Oncology dose optimization paradigms: knowledge gained and extrapolated from approved oncology therapeutics

Mittapalli, Rajendar K.; Guo, Cen; Drescher, Stefanie K.; Yin, Dong

doi:10.1007/s00280-022-04444-0

Cited by 12 publications

(14 citation statements)

References 12 publications

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“…Model-based approaches are planned to confirm the selected xevinapant dose/regimen once data from these phase III studies become available (Figure 1). Viewed from a broader perspective and in the context of the growing recognition of the importance of dose optimization in oncology drug development, 33,[37][38][39][40] these analyses illustrate the value of quantitative clinical pharmacological contextualization for dose and regimen selection. Importantly, they illustrate the value of a holistic integration of preclinical and clinical PK, PD, safety, and efficacy data and associated E-R relationships, with a totality of evidence approach, 41 in which confidence can be gained from consistency across multiple approaches and data sources integrated in a mechanism-informed manner through modeling and simulation.…”

Section: Discussionmentioning

confidence: 99%

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Vugmeyster,

Ravula,

Rouits

et al. 2023

Clin Pharma and Therapeutics

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Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase 2 study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1‐14 of a 3‐week cycle. To confirm 200 mg/day as the recommended phase 3 dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure‐response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100‐200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure‐response analyses of data from 62 patients in the phase 2 study showed exposure‐related increases in probabilities of locoregional control at 18 months (primary endpoint), overall response, complete response, and the radiosensitization mechanism‐related composite safety endpoint “mucositis and/or dysphagia” (p<0.05). Exposure‐response relationships were not discernible for 12 of 13 evaluated safety endpoints, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model‐derived target inhibition profiles, positive exposure‐efficacy relationships, and lack of discernible exposure‐safety relationships for most safety endpoints, supports selection of xevinapant 200 mg/day on days 1‐14 of a 3‐week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

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Section: Discussionmentioning

confidence: 99%

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Vugmeyster,

Ravula,

Rouits

et al. 2023

Clin Pharma and Therapeutics

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“…Combination therapies are often evaluated during the early clinical development of molecular targeted and immune‐oncology (IO) therapies—two classes representing most approved oncology drugs by the US Food and Drug Administration (FDA) in the past decade 1–3 . A new investigational agent can be combined with one or more approved agent(s) or investigational agent(s), to enhance anticancer activity, prolong clinical benefit, overcome primary or acquired drug resistance, or simply provide patients with multiple opportunities for a meaningful response 4,5 .…”

Section: Figurementioning

confidence: 99%

“…Combination therapies are often evaluated during the early clinical development of molecular targeted and immune-oncology (IO) therapies-two classes representing most approved oncology drugs by the US Food and Drug Administration (FDA) in the past decade. [1][2][3] A new investigational agent can be combined with one or more approved agent(s) or investigational agent(s), to enhance anticancer activity, prolong clinical benefit, overcome primary or acquired drug resistance, or simply provide patients with multiple opportunities for a meaningful response. 4,5 The FDA has provided guidance to expedite oncology drug development including considerations for combinations, enabling testing of combinations in expansion cohorts within first-in-human (FIH) studies under the investigational new drug application of a new compound with appropriate scientific rationale.…”

Section: Oncology Combination Dose-finding Study Design For Targeted ...mentioning

confidence: 99%

Oncology Combination Dose‐Finding Study Design for Targeted and Immuno‐Oncology Therapies

Zhou,

Reddy,

Mittapalli

et al. 2023

Clin Pharma and Therapeutics

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Combination therapies are often evaluated during the clinical development of oncology investigational agents. A new investigational agent may be combined with one or more approved agent(s) or investigational agent(s). As the initial step to test combination therapies, combination dose escalation of an investigational agent and an approved drug is generally conducted using one of the following designs: sequential design, parallel (staggered) design, healthy participant first‐in‐human prior to first‐in‐patient combination escalation, monotherapy lead‐in (intra‐patient “crossover”), and potentially combination escalation (no monotherapy component). Dose‐finding studies for the combinations of two investigational agents may follow similar principles and considerations, and a more conservative approach may be required. A comparison of the characteristics of these designs indicates an efficient design should consider factors including the predicted difference in dose/exposure‐response relationships between monotherapy and combination therapy, any potential for PK and PD interactions between the combinatory agents, and the benefit/risk to study participants, etc. In this report, we propose application scenarios for each trial design based on the above considerations and a review of internal database and published external studies. Generation of robust exposure‐response data via an appropriate design will assist the selection of appropriate doses for further assessment to support optimal dose selection as encouraged by the FDA based on Project Optimus.

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“…2,3 Still, a single dosing regimen, the MTD or the highest tested dose, has been traditionally evaluated in pivotal studies. 4,5 Exposure-response (E-R) characterization is at the heart of supporting dose selection. [6][7][8] The utility of E-R analysis for pivotal oncology studies is limited as they mainly utilize a single dosing regimen.…”

Section: Introductionmentioning

confidence: 99%

“…The US Food and Drug Administration's (FDA's) Project OPTIMUS 1 advocates for re‐assessing dose selection strategies for oncology compounds and recommends randomized dose‐finding trials as a preferred approach for dose optimization given that the maximum tolerated dose (MTD) might not be adequate for targeted therapies 2,3 . Still, a single dosing regimen, the MTD or the highest tested dose, has been traditionally evaluated in pivotal studies 4,5 …”

Section: Introductionmentioning

confidence: 99%

Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

Soltantabar,

Alhadab,

Hibma

et al. 2023

CPT Pharmacom & Syst Pharma

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Exposure‐response (E‐R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case–control matching to account for this bias and better understand the E‐R relationship for avelumab in urothelial carcinoma, a PD‐L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN‐100 was utilized which is a phase III study of avelumab in first‐line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best‐supportive care leading to approval in the United States, Europe, and other countries. A post hoc case‐control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.

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Oncology dose optimization paradigms: knowledge gained and extrapolated from approved oncology therapeutics

Cited by 12 publications

References 12 publications

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Oncology Combination Dose‐Finding Study Design for Targeted and Immuno‐Oncology Therapies

Case–control matching‐guided exposure‐efficacy relationship for avelumab in patients with urothelial carcinoma

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