scholarly journals 1002P Impact of pharmacodynamic biomarkers in phase I immune-oncology trials

2021 ◽  
Vol 32 ◽  
pp. S849-S850
Author(s):  
A.T. Salawu ◽  
R. Chen ◽  
A. Hernando Calvo ◽  
D.V. Araujo ◽  
M. Oliva ◽  
...  
Keyword(s):  
Phase I ◽  
Pharmacodynamic Biomarkers ◽  
Immune Oncology

Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Li Zhang
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Predictive Biomarker ◽  
Phase I Trials ◽  
Tumor Shrinkage ◽  
Target Engagement ◽  
Phase I Clinical Trials ◽  
Phase Ii Trials ◽  
Pharmacodynamic Biomarkers

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.

Measurement of IL-17AA and IL-17FF as Pharmacodynamic Biomarkers to Demonstrate Target Engagement in the Phase I Study of MCAF5352A

2018 ◽  
Vol 21 (1) ◽  
Author(s):  
Kun Peng ◽  
Yehong Wang ◽  
Ketevan Siradze ◽  
Rich Erickson ◽  
Saloumeh K. Fischer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Target Engagement ◽  
Pharmacodynamic Biomarkers

scholarly journals The i3+3 design for phase I clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3066-3066
Author(s):  
Yuan Ji ◽  
Meizi Liu
Keyword(s):  
Phase I ◽  
Dose Finding ◽  
Operating Characteristics ◽  
Phase I Clinical Trials ◽  
Rule Based ◽  
Model Based ◽  
Simple Rules ◽  
R Shiny ◽  
Statistical Designs ◽  
Immune Oncology

3066 Background: Other than the 3+3 design, new model-based statistical designs like the mTPI design (Ji and Wang, 2013, JCO) are alternative choices for oncology dose-finding trials, including immune oncology dose-finding trials (Atkins et al., 2018, Lancet Oncology). One major criticism of the 3+3 design is that it is based on simple rules, does not depend on statistical models for inference, and leads to unsafe and unreliable operating characteristics. However, the rule-based nature allows 3+3 to be easily understood and implemented in practice, making it practically attractive and friendly. Can friendly rule-based designs achieve great performance seen in model-based designs? For four decades, the answer has been NO. Methods: We propose a new rule-based design called i3+3, where the letter "i" represents the word "interval". The i3+3 design is based on simple but more clever rules that account for the variabilities in the observed data. In short, the i3+3 design simply asks clinicians to compare observed toxicity rates with a prespecified toxicity interval, and make dose escalation decisions according to three simple rules. No sophisticated modeling is needed and the entire design is transparent to clinicians. Results: We compare the operating characteristics for the proposed i3+3 design with other popular phase I designs by simulation. The i3+3 design is far superior than the 3+3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3+3 also demonstrates comparable performances. In other words, the i3+3 design possesses both simplicity and transparency of the rule-based approaches, and the superior operating characteristics seen in model-based approaches. An online R Shiny tool is provided to illustrate the i3+3 design, although in practice it requires no software to design or conduct a dose-finding trial using the design. Conclusions: The i3+3 design could be a practice-altering method for the clinical community. It may increase the safety and efficiency of dose finding trials.

Abstract B137: Pharmacokinetics and pharmacodynamic biomarkers for the dual PI3K/mTOR inhibitor GDC‐0980: Initial phase I evaluation

2009 ◽  
Author(s):  
Andrew J. Wagner ◽  
Howard A. Burris ◽  
Johann S. de Bono ◽  
Gordon C. Jayson ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Phase I ◽  
Initial Phase ◽  
Mtor Inhibitor ◽  
Pharmacodynamic Biomarkers

A phase I study (CA180021-Segment 2) of dasatinib in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14042-14042 ◽  
Author(s):  
F. M. Johnson ◽  
A. Chiappori ◽  
H. Burris ◽  
L. Rosen ◽  
B. McCann ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Fdg Pet ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Pharmacodynamic Biomarkers

