scholarly journals Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial

Author(s):  
Jifang Gong ◽  
Junning Cao ◽  
Qingyuan Zhang ◽  
Nong Xu ◽  
Yanqiu Zhao ◽  
...  

Abstract Background This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. Methods Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). Results As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1–2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3–5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. Conclusions Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  

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


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2564-2564
Author(s):  
Dominique Berton ◽  
Susana N. Banerjee ◽  
Giuseppe Curigliano ◽  
Sara Cresta ◽  
Hendrik-Tobias Arkenau ◽  
...  

2564 Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%–48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]


2020 ◽  
Vol 8 (1) ◽  
pp. e000437
Author(s):  
Lin Shen ◽  
Jun Guo ◽  
Qingyuan Zhang ◽  
Hongming Pan ◽  
Ying Yuan ◽  
...  

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.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Karen A. Autio ◽  
Talia Golan ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
...  

9509 Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cell–inflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points – primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3592-3592
Author(s):  
Keun Wook Lee ◽  
Sae-Won Han ◽  
Ji-Won Kim ◽  
Dae-Won Lee ◽  
Yong Sang Hong ◽  
...  

3592 Background: GC1118 is a novel anti-EGFR monoclonal antibody which has a unique binding epitope and superior ligand inhibition potential. It showed promising antitumor activity as a single agent in the phase I study. This study aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GC1118 in combination with irinotecan or FOLFIRI in metastatic solid tumors and evaluate the efficacy of GC1118 plus FOLFIRI as a second line therapy for RAS and BRAF wild-type metastatic colorectal cancer. Methods: Phase 1b part was designed to evaluate weekly GC1118 (starting from 3 mg/kg) in combination with biweekly irinotecan (180mg/m2) or FOLFIRI (irinotecan 180mg/m2, leucovorin 400mg/m2, 5-FU 400 mg/m2 bolus, and 5-FU 2400mg/m2 over 46hrs) in a 3+3 design. In the phase 2a part, the RP2D of GC1118 is administered in combination with FOLFIRI in a Simon’s two stage design with objective response rate (ORR) as the primary endpoint. Results: 13 pts were enrolled in phase 1b and received 3mg/kg of GC1118 with irinotecan (N = 6) or FOLFIRI (N = 7). DLT occurred in 2 pts (G4 neutropenia, G2 rash) in irinotecan arm and 1pt (G3 neutropenia) in FOLFIRI arm with 3mg/kg of GC1118 and it was determined as MTD and RP2D. Adverse events (AE) of grade ≥ 3 included neutropenia (61.5 %), skin rash (15.4 %) and diarrhea (15.4%). Dose reductions due to GC1118-related AE were required in 6 (46.2%) patients. Among 10 response-evaluable pts in phase 1b, best overall response was PR in 3 and SD in 6, and median PFS was 12 months. In stage 1 of phase 2a (N = 9), 4 PR and 5 SD were observed (ORR 44.4%, 95% CI 13.7 – 78.8). We moved to stage 2, and are currently enrolling additional 20 pts. AE of grade ≥ 3 included neutropenia (66.7%), skin rash (22.2%) and diarrhea (11.1%). Updated data of the phase 2a part will be presented at the meeting. Conclusions: The MTD and RP2D of weekly GC1118 in combination with irinotecan or FOLFIRI was 3mg/kg. Preliminary results of GC1118 and FOLFIRI as a 2nd line treatment in mCRC suggests promising antitumor activity and acceptable safety profile. Clinical trial information: NCT03454620 .


2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 33-33
Author(s):  
Shigehisa Kitano ◽  
Toshio Shimizu ◽  
Takafumi Koyama ◽  
Takahiro Ebata ◽  
Satoru Iwasa ◽  
...  

33 Background: Cemiplimab (REGN2810), a high-affinity, highly potent, human monoclonal antibody to PD-1, has demonstrated a safety profile comparable with that of other anti-PD-1 antibodies and antitumor activity in various solid tumors including cutaneous squamous cell carcinoma and non-small-cell lung cancer (NSCLC) in pts outside of Japan. We present analysis of Part 1 of a two-part, multicenter, open-label, Phase 1 study of cemiplimab in Japanese pts with advanced malignancies. Methods: Part 1 dose exploration pts received either cemiplimab 250 mg (n=6) or 350 mg (n=7) Q3W IV for up to 108 weeks. Tumor measurements were performed every 9 weeks according to RECIST 1.1. Data cut-off date was July 13, 2018. Results: Thirteen pts were enrolled: median age, 62 years (range: 33–75); 8 F. Twelve (92.3%) and 7 (53.8%) pts had received prior cancer-related systemic therapy and radiotherapy, respectively. Median duration of cemiplimab exposure was 13.1 weeks (range: 3.0–54.6). At the data cut-off date Part 1 was fully enrolled and 9 pts (69.2%) had discontinued treatment, primarily due to disease progression (n=7, 53.8%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection, each occurring in 3 pts (23.1%). The following grade ≥3 TEAEs occurred in 1 pt (7.7%): hypophosphatemia, hyponatremia, autoimmune colitis, and dehydration; the last two events occurred in the same pt. No dose-limiting toxicities were reported. Cemiplimab serum concentrations were as expected from the reported PK characteristics of cemiplimab. Objective response rate (ORR; complete response + partial response [PR]) and disease control rate (ORR + stable disease [SD]) were 23.1% (3 PR) and 53.8% (7/13; 4 SD), respectively. Conclusions: Cemiplimab exhibited substantial antitumor activity in Japanese pts with advanced malignancies. Cemiplimab 350 mg Q3W dosing regimen was selected for the expansion studies. The safety profile was comparable with those previously reported for cemiplimab and other anti-PD-1 agents. Part 2 is open and enrolling pts with NSCLC in Japan. Clinical trial information: NCT02760498.


2021 ◽  
pp. clincanres.0329.2021
Author(s):  
Naoko Takebe ◽  
Abdul Rafeh Naqash ◽  
Geraldine O'Sullivan Coyne ◽  
Shivaani Kummar ◽  
Khanh T. Do ◽  
...  

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3109-TPS3109 ◽  
Author(s):  
T.R. Jeffry Evans ◽  
Antoine Italiano ◽  
Ferry Eskens ◽  
Stefan Nicholas Symeonides ◽  
Alice Susannah Bexon ◽  
...  

TPS3109 Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.


2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS146-TPS146
Author(s):  
Joshua K. Sabari ◽  
Haeseong Park ◽  
Anthony W. Tolcher ◽  
Sai-Hong Ignatius Ou ◽  
Edward B. Garon ◽  
...  

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.


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