Predictors of exposure, therapeutic and adverse effects of drugs used in the treatment of advanced breast cancer and advanced colorectal cancer.

Proposal
1741

Title of Proposed Research

Lead Researcher

Dr Ashley Mark Hopkins

Affiliation

Flinders University

Funding Source

National Breast Cancer Foundation (Australia) Postdoctoral Fellowship. No for commercial organisations will be involved in the funding of this project.

Potential Conflicts of Interest

None

Data Sharing Agreement Date

31 Oct 2017

Lay Summary

Breast cancer and colorectal cancer are among the most commonly diagnosed cancers, with advanced disease being particularly difficult to treat. There have been a number of important advancements in the treatment of advanced breast and colorectal cancer in the last decade including the introduction of drugs targeting the Human Epidermal Growth Factor Receptor-2 (HER2), and drugs inhibiting the growth of new blood vessels. These medicines are ‘targeted therapeutics', but despite the term, response and toxicity to these medicines can be highly unpredictable. For example, over half the eligible patients do not respond to anti-HER2 targeted therapy. More research is required to confirm predictive markers with preliminary evidence (e.g. the level of exposure to the cancer medicine) and to identify additional predictive markers so that prediction performance may be improved. Furthermore, these targeted therapeutics are still commonly used in combination with chemotherapy. Despite being used for many decades, the ability to predict individuals at risk of severe toxicities resulting from chemotherapy (e.g. nerve and heart damage) is poor.

This project seeks to enable improved prediction of the therapeutic and adverse outcomes of patients using ‘targeted therapeutics' and associated chemotherapies in the treatment of advanced breast and advanced colorectal cancer. Being able to identify the expected prognosis and adverse effects may enable patients and clinicians to make better decisions regarding whether to commence, continue, discontinue or change dosing of these medicines.

Available data from patients using cancer medicines targeting blood vessel growth and HER2, and associated chemotherapies, for advanced breast and colorectal cancer will be analyzed to identify predictors of the most important adverse effects of each drug class, and predictors of therapeutic outcomes such as tumor shrinkage and survival. Examples of predictors to be explored include level of drug exposure, patient characteristics, laboratory and clinical factors, biomarkers, co-morbidities and concomitant medications.

