A phase I, open-label, nonrandomized, pharmacokinetic study of trifluridine/tipiracil (TAS-102) in Chinese patients with solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14079-e14079
Author(s):  
Xicheng Wang ◽  
Jianfeng Zhou ◽  
Yan Li ◽  
Yuping Ge ◽  
Yanping Zhou ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Open Label ◽  
Significant Difference ◽  
Inactive Metabolite ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Experienced Grade ◽  
Clinical Trial Information

e14079 Background: Trifluridine/tipiracil (TAS-102) is an oral combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and the thymidine phosphorylase inhibitor, tipiracil (TPI). Trifluridine/tipiracil is demonstrated as a valid treatment choice for Asian and Western patients (pts) with metastatic colorectal cancer refractory or intolerant to standard chemotherapies in earlier studies. Its pharmacokinetic (PK) profile was also investigated in American and Japanese phase 1 studies, but never in Chinese pts. This study was conducted to investigate the PK profile of Trifluridine/tipiracil in a Chinese population with solid tumors. Methods: Pts who has responded poorly to existing standard treatment received Trifluridine/tipiracil (35 mg/m2/dose), orally BID, on days 1-5 and days 8-12 every 4 weeks until one of discontinuation criteria was met. Blood samples for PK analysis of FTD (the active compound), fluorothymine (FTY, inactive metabolite) and TPI were collected after single and multiple doses of Trifluridine/tipiracil on days 1 and 12 of cycle 1. The safety, tolerability, and antitumor activity of Trifluridine/tipiracil were also assessed as secondary endpoints. Results: A total of 15 pts were administered Trifluridine/tipiracil and analyzed for PKs. The PKs of FTD, FTY, and TPI in Chinese pts were comparable to those in Japanese pts. Compared with American pts, although the AUC0-t of TPI on day 12 was significantly lower in Chinese pts, the Cmax and AUC0-t of FTD were not significantly different. Thirteen (86.7%) pts reported treatment-emergent adverse events (TEAEs), and eight (53.3%) pts experienced grade 3 TEAEs, of which anemia and fatigue were most frequently (≥10% of patients) reported. Grade 4 or 5 TEAEs were not observed. Conclusions: The PKs of Trifluridine/tipiracil in Chinese pts were comparable to those in Japanese pts. The exposure of FTD was showed without significant difference between Chinese, Japanese and American pts. Trifluridine/tipiracil was well-tolerated in Chinese pts and had the similar safety profile in comparison with previous studies. Clinical trial information: NCT02261532.

scholarly journals Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study

2020 ◽  
Vol 8 (1) ◽  
pp. e000437
Author(s):  
Lin Shen ◽  
Jun Guo ◽  
Qingyuan Zhang ◽  
Hongming Pan ◽  
Ying Yuan ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Verification ◽  
Open Label

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Raymond P. Perez ◽  
Matthew John Riese ◽  
Karl D. Lewis ◽  
Mansoor N. Saleh ◽  
Adil Daud ◽  
...  
Keyword(s):  
Phase 1 ◽  
Open Label ◽  
Common Grade ◽  
Open Label Phase ◽  
Study Population ◽  
N Dose ◽  
Grade 3 ◽  
Tumor Types ◽  
Preliminary Phase ◽  
Clinical Trial Information

3003 Background: ECHO-204 is an ongoing, open-label, phase 1/2 (P1/2) study of epacadostat (E; potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (NSCLC, MEL, OVC, CRC, SCCHN, B-cell NHL [including DLBCL], GBM). Preliminary P1/2 safety and tolerability outcomes for the overall study population and P2 response for select tumor types (SCCHN, MEL, OVC, CRC) are reported. Methods: In P1 dose escalation, pts received E (25, 50, 100, 300 mg BID) + N (3 mg/kg Q2W); in P2 cohort expansion, pts received E (100 or 300 mg BID) + N (240 mg Q2W). Safety/tolerability was assessed in pts receiving ≥1 E + N dose. Response was assessed in RECIST v1.1 evaluable pts; for recently enrolled pt subgroups, only preliminary DCR (CR+PR+SD) is presented. Results: As of 29OCT2016,241 pts (P1, n = 36; P2, n = 205) were enrolled. No DLT was observed in P1. Most common TRAEs (≥15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%, respectively), fatigue (26% and 31%), and nausea (24% and 19%). Rash was the most common grade ≥3 TRAE in E 100 mg and E 300 mg subgroups (10% and 12%). TRAEs led to discontinuation in 7% (E 100 mg) and 13% (E 300 mg) of pts. There were no TR-deaths. For the 23 recently enrolled, efficacy-evaluable SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14). Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD).Safety/efficacy evaluations are ongoing for all cohorts. Conclusions: E + N was generally well tolerated up to the maximum E 300-mg dose. P2 ORR/DCR outcomes are promising, particularly in SCCHN and MEL pts. Updated data will be presented at the meeting. Clinical trial information: NCT02327078.

Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Tara C. Gangadhar ◽  
Bryan J. Schneider ◽  
Todd Michael Bauer ◽  
Jeffrey S. Wasser ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Test Results ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase ◽  
History Of ◽  
Grade 3 ◽  
Preliminary Phase ◽  
Clinical Trial Information

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3557-3557 ◽  
Author(s):  
L. Chow ◽  
Z. Jiang ◽  
R. Epstein ◽  
I. Bondarenko ◽  
A. Awada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Metastatic Breast ◽  
Open Label ◽  
Disease Stabilization ◽  
Tumor Measurements ◽  
Grade 3 ◽  
Tumor Types ◽  
Age Range

3557 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB inhibitor of the tyrosine kinase receptors, erbB-1,-2 and -4. In this phase 1 study, a combination dose of neratinib plus paclitaxel that is tolerable was determined in patients (pts) with solid tumors, and safety and preliminary efficacy were assessed in pts with erbB-2+ metastatic breast cancer. Methods: In this open label, 2-part study, ascending multiple daily oral doses of neratinib (160 mg, 240 mg) were administered in combination with IV paclitaxel 80 mg/m2, if tolerable, or 70 mg/m2 on days 1, 8 and 15. Pts with solid tumors and pts with only metastatic erbB-2+ breast cancer are enrolled in part 1 and 2, respectively. Tumor measurements were made at screening and at every 8 weeks (2 cycles) by modified RECIST criteria. Timed blood samples were collected for neratinib and paclitaxel plasma concentration determination, and PK analyses were performed using a noncompartmental method. Results: Data for 54 pts as of 30 Oct 2008 are presented (median age [range] of 51.5 [20–74] yrs; 91% female; 26 % with prior trastuzumab treatment of median duration [range] 32.5 [10–52] wks; 15% with prior lapatinib treatment). Tumor types in part 1 included breast, endometrial, cervical, colorectal and esophageal cancer. There were no dose-limiting toxicities (DLTs) at the 240 mg neratinib-80 mg/m2 paclitaxel dose, and as standard doses of neratinib and paclitaxel were reached, there was no reason for further escalation. Neratinib-related AEs, any grade in ≥10% of pts included diarrhea (50%), neutropenia (17%), rash (13%), nausea (11%) and vomiting (11%). Neratinib- related AEs, grade ≥3 in ≥2% of pts were diarrhea (20%), neutropenia (9%) and dehydration (4%). Only 2 pts (at the 240 mg neratinib-80 mg/m2 paclitaxel dose) had dose reductions due to diarrhea. In 35 efficacy evaluable pts, 5 had confirmed partial response (PR). Confirmed clinical benefit (PR and prolonged disease stabilization) was seen in 2 pts in part 1, 1 pt with endometrial cancer and 1 pt with cervical cancer. Conclusions: This combination of 240 mg neratinib and 80 mg/m2 paclitaxel was tolerable with a toxicity profile similar to that observed for neratinib, and had promising antitumor activity in pts with solid tumors and erbB-2 + breast cancer. [Table: see text]

A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2538-2538 ◽  
Author(s):  
Sarah Leary ◽  
Julie R. Park ◽  
Joel M. Reid ◽  
Andrew T. Ralya ◽  
Sylvain Baruchel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Central Line ◽  
Maximum Tolerated Dose ◽  
Tie2 Receptor ◽  
Grade 3 ◽  
Angiopoietin 2 ◽  
Dose Levels ◽  
Clinical Trial Information ◽  
Angiopoietin 1

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.

Pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) in patients with gastric cancer and peritoneal metastasis (PIPAC-GA1).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Florian Struller ◽  
Philipp Horvath ◽  
Wiebke Solass ◽  
Frank Jurgen Weinreich ◽  
Alfred Konigsrainer ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Peritoneal Metastasis ◽  
Low Dose ◽  
Tumor Regression ◽  
Open Label ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Clinical Trial Information

99 Background: Efficacy of 2nd and 3rdline chemotherapy in recurrent gastric cancer with peritoneal metastasis (RGCPM) is limited. We assessed the feasibility, safety and activity of intraperitoneal chemotherapy as PIPAC C/D in RGCPM after > 1 line of intravenous chemotherapy. Methods: Open-label, single-arm, Phase II ICH-GCP Clinical Trial (NCT01854255) Patients were scheduled for 3 courses q42 days of low-dose PIPAC with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2. Primary endpoint was objective tumor response (RECIST 1.1). Secondary endpoints were safety (CTCAE 4.0), histological tumor regression (PRGS) and overall survival. Results: 25 patients were enrolled. 10/25 (40 %, ITT) patients had an OTR. Complete or major regression on histology was observed in 9/12 (75 %) patients who underwent at least 2 PIPAC cycles. Mean overall survival was 8.4 months (13.1 months in patients with PCI < 12). There were no treatment-related deaths, no grade 4 toxicity and four (16%) grade 3 toxicities. Conclusions: PIPAC C/D is well tolerated and active in patients with RGCPM. Survival is encouraging. Randomized controlled trials should now be designed. Clinical trial information: NCT01854255. [Table: see text]

Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3017-3017 ◽  
Author(s):  
Salvatore Siena ◽  
Robert Charles Doebele ◽  
Alice Tsang Shaw ◽  
Christos Stelios Karapetis ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Integrated Analysis ◽  
Data Sets ◽  
Cns Metastases ◽  
Prior Therapy ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Clinical Trial Information

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]

Updated safety and efficacy of MSB2311 (an anti-programmed death-ligand 1 antibody) in Chinese patients with advanced solid tumors and hematological malignancies from a phase 1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14547-e14547
Author(s):  
Lin Shen ◽  
Jifang Gong ◽  
Jian Zhang ◽  
Dongmei Ji ◽  
Haijun Zhong ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Phase 1 ◽  
Chinese Patients ◽  
Binding Property ◽  
Advanced Solid Tumors ◽  
Tumor Patients ◽  
Durable Response ◽  
Programmed Death ◽  
Grade 3

e14547 Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.

A phase 1/2 study of intratumoral INT230-6 alone (IT-01) or in combination with pembrolizumab [KEYNOTE-A10] in adult subjects with locally advanced, unresectable and metastatic solid tumors refractory to therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2592-2592
Author(s):  
Anthony B. El-Khoueiry ◽  
Jacob Stephen Thomas ◽  
Anthony J. Olszanski ◽  
Nilofer Saba Azad ◽  
Giles Francis Whalen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tumor Regression ◽  
Phase 1 ◽  
Locally Advanced ◽  
Tumor Burden ◽  
Exploratory Analysis ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3 ◽  
Metastatic Sites

2592 Background: Study IT-01 (KEYNOTE-A10) evaluates INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer designed for intratumoral (IT) administration, alone or in combination with pembrolizumab (PEM), an antibody to PD-1. INT230-6 dosing is set by a tumor’s volume. In preclinical studies, INT230-6 increases drug dispersion throughout the tumor, allows drug diffusion into cancer cells and recruits dendritic, CD4 and CD8 T cells. The addition of PEM has been shown to improve these responses in models. Phase 1 data indicated INT230-6 alone induced tumor regression in both injected and non-injected lesions. Considering the large volume of drug injected and retained in the tumor, coupled with immune infiltration on biopsies, RECIST response methodology may not capture the benefit of INT230-6 treatment. Methods: IT-01 is an open-label phase 1/2 study, currently enrolling adult subjects with solid tumors in phase 2. INT230-6 was administered IT Q2W for 5 doses alone or with PEM 200mg Q3W. The study seeks to assess the safety and efficacy of IT INT230-6 alone and in combination with PEM. Results: 67 subjects have been enrolled (58 mono and 12 INT230-6 + PEM (3 started in mono, then received combo)) having a median of 3 prior therapies (0, 10). Median age was 60 (42, 85). 20+ cancer types were accrued; breast cancer and sarcoma were the most frequent. Over 500 image guided INT230-6 IT injections were given (253 to deep tumors) at doses of 0.3 to 172mL (86 mg CIS, 17.2 mg VIN) in a single session, which are higher amounts than typical IV doses. PK shows that 95% of INT230-6 active agents remain in the tumor. The most common (> 20%) related TEAEs for INT230-6 alone were localized pain (57%), nausea (36%), fatigue (29%) and vomiting (24%); with grade 3 TEAEs (> 1) of localized pain (5%) and anemia (3%). The safety in the combination was similar. There were no related grade 4 or 5 TEAEs. In evaluable monotherapy subjects (n = 43), the disease control rate (DCR) was 65% vs. 100% in PEM subjects (n = 5). Given the range of dose and entering tumor burden, an exploratory analysis of dose relative to tumor burden (TB) showed that subjects receiving a dose of INT230-6 < 50% of their reported TB (n = 30) had a mOS of 3.5 months. While in subjects receiving a dose of INT230-6 to ≥50% of TB (n = 37), mOS has not yet been reached after a median follow up of 9.5 months (HR: 0.26 (0.13,0.51)). Conclusions: INT230-6 is well tolerated when administered IT as monotherapy and combined with PEM. Given the challenge in assessing overall response rate following IT delivery, an exploratory analysis suggests prolonged survival for subjects receiving an INT230-6 dose ≥50% of their tumor burden compares favorably to the < 50% group and to literature accounting for prognostic factors (ECOG, LDH, # of metastatic sites). Clinical trial information: 03058289.

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