288 A phase 1 study of IMC-001, a PD-L1 blocker, in patients with metastatic or locally advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A315-A315
Author(s):  
Bhumsuk Keam ◽  
Tae Min Kim ◽  
Do-Youn Oh ◽  
Chan-Young Ock ◽  
Won Ki Kang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Dose Range ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Tract Cancer

BackgroundIMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 and mediate the antibody-dependent cell-mediated cytotoxicity. The main objectives of this study were to evaluate the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Here, we report final result of the phase 1 study of IMC-001.MethodsThis open-labeled phase 1 study used standard 3+3 dose-escalation design, dose ranging from 2 to 20 mg. IMC-001 was administered intravenously every two weeks until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) window was defined as 21 days from the first dose. Adverse events (AEs) were assessed using CTCAE v4.03, and tumor response was assessed by and the Response Evaluation Criteria In Solid Tumors (RECIST) version v1.1.ResultsFifteen subjects (8 Male, 7 Female; Median age : 58 [range 39–69]) were included in 5 dose escalation cohorts. No DLT was observed and the maximum tolerated dose was not reached. Most common AEs were general weakness, decreased appetite, fever, and cough. No Grade 4 or 5 treatment emergent AEs (TEAEs) were reported during the study and no TEAE or serious AE led to treatment discontinuation or death. There were no infusion-related reactions during this study. Grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001 were seen in one subject at 2 mg/kg cohort. Over the dose range of 2 to 20 mg/kg IMC-001, AUC 0-14d, AUC 0—∞, and Cmax generally appeared to increase in a dose proportional manner for each step of dose escalation. Of the 15 enrolled patients, one subject with colon cancer showed partial response, and disease control rate was 33.3%. There were total 3 biliary tract cancer patients (1 GB cancer, 2 Cholangiocarcinoma) who received ≥3 lines of systemic therapies prior to this trial. They all had stable disease during IMC-001 treatment, and one cholangiocarcinoma subject received the treatment for 434 days.ConclusionsIMC-001 demonstrated a favorable safety profile up to 20 mg/kg given IV every 2 weeks and showed encouraging preliminary efficacy in patients with advanced solid tumors. Based on PK and PD data, 20 mg/kg was selected as recommended Phase 2 dose (RP2D).Ethics ApprovalThis study was approved by Institutional Review Board; approval number SMC 2018-01-007-001 and H-1801-042-913.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul Harnett ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Autoimmune Hepatitis ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Karen A. Autio ◽  
Talia Golan ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Phase 1 Study

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.

Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2521-2521 ◽  
Author(s):  
Ben Tran ◽  
Richard D. Carvajal ◽  
Aurelien Marabelle ◽  
Sandip P. Patel ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Transitional Cell ◽  
Costimulatory Molecule ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

2521 Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade > 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses > 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.

Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Dae Ho Lee ◽  
Aflah Roohullah ◽  
Byoung Chul Cho ◽  
Charlotte Rose Lemech ◽  
Paul L. de Souza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Jason J. Luke ◽  
Anthony J. Olszanski ◽  
Igor Puzanov ◽  
Dan Lu ◽  
Adrian Hackett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Efficacy Evaluation ◽  
Open Label

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Marwan Fakih ◽  
Bert O'Neil ◽  
Timothy Jay Price ◽  
Gerald Steven Falchook ◽  
Jayesh Desai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Small Molecule ◽  
Phase 1 ◽  
Locally Advanced ◽  
Bound State ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Ecog Ps ◽  
Tumor Types

3003 Background: The KRASG12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRASG12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRASG12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.

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