First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3550-3550 ◽  
Author(s):  
Rui-hua Xu ◽  
Miao-Zhen Qiu ◽  
Yang Zhang ◽  
Xiao-Li Wei ◽  
Chaohong Hu
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Egfr Expression ◽  
Human Dose

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .

scholarly journals Phase I, First‐in‐Human, Dose‐Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

2018 ◽  
Vol 24 (4) ◽  
pp. 455 ◽  
Author(s):  
Johanna C. Bendell ◽  
Manish R. Patel ◽  
Kathleen N. Moore ◽  
Cynthia C. Chua ◽  
Hendrik‐Tobias Arkenau ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Human Dose

Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13026-13026 ◽  
Author(s):  
R. C. Donehower ◽  
A. Jimeno ◽  
J. Li PhD ◽  
K. Galvin ◽  
F. Anthony ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cross Resistance ◽  
Dose Escalation Study ◽  
Cell Cycle Inhibitor ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

13026 Background: ON-1910.Na is a new chemical entity, novel cell cycle inhibitor which arrests cells in G2/M, affects phosphorylation of several regulatory kinases and lacks cross resistance to other standard chemotherapy agents. This is a first-in-man Phase I dose escalation study to determine the dose limiting toxicities, recommended Phase II dose, and pharmacokinetic (PK) profile, and to document any antitumor activity of ON-01910.Na. Methods: Patients had histologically confirmed solid tumors refractory to standard therapy. ON-1910.Na, formulated as a solution in PEG400, was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 followed by a 10 day observation period for a total of 28 days per cycle. The initial dose was 80 mg and was escalated using an accelerated titration schedule; one patient was treated per cohort until grade 2 toxicity was documented. A dose confirmation cohort of up to 12 patients will be treated at the maximun tolerated dose (MTD). A comprehensive PK study was performed on days 1 and 15 of the first cycle, plus trough samples were collected. Results: Thirteen patients (7F, 6M; ages 46–73) have received 20 cycles. Dose levels of 80, 160, 320, 480, 800, 1280, 2080, and 3120 mg were evaluated in 8 patients, and a further dose of 4370 mg has been evaluated in 5 patients. Toxicities have been anemia (2 G1, 1 G2), leucopenia (1 G1, 1 G2), hyperglycemia (2 G1), elevated AST/ALT (1 G1, 1 G2), nausea (3 G1), diarrhea (3 G1), skeletal pain (5 G1, 1 G2), abdominal pain (2 G1), tumor pain (1 G2), and fatigue (3 G1, 1 G2), and have clustered at the latter 3 dose levels. PK analysis shows increasing ON-1910.Na exposure with increasing doses. ON-1910.Na has a low clearance (13 L/h), long half-life (20 h), distribution in excess of blood volume (58 L) and PK parameters are similar on days 1 and 15. Approximately 3-fold and 5-fold inter-subject variation in ON-1910.Na clearance was observed on days 1 and 15, respectively. No antitumor activity has been documented by standard criteria. Conclusions: Dose escalation is continuing. [Table: see text]

Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8519-8519 ◽  
Author(s):  
Julie Ann Means-Powell ◽  
Alex A. Adjei ◽  
Igor Puzanov ◽  
Grace K. Dy ◽  
Laura Williams Goff ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Met Inhibitor ◽  
Unacceptable Toxicity

8519 Background: The MET receptor tyrosine kinase is implicated in tumor cell proliferation, invasion, and metastasis, and is activated in NRAS mutant melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity in several tumor models. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with melanoma or other tumors. Pts were treated until disease progression or unacceptable toxicity. Results: 16 pts with melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts are still on study. 12 pts received ≥ 1 previous systemic anticancer treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK inhibitor (1 pt). Common adverse events (≥ 25%) were rash (50%), diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea (31% each), and anemia, weight decrease, and hypophosphatemia (25% each). Best responses were complete response (CR) in 1 pt, partial response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had progressive disease and 5 pts were not evaluable (3 pts had not reached first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable toxicity). The overall response rate and disease control rate were 25% and 44%, respectively. Median progression-free survival (mPFS) was 5.3 mo (95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. Conclusions: Tivantinib plus sorafenib combination therapy was well tolerated and exhibited preliminary anticancer activity in pts with melanoma. Dual inhibition of MET and angiogenesis may be an effective treatment strategy in NRAS-mutant melanoma.

First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8093-8093 ◽  
Author(s):  
Jonathan Wade Goldman ◽  
Lee S. Rosen ◽  
Alain Patrick Algazi ◽  
Patricia Kellie Turner ◽  
Volker Wacheck ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Human Dose ◽  
Recommended Phase Ii Dose

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.

First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1101-TPS1101 ◽  
Author(s):  
Jin Li ◽  
Ye Guo ◽  
Junli Xue ◽  
Wei Peng ◽  
Xiaoxiao Ge ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Single Agent ◽  
Locally Advanced ◽  
Salivary Gland Cancer ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3016-3016
Author(s):  
Patricia LoRusso ◽  
Mrinal M. Gounder ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Dose Range ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

scholarly journals A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

2014 ◽  
Vol 20 (7) ◽  
pp. 1900-1909 ◽  
Author(s):  
Jordi Rodon ◽  
Hussein A. Tawbi ◽  
Anne L. Thomas ◽  
Ronald G. Stoller ◽  
Christian P. Turtschi ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Human Dose
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