Lead Investigator: Ashley Hopkins, Flinders University
Title of Proposal Research: Predictors of therapeutic and adverse effects of medicines used in the treatment of breast cancer
Vivli Data Request: 5289, 5323
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. There were over 2 million new cases in 2018. There are many important medicines used in the treatment of breast cancer. However, response and toxicity to many therapies is highly unpredictable. For example, over half the eligible patients do not respond to anti-human epidermal growth factor receptor 2 (HER2) targeted therapy when used in the treatment of advanced breast cancer. Thus, more research is required to confirm and explore novel predictive markers of therapeutic and adverse effects of medicines used in the treatment of breast cancer.
Using the diverse range of data collected from clinical trials, it is possible to develop clinical tools that enable improved prediction of therapeutic and adverse outcomes of patients using medicines in the treatment of breast cancer. Being able to identify the expected response and adverse effect profile may enable patients and clinicians to make better decisions regarding whether to commence, continue, discontinue or change dosing of medicines used in the treatment of breast cancer.
Statistical Analysis Plan:
Breast cancer patients treated with contemporary treatment options.
A pooled observational cohort design will be used to identify baseline and on-treatment predictors of adverse effects to medicines, and the measures of the therapeutic response (best overall response based on Response Evaluation Criteria in Solid Tumors (RECIST), duration of response, progression, overall and progression-free survival).
Data are required for the outcomes including response (early, depth, best overall), overall survival, progression-free survival, adverse event outcomes (clinician / patient reported adverse effects that have been defined according to the international common toxicity criteria, and adverse events requiring medication changes), and drug exposure (concentration). The most recent in scope data cuts of these variables are required.
Potential predictors of the adverse event or therapeutic outcomes will be screened according to biological and clinical plausibility and empirical evidence based on prior research. While exploratory univariate analyses will be conducted, a major focus will be on the development of optimal predictive performance multivariable models that can be developed into clinical prediction tools, thus facilitating a comparison between treatment options which ultimately will allow patients and clinicians to make better decisions regarding whether to commence, continue, discontinue or change dosing of these medicines.
As most of the data commonly collected within a clinical trial contains some information on the immune system, disease severity and prognosis, toxicity risk or drug exposure, it is important to have access to all the baseline and follow-up clinical/biological/patient characteristic data collected on an individual for any given study. Covariates to be explored include, but not limited to:
- Baseline values. Baseline values are defined as the value closest and prior to the first dose of study treatment. Variables include:
- Basic patient characteristics – e.g. age, sex, race / ethnicity, (BMI), weight, weight loss prior to diagnosis and therapy initiation, smoking status, alcohol consumption, family history of disorders, and measures of performance status
- Laboratory data – e.g. levels of lactate dehydrogenase (LDH), alkaline phosphatase, albumin, bilirubin, leucocyte and leucocyte subtype counts (e.g. total WBC, lymphocyte, monocyte or eosinophils, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR)), haemoglobin, platelets, glucose, glycosylated haemoglobin (HBA1C), creatinine, C-reactive protein, circulating tumour cells, calcium, total protein, total triglycerides, cholesterol, blood urea nitrogen, international normalized ratio, and anaemia
- Disease classification data – e.g. tumour stage and grade, site and histology/subtype of primary tumour, prior therapy, prior surgery, time to response / progression for previous therapies, sum of longest tumour diameter, time since diagnosis, number and sites of metastases, mutation and expression status of disease specific oncogenes (e.g. programmed death-ligand 1 (PD_1 / PD-L1)), line of therapy, pathological features of tumour cells, tumour infiltrating lymphocytes, number of nodes with tumour, cancer antigen levels
- Other common predictors – e.g. concomitant medications, respiratory comorbidity (e.g. asthma / chronic obstructive pulmonary disease (COPD)), other comorbid diseases (e.g. peripheral vascular disease, cerebrovascular disease, diabetes, Hepatitis C infection), simplified comorbidity score, organ dysfunction (e.g. liver, lung or renal impairment), and other clinical, biological, vital statistics, laboratory, imaging, pharmacokinetic and patient-reported outcomes measures that are commonly collected in clinical trials and are commonly related to therapeutic, adverse and exposure outcomes
- Post-baseline values. Post-baseline values (including longitudinal relationships/patterns) can be useful early markers of tumor response, progression, survival, exposure or adverse events. Variables include time-varying clinical (including adverse events such as rash and comorbidities), radiological (e.g. tumour size and spread), biological/laboratory (e.g. LDH, immunological markers, liver function markers, drug exposure/concentration), vital statistics (e.g. weight, heart rate, blood pressure), disease classification, performance status, patient-reported outcomes, and other common time-dependent predictor data.
