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.

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.

SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2578-2578 ◽  
Author(s):  
Alain Patrick Algazi ◽  
James Moon ◽  
Bartosz Chmielowski ◽  
Roger Lo ◽  
Kari Lynn Kendra ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Advanced Solid Tumors ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Braf Mutant

2578 Background: Aberrant PI3K/AKT signaling in BRAF mutant cancers contributes to resistance to MAPK pathway blockade. We conducted parallel phase 1 dose escalation studies of the doublet of the BRAFi dabrafenib with the AKT inhibitor GSK2141795 and of the triplet of dabrafenib, the MEKi trametinib, and GSK2141795. Methods: Patients (pts) with BRAF-V600E/K mutant advanced solid tumors with adequate end-organ function were eligible regardless of prior BRAFi and MEKi exposure. All pts received dabrafenib at 150 mg twice daily (bid), in the doublet cohorts together with dose escalation (3 + 3 scheme) of GSK2141795 started at 50 mg daily (qd), and in the triplet cohorts with dose escalation of both trametinib starting at 1.5 mg qd and GSK2141795 starting at 25 mg qd. DLTs included significant grade 3 and 4 adverse events (CTCAE v4) within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. Results: No DLTs were observed in the doublet cohorts (N = 8) up to dabrafenib 150 mg bid and GSK2141795 75 mg qd. In the triplet cohorts (N = 11), no DLTs were observed at doses of up to trametinib 1.5 mg daily with GSK2141795 75 mg daily. At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash. 2/2 treatment-naïve in the doublet cohorts had PRs (1 melanoma and 1 thyroid) the latter lasting over 1 year. 1/6 BRAF inhibitor-refractory (melanoma) pts also had an objective response. In the triplet cohorts, 3 of 6 treatment-naïve pts had a PR (1 melanoma, 2 lung). One lung pt remains in PR at 2 months and the otherhas an uPR at 1.2 months. Conclusions: Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted. Funding: Supported in part by NIH/NCI grants CA180888, CA180819; and in part by Novartis Pharmaceuticals Corporation and GlaxoSmithKline, LLC. Clinical trial information: NCT01902173.

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.

SGN228-001: A phase I open-label dose-escalation, and expansion study of SGN-CD228A in select advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3652-TPS3652 ◽  
Author(s):  
Amita Patnaik ◽  
Funda Meric-Bernstam ◽  
Caio Max Sao Pedro Rocha Lima ◽  
Francisco Robert ◽  
Afshin Dowlati ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Metastatic Breast ◽  
Ductal Adenocarcinoma ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Disease Specific

TPS3652 Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480 .

AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody with improved therapeutic potential for the treatment of patients with advanced malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Steven O'Day ◽  
Chethan Ramamurthy ◽  
Andrea J. Bullock ◽  
Anthony B. El-Khoueiry ◽  
Lernik Ohanjanian ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
First Generation ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Study

TPS3157 Background: AGEN1181 is a novel Fc-optimized anti-CTLA4 antibody, currently being evaluated in an ongoing multi-center, open-label, phase 1 study in all advanced solid tumors as mono-therapy and combination with anti-PD-1 antibody, AGEN2034 (NCT03860272). AGEN1181 is Fc-engineered to harness a novel mechanism for enhanced FcγR-dependent functionality relative to first-generation CTLA-4 antibodies. In pre-clinical models, AGEN1181 enhances T cell priming, depletion of intratumoral regulatory T cells (Treg) and improved memory formation compared to first-generation anti-CTLA-4 antibodies. Most notably, AGEN1181 demonstrates improved binding to FcyRIIIA and superior T cell responsiveness in populations that only express the low affinity FcγRIIIA receptor relative to first-generation IgG1 CTLA-4 antibodies. The combination of AGEN1181 and AGEN2034 further enhances T cell activation and effector function. Methods: This phase 1 study is an open-label, multi-center dose-escalation designed to evaluate the safety, tolerability, dose limiting toxicity (DLT) PK, and pharmacodynamic profiles of patients with refractory advanced solid tumors who did not receive an anti-CTLA4 previously. The study is being conducted in 3 arms; with patients assigned using a standard 3+3 dose escalation design in the mono-therapy arms with AGEN1181 and an accelerated design in the combination with AGEN2034 arm. AGEN1181 is administered as IV infusion as mono-therapy on Day 1 of every 3 weeks (0.1,0.3,1,2,4 mg/kg), every 6-weeks (1,2,4 mg/kg) in parallel cohorts and every 6-weeks (0.1,0.3,1,2,4 mg/kg) in combination with AGEN2034 (3mg/kg Q2Weeks) until disease progression or unacceptable toxicity (maximum 2 years). All 3 Arms are open and enrolling patients. The study is expected to enroll approximately 80 evaluable patients with solid tumors. Dose reductions are not allowed in the event of AGEN1181-related toxicities. Currently 3 cohorts have been completed, first cohort in the combination arm and the fourth cohort in the monotherapy arm are enrolling. Preclinical and clinical assessment of AGEN1181 supports continued development as a potential therapy for refractory or relapsed advanced solid tumors. Clinical trial information: NCT03860272 .

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

scholarly journals CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

2021 ◽  
Vol 9 (7) ◽  
pp. e002446
Author(s):  
Rachel E Sanborn ◽  
Omid Hamid ◽  
Elisabeth GE de Vries ◽  
Patrick A Ott ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Anal Squamous Cell Carcinoma ◽  
Grade 3

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

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