Kwong ◽  
June Xu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Human Study ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Duration Of Treatment ◽  
Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15068-e15068
Author(s):  
Vaibhav G. Patel ◽  
Qian Qin ◽  
Bo Wang ◽  
Mahalya Gogerly-Moragoda ◽  
George Mellgard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Model Systems ◽  
Beta Blockade ◽  
Clinical Activity ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Adrenergic Signaling

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.

A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
Sue Richter ◽  
Elaine McWhirter ◽  
Eric Xueyu Chen ◽  
Ben Tran ◽  
Sebastien J. Hotte ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Solid Tumors ◽  
Maculopapular Rash ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Gamma Secretase ◽  
Best Response ◽  
Recommended Phase Ii Dose ◽  
To Receive

3082 Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within <14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease > 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2654-TPS2654 ◽  
Author(s):  
Matthew David Hellmann ◽  
Toshio Shimizu ◽  
Toshihiko Doi ◽  
F. Stephen Hodi ◽  
Sylvie Rottey ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Phase ◽  
Phase 1B

TPS2654 Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

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