The most recent in scope data cuts of these variables are required.
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. Time-dependent analyses will be used to assess the nature and patterns of longitudinal changes of key continuous variables (e.g. drug concentration, tumour size, neutrophil counts). It is understood that individual participant data will not be transferable between transparency portals. Standard meta-analysis methods will be employed to conduct cross platform pooling of identified associations (HR and OR pooling) in breast cancer patients treated with contemporary treatment options with transparently shared data.
The R Software (R Core Team) will be used for data preparation, modelling and graphical output.
Potential predictors will be prioritised according to biological/clinical plausibility and prior evidence of association with the relevant outcome (adverse events, therapeutic response, drug exposure). Should 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. Crude associations will be reported based on univariate analysis (adjusting only for the clinical trial and where appropriate the cancer medicine), and adjusted associations based on a multivariable analysis. Continuous variables will be assessed for non-linearity of association with the outcome using restricted cubic splines. Clinical prediction models will be developed using multivariable analysis and will generally include all available known baseline predictors of the outcome of interest as well as covariates identified in univariate analysis. Penalised models will be used to minimise risk of overfitting. Early markers of exposure, response and toxicity will be primarily evaluated using a landmark approach where possible, 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. As it is expected that < 5% of data will be missing for any variable a complete case analysis is planned. Should variables with substantial missing data be present, the pattern and likely cause of the missing data will be evaluated and if missing at random is reasonable to assume then single regression imputation will be undertaken.
Analyses will also include evaluating the heterogeneity in toxicity incidence and response profiles according to model risk, as well as evaluating the predictors of the main adverse effects and response profiles for the medicines used in relevant comparator arms. Such analyses will allow a better understanding of the benefits of specific therapies, and whether the relationships identified are medicine specific or are common to multiple therapies.
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 600 is required to detect a predictor (with a 10% frequency within the population) associated with a two-fold risk (α=0.05 with 80% power). Based upon an event rate of 40% during trial follow-up (e.g. for progression), approximately 450 participants are required for 80% power to detect a predictor (with a 10% frequency within the population) associated with a two-fold hazard of the event (α=0.05). Reference: Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics Series. page 177.
These samples sizes are well within scope for many medicines within the selected population. Sample sizes greater than this will allow the investigation of more complex relationships with greater predictive performance, which is a primary objective of this study.
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 clinical study reports (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 biostatistician involved in the project.
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting
Sponsor: Eli Lilly and Company
Study ID: NCT02246621
Sponsor ID: 15417
MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT02107703
Sponsor ID: 15362
A Phase 2 Study of LY2835219 for Patients With Previously Treated Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT02102490
Sponsor ID: 15419
(Note: Additional studies added as part of data request 5289)
PHASE 1/2, OPEN-LABEL, RANDOMIZED STUDY OF THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF LETROZOLE PLUS PD 0332991 (ORAL CDK 4/6 INHIBITOR) AND LETROZOLE SINGLE AGENT FOR THE FIRST-LINE TREATMENT OF ER POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER IN POSTMENOPAUSAL WOMEN
Data Contributor: Pfizer Inc.
Study ID: NCT00721409
Sponsor ID: NCT00721409
A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer
Study ID: NCT01663727
Sponsor ID: GO25632
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
Study ID: NCT01419197
Sponsor ID: TDM4997g
A Randomized, Multi-Center Cross-Over Study to Evaluate Patient Preference and Health Care Professional (HCP) Satisfaction With Subcutaneous (SC) Administration of Trastuzumab in HER2-Positive Early Breast Cancer (EBC)
Study ID: NCT01401166
Sponsor ID: MO22982
A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer
Study ID: NCT01120184
Sponsor ID: BO22589
A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)
Study ID: NCT00950300
Sponsor ID: BO22227
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 Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy
Study ID: NCT00829166
Sponsor ID: BO21977
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
Study ID: NCT00545688
Sponsor ID: WO20697
An International Multi-centre Open-label 2-arm Phase III Trial of Adjuvant Bevacizumab in “Triple Negative” Breast Cancer.
Study ID: NCT00528567
Sponsor ID: BO20289
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.
Study ID: NCT00391092
Sponsor ID: BO20231
A Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Bevacizumab in Combination With Docetaxel in Comparison With Docetaxel Plus Placebo, as First Line Treatment for Patients With HER2 Negative Metastatic and Locally Recurrent Breast Cancer.
