Abstract CT228: Formulation switch and pharmacokinetics/pharmacodynamics of Debio 1347 (CH5183284), a novel FGFR inhibitor, in a first-in-human dose escalation trial in solid tumors patients

2015 ◽  
Author(s):  
Valerie Nicolas-Metral ◽  
Anne Vaslin ◽  
Jeffrey G. Supko ◽  
Kiyohiko Nakai ◽  
Nobuya Ishii ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Human Dose

First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2547-2547
Author(s):  
Justin C Moser ◽  
Mark Voskoboynik ◽  
Nehal J. Lakhani ◽  
Michael Millward ◽  
Diwakar Davar ◽  
...  
Keyword(s):  
T Cell ◽  
Colorectal Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Low Grade ◽  
Checkpoint Inhibition ◽  
Human Dose ◽  
Cd28 Costimulation ◽  
Advanced Malignancies ◽  
Dose Levels

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]

P47.13 First-in-Human, Dose Escalation and Expansion Study of MT-6402 in Patients With PD-L1 Expressing Advanced Solid Tumors

2021 ◽  
Vol 16 (10) ◽  
pp. S1102
Author(s):  
D.R. Spigel ◽  
B. Anand ◽  
K. Carroll ◽  
J. Dekker ◽  
A. Georgy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Human Dose

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

First-in-human, dose-escalation, safety, and PK study of a novel 5T4-ADC in patients with advanced solid tumors.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS2603-TPS2603
Author(s):  
Geoffrey Shapiro ◽  
Patricia LoRusso ◽  
Ulka N. Vaishampayan ◽  
Muaiad Kittaneh ◽  
John Frederick Hilton ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Human Dose

First-in-human dose escalation study of oral ONC201 in advanced solid tumors.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS2623-TPS2623 ◽  
Author(s):  
Mark N. Stein ◽  
Tina M. Mayer ◽  
Rebecca Anne Moss ◽  
Ann W. Silk ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Human Dose

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 .

Safety and preliminary efficacy from the phase 1 portion of MasterKey-01: A First-in-human dose-escalation study to determine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients (pts) with advanced solid malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3086-3086
Author(s):  
Alison M. Schram ◽  
Jordi Rodon Ahnert ◽  
Manish R. Patel ◽  
Shekeab Jauhari ◽  
Jasgit C. Sachdev ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Locally Advanced ◽  
Tumor Growth Inhibition ◽  
Insertion Mutant ◽  
Insertion Mutation ◽  
Her2 Amplification ◽  
Human Dose ◽  
Exon 20 ◽  
Exon 19

3086 Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.

Abstract C137: First-in-human dose escalation study of oral ONC201 in advanced solid tumors

2015 ◽  
Author(s):  
Mark N. Stein ◽  
Rebecca Moss ◽  
Tina Mayer ◽  
Ann W. Silk ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Human Dose
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