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.

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.

A phase I/II, open-label, dose-escalation, and cohort-expansion study evaluating the safety, pharmacokinetics, and therapeutic activity of OBI-999 in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3657-TPS3657
Author(s):  
Apostolia Maria Tsimberidou ◽  
Jaffer A. Ajani ◽  
Pei Hsu ◽  
I-Ju Chen ◽  
Tillman E. Pearce
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Objective Response ◽  
Membrane Microdomains ◽  
Clinical Activity ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Tumor Cell Death

TPS3657 Background: Aberrant glycosylation is a hallmark of cancer. Glycosphingolipids (GSLs), glycans conjugated to a lipid (ceramide) core, are essential for the recruitment of immune-related proteins to specific membrane microdomains. Globo H (GH) is a GSL found on normal cells but highly overexpressed on various epithelial tumors playing a role in tumor development and progression. GH is a promising target for immunotherapy. OBI-999 is an ADC composed of a human recombinant immunoglobulin G (IgG) monoclonal antibody that selectively and specifically binds to GH, attached by a linker to the antimitotic agent monomethyl auristatin E (MMAE). Its mechanism of action is based on tumor-selective delivery of MMAE to GH-expressing tumors with subsequent tumor cell death. Preclinical studies demonstrated that OBI-999 antibody binds specifically to the GH antigen, and antitumor efficacy was noted in breast, gastric, pancreatic, and lung cancer xenograft models. The pharmacokinetics (PK) of OBI-999 were determined in normal and tumor-bearing mice, rats, and monkeys. Exposure of OBI-999 increased proportionally with dose. No sex difference or accumulation was seen. The primary objectives are to determine dose limiting toxicities (DLTs), the maximum tolerated dose (MTD), and the phase 2 recommended dose (P2RD). The secondary objectives are to assess the rates of objective response and clinical benefit, the duration of progression-free survival, the immunogenicity of OBI-999, and the PK and pharmacodynamics (PD) of OBI-999 and MMAE. Methods: In Part 1, a "3+3" dose-escalation part of the study, up to 30 patients with advanced solid tumors refractory to ≥1 line of systemic therapy, who cannot tolerate standard therapy, or for whom no standard treatment is available, regardless of GH status will be treated. OBI-999 will be administered as a 60-minute IV infusion using a dose range of 0.4, 0.8, 1.2, 1.6, and 2.0 mg/kg on day 1 of every 21-day cycle. In Part 2, the cohort-expansion portion of the study, patients will be treated at the MTD or at a lower RP2D as determined by cumulative toxicities and tolerability profile. The study will determine the preliminary clinical activity and safety of OBI-999 in up to 155 patients with advanced solid tumors, pancreatic, gastric, esophageal, and colorectal cancer according to a Simon two-stage phase 2 design. Patients must have GH overexpression defined as an H-score of ≥100 according to an FDA Investigational Device Exempt (IDE) validated IHC assay. Clinical trial information: NCT04084366 .

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

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 ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

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.

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

Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5097-5097 ◽  
Author(s):  
P. H. Patel ◽  
G. V. Kondagunta ◽  
B. G. Redman ◽  
G. R. Hudes ◽  
S. T. Kim ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Ejection Fraction ◽  
Dose Level ◽  
Egf Receptor ◽  
Phase 1 ◽  
Objective Response ◽  
Cytokine Therapy ◽  
Phase 2 ◽  
Sunitinib Malate ◽  
Grade 3

5097 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up. No significant financial relationships to disclose.

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.

A phase 1/2 trial of ORIN1001, a first-in-class IRE1 inhibitor, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3080-3080
Author(s):  
Nashat Y. Gabrail ◽  
Erika P. Hamilton ◽  
Anthony D. Elias ◽  
Mothaffar F. Rimawi ◽  
Chao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Open Label

3080 Background: ORIN1001 is a first-in-class small molecule with a novel, unique enzyme and mode of inhibition that selectively inhibits Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum (ER). IRE1α/XBP1 has been implicated in a host of pathologies, and molecules that modulate it are under intense investigation for the treatment of oncologic, metabolic, neurodegenerative and other diseases. ORIN1001 has demonstrated preclinical anti-tumor activity alone and in combination with standard of care across multiple animal models including breast, prostate, lung, liver, pancreatic, brain, colon, ovarian, esophageal, and hematologic cancers and is now undergoing first-in-human testing. Methods: A phase 1, open label, 3+3 dose escalation trial is testing ORIN1001 administered PO daily to patients (pts) with advanced solid tumors (single agent) or relapsed refractory breast cancer (in combination with Abraxane). The phase 1 dose escalation part of the trial evaluates the safety, tolerability, pharmacokinetics and preliminary efficacy of ORIN1001. After identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) for the single agent, the dose expansion part of the trial will test ORIN1001 in combination with Abraxane. Results: As of Jan 25, 2021, 22 patients with advanced cancer have received ORIN1001 dosed at 100mg, 200mg or 300mg per day in 21-day continuous cycles with a median age of 61 (range 42-77). The pts had received a median of 4 prior line of treatments. Two DLTs were observed at 200 mg with thrombocytopenia and rash. MTD has not been reached. Common (>15%) treatment-emergent adverse events (TEAEs) included nausea, vomiting, rash, fatigue, and hypokalaemia. The vast majority of these events were Grade 1-2 in severity. Seven (32%) pts had at least 1 TRAE grade≥ 3, the most frequent of which were thrombocytopenia (N=3) and rash (N=3). Preliminary pharmacokinetic analysis showed ORIN1001 exposure to increase in a dose proportional manner. Mean t1/2 at steady state was 18 hrs. Thirteen pts were evaluated for preliminary efficacy. Best response, per RECIST 1.1, was stable disease (SD) in 8 pts while 5 pts had progressive disease (PD). For 2 ongoing patients with advanced liver or colorectal cancer, duration of treatment has exceeded 300 days and 570 days, respectively. Conclusions: To date, the phase 1 part of the first-in-human trial has demonstrated a reasonable safety and pharmacokinetic profile for ORIN1001 at 100mg and 200mg dose levels. While efficacy data have yet to mature, chronic dosing achieved in pts with heavily treated advanced solid tumors, suggests clinical potential for in the setting of advanced solid cancers. The phase 2 part of the trial testing ORIN1001 in combination with Abraxane is currently enrolling pts with advanced breast cancer. Clinical trial information: NCT03950570.

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