Study ID: NCT00333775
Sponsor ID: BO17708
A Randomized, Open-label Study of the Effect of Adjuvant Therapy With Adriamycin Plus Cytoxan Followed by Taxotere or Taxotere Plus Xeloda on Overall Survival in Female Patients With High-risk Breast Cancer
Study ID: NCT00089479
Sponsor ID: NO17629
A Randomized Three-Arm, Multicenter Comparison of 1 Year and 2 Years of Herceptin Versus No Herceptin in Women With HER2-Positive Primary Breast Cancer Who Have Completed Adjuvant Chemotherapy
Study ID: NCT00045032
Sponsor ID: BO16348
LUX-Breast 1; An Open Label, Randomised Phase III Trial of BIBW 2992 and Vinorelbine Versus Trastuzumab and Vinorelbine in Patients With Metastatic HER2-overexpressing Breast Cancer Failing One Prior Trastuzumab Treatment
Sponsor: Boehringer Ingelheim
Study ID: NCT01125566
Sponsor ID: 1200.75
A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
Study ID: NCT00567190
Sponsor ID: TOC4129g
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
Study ID: NCT00281697
Sponsor ID: AVF3693g
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
Study ID: NCT00262067
Sponsor ID: AVF3694g
neoMONARCH: A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination With Anastrozole to Those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy With Abemaciclib in Combination With Anastrozole in Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT02441946
Sponsor ID: 15805
An Exploratory Phase II, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Pertuzumab and Herceptin (Trastuzumab) in Patients With HER2-Positive Metastatic Breast Cancer
Study ID: NCT01674062
Sponsor ID: BO17929
A Randomised, Multicentre, Multinational Phase II 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 Regimen, as Neoadjuvant Therapy for Patients With Locally Advanced, Inflammatory or Early Stage HER2-positive Breast Cancer
Study ID: NCT00976989
Sponsor ID: BO22280
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 Chemotherapy for Metastatic Disease
Study ID: NCT00679341
Sponsor ID: BO21976
A Phase II, Single-Arm, Open-Label Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer
Study ID: NCT00679211
Sponsor ID: TDM4374g
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
Study ID: NCT00509769
Sponsor ID: TDM4258g
Lux-Breast 3; Randomised Phase II Study of Afatinib Alone or in Combination With Vinorelbine Versus Investigator’s Choice of Treatment in Patients With HER2 Positive Breast Cancer With Progressive Brain Metastases After Trastuzumab and/or Lapatinib Based Therapy
Sponsor: Boehringer Ingelheim
Study ID: NCT01441596
Sponsor ID: 1200.67
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.
Sponsor ID: H0648G
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.
Sponsor ID: H0659G
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.
Sponsor ID: H0649G
A multinational randomized single-blind study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2lneu overexpression who have not received prior cytotoxic chemotherapy for metastatic breast cancer.
Sponsor ID: H0650G
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.
Sponsor ID: H0693G
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
Sponsor ID: M77001
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.
Sponsor ID: MO16419
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
Study ID: NCT00109239
Sponsor ID: AVF2119g
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
Study ID: NCT00022672
Sponsor ID: BO16216
Phase III Study of Gemcitabine Plus Paclitaxel Versus Paclitaxel in Patients With Unresectable, Locally Recurrent or Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT00006459
Sponsor ID: 2017
monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib Plus Trastuzumab With or Without Fulvestrant to Standard-of-Care Chemotherapy of Physician’s Choice Plus Trastuzumab in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT02675231
Sponsor ID: 15804
A Phase II Randomized, Double-Blind Study of Neoadjuvant Letrozole Plus GDC-0032 Versus Letrozole Plus Placebo in Postmenopausal Women With ER-positive/HER2-negative, Early Stage Breast Cancer
Study ID: NCT02273973
Sponsor ID: GO28888
A Phase III Prospective, Two-Cohort Non-Randomized, Multi-Centre, Multinational, Open-Label Study to Assess the Safety of Assisted- and Self-Administered Subcutaneous Trastuzumab as Therapy in Patients With Operable HER2-Positive Early Breast Cancer
Study ID: NCT01566721
Sponsor ID: MO28048
A Phase III Randomized Study Evaluating the Efficacy and Safety of Continued and Re-induced Bevacizumab in Combination With Chemotherapy for Patients With Locally Recurrent or Metastatic Breast Cancer After First-line Chemotherapy and Bevacizumab Treatment
Study ID: NCT01250379
Sponsor ID: MO22998
A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT00703326
Sponsor ID: 13892
An Open-label Study to Evaluate the Safety and Effect on Disease Progression and Overall Survival of Avastin Plus Taxane-based Chemotherapy in Patients With Locally Recurrent or Metastatic Breast Cancer
Study ID: NCT00448591
Sponsor ID: MO19391
Prediction of severe neutropenia and diarrhoea in breast cancer patients treated with abemaciclib. Modi, Natansh D. et al. The Breast, Volume 58, 57 – 62. DOI: https://doi.org/10.1016/j.breast.2021.04.003