Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer

Bruno, René; Lindbom, Lars; Stark, F. Schaedeli; Chanu, Pascal; Gilberg, Frank; Frey, Nicolas; Claret, Laurent

doi:10.1038/psp.2012.20

Cited by 17 publications

(27 citation statements)

References 17 publications

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“…However, any estimate of untreated TG is complicated by the lack of information on TG and death in the absence of treatment because all patients received ECX, and the estimate of TG is based on data from patients who are resistant or develop resistance to treatment. The gastric/GEJ tumor doubling time is slightly higher than the time for colorectal tumors, 8 to 12 months (31), but lower than the 40 months needed in breast tumors (32). These findings clearly reflect the differences in disease progression due to the primary tumor origin.…”

Section: Discussionsupporting

confidence: 48%

“…The effect of ECX in killing tumor cells indicated that the time to reduce tumor size by half from baseline was approximately 2 months, and it took 1.5 months on average to develop resistance to ECX treatment. The dynamic for the resistance phenomena has been previously determined for other anticancer drugs (32). Thus, in breast cancer, the half-lives of the resistance phenomenon for capecitabine and docetaxel were determined to be 3.25 and 4 months, respectively (32).…”

Section: Discussionmentioning

confidence: 99%

“…The dynamic for the resistance phenomena has been previously determined for other anticancer drugs (32). Thus, in breast cancer, the half-lives of the resistance phenomenon for capecitabine and docetaxel were determined to be 3.25 and 4 months, respectively (32).…”

Section: Discussionmentioning

confidence: 99%

“…The change in tumor size from baseline at week 6 or 8 has been proposed to capture the treatment effect and predict survival in several tumor types (29,(31)(32)(33). However, it has been postulated that these times might not fully capture the treatment effect, particularly for the new targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

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Rilotumumab Exposure–Response Relationship in Patients with Advanced or Metastatic Gastric Cancer

Doshi

Gisleskog²,

Zhang

et al. 2015

Clinical Cancer Research

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Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab.Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors.Simulations were undertaken to predict the relationship between rilotumumab dose and OS.Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. METpositive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W.Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/ kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rilotumumab Exposure–Response Relationship in Patients with Advanced or Metastatic Gastric Cancer

Doshi

Gisleskog²,

Zhang

et al. 2015

Clinical Cancer Research

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“…Bruno et al . described SLD data from metastatic breast cancer patients treated with a combination of docetaxel and capecitabine using the TGI model assuming an additive effect of both drugs and resistance development for both drugs.…”

Section: Population Modelling Of Tumour Sizementioning

confidence: 99%

Population pharmacokinetic–pharmacodynamic modelling in oncology: a tool for predicting clinical response

Bender

Schindler

Friberg

2014

Brit J Clinical Pharma

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In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic–pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.

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Model‐informed Evidence for Clinical Non‐inferiority of Every‐2‐Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer

Milenković‐Grišić,

Hayes,

Farrell

et al. 2024

Clin Pharma and Therapeutics

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Cetuximab was initially developed and approved as a first‐line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every‐2‐weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non‐inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I–III clinical trials in 852 patients with KRAS wild‐type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure–tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi‐mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration‐time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model‐based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non‐inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non‐inferiority in 94% of cases. Taken together, these analyses provide model‐based evidence for clinical non‐inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.

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Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer

Cited by 17 publications

References 17 publications

Rilotumumab Exposure–Response Relationship in Patients with Advanced or Metastatic Gastric Cancer

Rilotumumab Exposure–Response Relationship in Patients with Advanced or Metastatic Gastric Cancer

Population pharmacokinetic–pharmacodynamic modelling in oncology: a tool for predicting clinical response

Model‐informed Evidence for Clinical Non‐inferiority of Every‐2‐Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer

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