Study Data Provided

[{ "PostingID": 1308, "Title": "ROCHE-AVF2119G", "Description": "A multicenter, open-label, phase III, randomized, active-controlled trial evaluating the efficacy, safety, and pharmacokinetics of rhuMAb VEGF (bevacizumab), in combination with capecitabine chemotherapy, in subjects with previously treated metastatic breast cancer" },{ "PostingID": 1309, "Title": "ROCHE-BO17708", "Description": "A randomized, double-blind study of the effect of first line treatment with Avastin (bevacizumab) in combination with docetaxel on progression-free survival and disease response in patients with HER2 negative metastatic breast cancer" },{ "PostingID": 1310, "Title": "ROCHE-AVF3694G", "Description": "A multicenter, phase III, randomized, placebo-controlled trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy regimens in subjects with previously untreated metastatic breast cancer" },{ "PostingID": 1312, "Title": "ROCHE-AVF2107g", "Description": "A phase III, multicenter, randomized, active-controlled clinical trial to evaluate the efficacy and safety of rhumab vegf (bevacizumab) in combination with standard chemotherapy in subjects with metastatic colorectal cancer" },{ "PostingID": 1313, "Title": "ROCHE-AVF2192g", "Description": "A phase II, multicenter, double-blind, randomized, active-controlled clinical trial to evaluate the efficacy and safety of rhumab vegf (bevacizumab), a recombinant humanized monoclonal antibody to vascular endothelial growth factor, in combination with 5-fluorouracil and leucovorin chemotherapy in subjects with metastatic colorectal cancer who are not optimal candidates for first-line cpt-11" },{ "PostingID": 1316, "Title": "ROCHE-NO16966", "Description": "2 x 2 Factorial randomized phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (q3w) (\"XELOX\") with/without intravenous bevacizumab (q3w) versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (q2w) (\"FOLFOX-4\") with/without intravenous bevacizumab (q2w) as first-line treatment for patients with metastatic colorectal cancer." },{ "PostingID": 1340, "Title": "ROCHE-WO20698 (CLEOPATRA)", "Description": "A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of Herceptin + docetaxel + pertuzumab versus Herceptin + docetaxel + placebo in previously untreated HER2-positive metastatic breast cancer" },{ "PostingID": 1364, "Title": "ROCHE-TDM4374g", "Description": "A Phase II, single-arm, open-label study, of Trastuzumab-MCC-DM1 adminstered intravenously to patients with HER2-positive metastatic breast cancer" },{ "PostingID": 1365, "Title": "ROCHE-TDM4258g", "Description": "A phase II, single-arm, open-label study of Trastuzumab-MCC-DM1 administered intravenously to patients with HER2-positive metastatic breast cancer who have progressed while receiving HER2-directed therapy" },{ "PostingID": 2547, "Title": "ROCHE-BO20231", "Description": "A Randomized, Open-label Study to Compare the Effect of First-line Treatment With Avastin in Combination With Herceptin/Docetaxel and Herceptin/Docetaxel Alone on Progression-free Survival in Patients With HER2 Positive Locally Recurrent or Metastatic Breast Cancer." },{ "PostingID": 2549, "Title": "ROCHE-AVF3693G", "Description": "A Phase III, Multicenter, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy Regimens in Subjects With Previously Treated Metastatic Breast Cancer" },{ "PostingID": 2559, "Title": "ROCHE-AVF0780G", "Description": "Trial of rhuMAb VEGF Antibody Combined With 5 Fluourouracil and Leucovorin in Subjects With Locally Advanced or Metastatic Colorectal Cancer" },{ "PostingID": 2561, "Title": "ROCHE-NO16967", "Description": "A Randomized, Open-label Study of the Effect of Intermittent Xeloda Versus iv Fluorouracil/Leucovorin, Both in Combination With Eloxatin, on Tumor Progression in Patients With Metastatic Colorectal Cancer Who Received Prior CPT-11 and 5-fluorouracil/Leucovorin" },{ "PostingID": 2572, "Title": "ROCHE-BO16934", "Description": "A randomized, open-label study of the effect of different doses of pertuzumab on treatment response in patients with metastatic breast cancer with low HER2 expression" },{ "PostingID": 2573, "Title": "ROCHE-BO21976", "Description": "A randomized, multicenter phase II study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin) and Docetaxel (Taxotere) in patients with metastatic HER2-positive breast cancer who have not received prior therapy for metastatic disease." },{ "PostingID": 2574, "Title": "ROCHE-BO21977", "Description": "A randomized, Multicenter, Phase III Open-Label study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in patients with HER2-Positive locally advanced or metastic breast cancer who have received prior Trastuzumab-based therapy." },{ "PostingID": 3014, "Title": "ROCHE-MO18458", "Description": "A single arm study to assess the efficacy and safety of bevacizumab in combination with irinotecan and infusional 5-fluorouracil/folic acid regimens as first line treatment for patients with metastatic colorectal cancer." },{ "PostingID": 3358, "Title": "ROCHE-BO16216", "Description": "A randomized, open-label study of the effect of Herceptin plus Arimidex compared with Arimidex alone on progression-free survival in patients with HER2-positive and hormone-receptor positive metastatic breast cancer" },{ "PostingID": 3359, "Title": "ROCHE-H0648G", "Description": "Chemotherapy and Antibody Response Evaluation (CARE): A phase III, multinational, randomized study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) combined with chemotherapy in patients with HER2 overexpression who have not received cytotoxic chemotherapy for metastatic breast cancer." },{ "PostingID": 3360, "Title": "ROCHE-H0649G", "Description": "A multinational open-label study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2lneu overexpression who have relapsed following one or two cytotoxic chemotherapy regimens for metastatic breast cancer." },{ "PostingID": 3362, "Title": "ROCHE-H0659G", "Description": "An open-label extension study with recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) for patients whose metastatic breast cancer progressed during treatment on protocol H0648g." },{ "PostingID": 3363, "Title": "ROCHE-H0693G", "Description": "A multicenter, expanded access, open-label safety study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2 overexpression who relapsed following multiple cytotoxic chemotherapy regimens for metastatic breast cancer." },{ "PostingID": 3364, "Title": "ROCHE-M77001", "Description": "A Multicenter, Randomized Comparative Study on the Efficacy and Safety of Herceptin (Trastuzumab) Plus Docetaxel (Taxotere) Versus Docetaxel Alone as First Line Treatment in Patients with HER2-Positive Metastatic Breast Cancer" },{ "PostingID": 3365, "Title": "ROCHE-MO16419", "Description": "An open-label, randomized phase II study of Herceptin (trastuzumab), Taxotere (docetaxel) and Xeloda (capecitabine) in combination, versus Herceptin (trastuzumab) plus Taxotere (docetaxel), in patients with advanced and/or metastatic breast cancers that overexpress HER2." },{ "PostingID": 4148, "Title": "NOVARTIS-EGF100151", "Description": "A Phase III, Randomized, Open-label, Multicenter Study Comparing GW572016 and Capecitabine (XELODA) versus Capecitabine in Women with Refractory Advanced or Metastatic Breast Cancer" },{ "PostingID": 4151, "Title": "NOVARTIS-EGF20008", "Description": "An Open-Label, Multicenter, Single Arm Phase II Study of Oral GW572016 as Single Agent Therapy in Subjects with Advanced or Metastatic Breast Cancer Who Have Progressed While Receiving HERCEPTIN-Containing Regimens" },{ "PostingID": 4154, "Title": "NOVARTIS-EGF104900", "Description": "A Randomized, Multicenter, Open-Label, Phase III Study of Lapatinib in Combination with Trastuzumab versus Lapatinib Monotherapy in Subjects with HER2-positive Metastatic Breast Cancer whose disease has progressed on Trastuzumab-Containing Regimens" },{ "PostingID": 4155, "Title": "NOVARTIS-EGF30001", "Description": "A Randomized, Multicenter, Double-Blind, Placebo-Controlled, 2-Arm, Phase III Study of Oral GW572016 in Combination with Paclitaxel in Subjects Previously Untreated or Advanced or Metastatic Breast Cancer" },{ "PostingID": 4335, "Title": "ROCHE-WO20697", "Description": "A randomized, open label study to compare the complete pathological response rate achieved with 4 combinations of Herceptin, docetaxel and pertuzumab in patients with locally advanced, inflammatory or early stage HER2 positive breast cancer" },{ "PostingID": 4336, "Title": "*ROCHE-BO22280", "Description": "A randomized study to evaluate pertuzumab in combination with trastuzumab given either concomitantly or sequentially with standard anthracycline based chemotherapy or concomitantly with a non-anthracycline based chemotherapy, as neoadjuvant therapy for patients with HER2-positive breast cancer.

