Challenges and Opportunities in Dose Finding in Oncology and Immuno‐oncology

Ji, Yan; Jin, Jin Y.; Hyman, David M.; Kim, Geoffrey; Suri, Ajit

doi:10.1111/cts.12540

Cited by 45 publications

(53 citation statements)

References 34 publications

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“…Population pharmacokinetic (PopPK) and exposure–response modeling are crucial in anticancer drug development to characterize the mechanistically and clinically relevant determinants of systemic drug exposure, to identify patient factors (covariates) that influence response and toxicity, and to optimize posology for maximizing benefit vs. risk . The pharmacokinetics (PK) of brentuximab vedotin have previously been reported in sALCL, R/R cHL, and CTCL but not in the setting of frontline treatment of advanced‐stage cHL in combination with AVD.…”

mentioning

confidence: 99%

Population Pharmacokinetic Modeling and Exposure–Response Assessment for the Antibody‐Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON‐1 Study

Suri

Mould

Song

et al. 2019

Clin Pharma and Therapeutics

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The efficacy of the CD30‐directed antibody‐drug conjugate (ADC) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin's lymphoma in the randomized phase III ECHELON‐1 study. Population pharmacokinetic (PK) and exposure–response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy end points in ECHELON‐1. The influence of patient‐specific factors on the PK of the ADC and the microtubule‐disrupting payload monomethyl auristatin E (MMAE) was investigated; none of the significant covariates had a clinically relevant impact. Exposure–response analyses evaluated relationships between time‐averaged area under the curve (AUC; ADC, MMAE) and efficacy end points (ADC) or safety parameters (ADC, MMAE). Exposure–efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposure‐safety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony‐stimulating factor primary prophylaxis.

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confidence: 99%

Population Pharmacokinetic Modeling and Exposure–Response Assessment for the Antibody‐Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON‐1 Study

Suri

Mould

Song

et al. 2019

Clin Pharma and Therapeutics

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“…The relationship between drug exposure-efficacy and exposure-safety outcomes is a key component to optimizing the benefit-risk profile and dose selection of new and existing therapies. [13][14][15] This study assessed the relationship between exposure and selected hematologic AEs reported with talazoparib treatment (grade ≥ 3 anemia, thrombocytopenia, and neutropenia) in patients with advanced breast cancer and gBRCA1/2 mutations in the phase 3 EMBRACA and phase 2 ABRAZO trials. The results of this analysis showed that higher C avg,t was associated with grade ≥ 3 anemia and thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Exposure‐Safety Analyses of Talazoparib in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials

Elmeliegy

Litton

et al. 2020

The Journal of Clinical Pharma

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Poly(ADP‐ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time‐varying average talazoparib concentration (Cavg,t), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models. The results indicated that higher Cavg,t was associated with a higher risk of anemia and thrombocytopenia. A trend toward an association between higher Cavg,t and neutropenia was observed, although not statistically significant. Higher risk of all tested safety end points was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower body weight. These findings support the proposed management of AEs through talazoparib dosing modification.

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“…This finding highlighted that relatively lower doses or partial target engagement can sufficiently activate effector, which make the host immune functions become critical for antibodies in the IF group. 34 For example, in patients with squamous cell carcinoma treated with cetuximab, survival was much higher in individuals with stronger immune responses 35 . Thus, quantitative analyses of the immune functions during antibody treatment are beneficial to establishing dose-response relationships.…”

Section: Discussionmentioning

confidence: 99%

Quantitatively Modeling Factors that Influence the Therapeutic Doses of Antibodies

Tang

Cao

2020

Preprint

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163/250 words)Dose selection and confirmation are critical tasks in the development of therapeutic antibodies. These tasks could become particularly challenging in the absence of robust pharmacodynamics biomarkers or at very flat dose-response curves. Although much knowledge has been acquired in the past decade, it remains uncertain which factors are relevant and how to select doses more rationally. In this study, we developed a quantitative metric, Therapeutic Exposure Affinity Ratio (TEAR), to retrospectively evaluate up to 60 approved antibodies and their therapeutic doses (TDs), and systematically assessed the factors that are relevant to antibody TDs and dose selection patterns. This metric supported us to analyze many factors that are beyond antibody pharmacokinetics and target binding affinity. Our results challenged the traditional perceptions about the importance of target turnovers and target anatomical locations in the selection of TDs, highlighted the relevance of an overlooked factor, antibody mechanisms of action. Overall, this study provided insights into antibody dose selection and confirmation in the development of therapeutic antibodies.3

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Challenges and Opportunities in Dose Finding in Oncology and Immuno‐oncology

Cited by 45 publications

References 34 publications

Population Pharmacokinetic Modeling and Exposure–Response Assessment for the Antibody‐Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON‐1 Study

Population Pharmacokinetic Modeling and Exposure–Response Assessment for the Antibody‐Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON‐1 Study

Exposure‐Safety Analyses of Talazoparib in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials

Quantitatively Modeling Factors that Influence the Therapeutic Doses of Antibodies

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