14042 Background: SPRYCEL™ is a potent, orally active, multi-targeted kinase inhibitor, active against BCR-ABL and SRC family kinases. We report the results of a Phase I dose-escalation study evaluating safety, tolerability, pharmacokinetics, and biomarkers of dasatinib in pts with advanced solid tumors. Methods: Pts with adequate hematologic, renal, cardiac and liver function received oral dasatinib once daily for 7 days per week. Three doses and schedules were examined: 90 mg BID; 140 mg QD; and 180 mg QD. Pharmacokinetics and pharmacodynamic biomarkers were collected on Days 1 and 26 of Cycle 1. Tissue biomarkers were assessed at screening. CT was performed at least every 8 weeks, and FDG-PET at weeks 4, and 8. Results: 26 pts [M=15, F=11] ECOG PS ≤ 2 with epithelial tumors (n=14) or other solid tumors (n=12) have been treated in escalating dose levels. Toxicity was generally mild; most patients came off study for progressive disease. DLTs of pleural effusions were seen in 3/9 subjects on the 180 mg cohort, 2 of whom had pre-existing effusions. Patients with pleural effusion have been excluded from future enrollment. The maximum tolerated dose has not been identified. There have been no objective responses on CT. Six patients have had stable disease with continued study treatment for 2–10 months. Conclusions: Dasatinib can be safely administered at doses of 140 and 180 mg QD. Clinical efficacy, pharmacokinetics, and correlative studies of tumor biopsy material and early FDG-PET results will be reported. No significant financial relationships to disclose.

scholarly journals Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

2016 ◽  
Vol 15 (6) ◽  
pp. 1412-1424 ◽  
Author(s):  
Joo Ern Ang ◽  
Rupinder Pandher ◽  
Joo Chew Ang ◽  
Yasmin J. Asad ◽  
Alan T. Henley ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Pi3k Inhibition ◽  
Pharmacodynamic Biomarkers

223 POSTER Pharmacokinetics and pharmacodynamic biomarkers for the pan-PI3K inhibitor GDC-0941: Initial Phase I evaluation

2008 ◽  
Vol 6 (12) ◽  
pp. 70-71 ◽  
Author(s):  
P. LoRusso ◽  
D. Sarker ◽  
D. Von Hoff ◽  
R. Tibes ◽  
M.K. Derynck ◽  
...  
Keyword(s):  
Phase I ◽  
Initial Phase ◽  
Pi3k Inhibitor ◽  
Pharmacodynamic Biomarkers

The Geldanamycin Derivative DMAG Demonstrates Improved Cytotoxicity and Down-Modulation of Hsp90 Client Proteins Relative to 17-AAG in Chronic Lymphocytic Leukemia (CLL) Cells: Justification for Clinical Trials in CLL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2101-2101
Author(s):  
Amy J. Johnson ◽  
Amy J. Wagner ◽  
Lisa L. Smith ◽  
David M. Lucas ◽  
Michael D. De Lay ◽  
...  
Keyword(s):  
Phase I ◽  
Immunoblot Analysis ◽  
Clinical Development ◽  
Lymphocytic Leukemia ◽  
Pharmacological Properties ◽  
Down Regulation ◽  
Cancer Types ◽  
Client Proteins ◽  
Pharmacodynamic Biomarkers

Abstract The heat shock protein Hsp90 functions to stabilize important cell survival- and proliferation-related kinases such as AKT, IKK, c-Src, Raf-1, and cdk9. Cancer cells have activated Hsp90 as compared to normal cells, making this a relevant therapeutic target to eliminate these kinases. The semi-synthetic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) binds to and inhibits the activity of Hsp90, and previous work demonstrated the ability of 17-AAG to deplete AKT in several cancer types in vitro. A newer geldanamycin derivative, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) has improved pharmacological properties including solubility and oral bioavailability, and was shown to be more effective than 17-AAG in melanoma and pancreatic carcinoma mouse xenograft mouse models. We therefore examined the effects of 17-AAG and DMAG against CD19-positive tumor cells from CLL patients. Cell viability was examined by the MTT assay, and AKT and IKK protein expression was examined by immunoblot analysis. In samples from seven CLL patients, 1.0uM DMAG resulted in 31.5% viability (95% CI: 13.1–50.0%), compared to 61.5% viability (95% CI: 45.0–78.0%) using the same concentration of 17-AAG. In four CLL patient samples treated with 1.0uM DMAG for 24 hours, AKT was decreased an average of 72.5% (95% CI: 57.7–87.3%) relative to the untreated controls. This is in comparison to 1.0uM 17-AAG, which caused a 52.7% decrease in AKT (95%CI: 39.7–65.6%). IKK protein was also decreased at similar levels in all patient samples examined. This data indicates that in CLL cells, DMAG has superior activity both in cytotoxicity and in reduction of relevant Hsp90 client proteins. 17-AAG is currently undergoing Phase I clinical testing in CLL, and DMAG is completing phase I clinical development in solid tumor malignancies. Overall, our data and that of others support clinical development of DMAG in CLL, based on the improved pharmacologic properties, enhanced efficacy relative to 17-AAG, and expected down-regulation of target proteins. In addition, our in vitro observations support using measurement of protein down-regulation of AKT and IKK as pharmacodynamic biomarkers of activity in patients undergoing therapy with these agents.

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