Medicine: Pertuzumab, Condition: malignant neoplasm of breast, Phase: 2, Clinical Study ID: BO22280, Sponsor: Roche" },{ "PostingID": 4541, "Title": "LILLY-I4T-MC-JVBB", "Description": "A Randomized, Double-Blind, Multicenter Phase 3 Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine (RAISE)" },{ "PostingID": 4550, "Title": "ROCHE-BO22589", "Description": "A Study of Trastuzumab-DM1 Plus Pertuzumab Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer" },{ "PostingID": 4551, "Title": "ROCHE-BO25734", "Description": "A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy" }]

Statistical Analysis Plan

General model development:Cox-proportional hazard / time-to-event models will be used to assess the association between potential predictors and the time to an adverse effect or survival time. Associations will be reported primarily as hazard ratios with 95% confidence intervals. The association of potential predictors with binary outcomes (e.g. best overall response) will be modelled using logistic regression and will be reported as odds ratios with 95% confidence intervals. Linear and non-linear mixed effect modelling will be used to assess the nature of longitudinal changes of key continuous variables (e.g. drug concentration, tumour size, neutrophil counts).Software:The R Software (R Core Team) will be used for data preparation, modelling and graphical output. Non-linear mixed effect modelling of concentration and tumour size data will be evaluated using the “R” Software (R Core Team) with Rtools (an Rtoolset), and the R packages ‘RxODE', ‘nlmixr', ‘pmetrics' and ‘mrgsolve'. Covariate analyses:Potential predictors will be included according to biological plausibility and prior evidence of association with the pharmacokinetics, adverse effects and therapeutic response. Crude associations will be reported based on univariate analysis (adjusting only for the clinical trial and specific drug), and adjusted associations based on a multivariable analysis. Multivariable analysis will generally include all available known baseline predictors of the outcome of interest as well as covariates identified in univariate analysis. Early markers of exposure, response and toxicity will be primarily evaluated using a landmark approach, with sensitivity analyses based on the use of time-dependent covariates. Landmark time will be dependent on the time points available in individual studies, and the time frame of changes in each specific predictor variable. As this analysis is primarily hypothesis generating and will require subsequent validation of any findings, no formal adjustment for multiple testing is intended. However, this limitation will be clearly stated in any publications of results. Multiple imputation (n=20) will be undertaken for analyses in which there is > 5% missing data.Secondary analyses of predictors for the target medicines will include evaluating the main adverse effects and response profiles to the chemotherapies used in the comparator arms of the studies. Many of these chemotherapies are used in combination with ‘targeted therapeutics' in both advanced breast and advanced colorectal cancer, and thus a simultaneous analysis will allow a better understanding of whether the relationships identified are specific to the ‘targeted therapeutics', concomitant chemotherapies or the disease itself.Covariates to be explored include:• Baseline values. Baseline values are defined as the value closest and prior to the first dose of study treatment. o Basic demographics - age, sex, ethnicity, BMI, smoking statuso Covariates commonly reported to be prognostic across a range of different cancers such as performance status, site and histology/subtype of primary tumor, number and sites of metastases, tumor size, abnormal laboratory values (e.g. LDH) and biomarkers including mutation or overexpression of disease specific oncogenes (e.g. HER2, EGFR, RAS, BRAF).o Comorbidities, use of specific medicines, and other clinical, biological, laboratory and patient-reported values that are potentially related to the outcome being analyzed based on clinical opinion and literature review • Post-baseline valueso Onset of early adverse events (e.g. hypertension) and the time-dependent subset of predictors defined above (e.g. changes in LDH, tumor size) as early markers of tumor response, survival, exposure or other adverse eventso Exposure (drug concentration) as a potential predictor of tumor response, survival, and adverse eventsShould multiple values of a covariate be recorded multiple times for a single visit (e.g. blood pressure) the mean of the multiple reads taken at each visit will be used.Power:Predictors that have a clinically meaningful (e.g. double the risk) effect on mortality and adverse effects will be of primary interest. Based upon a 30% incidence of toxicity, a sample size of approximately 180 is required to detect a predictor associated with a two-fold risk (a=0.05 with 80% power). Based upon a mortality of 40% during trial follow-up, approximately 160 participants are required for 80% power to detect a predictor associated with a two-fold hazard of mortality (a=0.05). These sample sizes are well within the number of participants with data available for each drug to be studied.Quality Control:Data will be explored for inconsistencies in time recordings, physiologically unreasonable covariate values, and unit errors. Prior to beginning analyses, individual data values will be extracted/constructed based on the raw and analysis datasets provided. To ensure that each variable has been correctly extracted/constructed from the data provided, basic analyses and descriptive statistics will be reproduced to check for consistency with pertinent results in published manuscripts or CSRs relating to the specific trial. Where there are insufficient published results to confirm the proper extraction of the variable, the extracted values will be manually checked against a random sample of the original dataset values. Analyses and results will be reviewed by a second biostatistician involved in the project.

Publication Citation

https://www.frontiersin.org/articles/10.3389/fonc.2019.00789/full
Lim, H.H., Hopkins, A.M., Rowland, A. et al. Targ Oncol (2019) 14: 743. https://doi.org/10.1007/s11523-019-00683-z