Lead Investigator: Ashley Hopkins, Flinders University
Title of Proposal Research: Predictors of therapeutic and adverse effects of medicines used in the treatment of gastrointestinal cancers
Vivli Data Request: 5290
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
There are many important medicines used in the treatment of gastrointestinal cancers. However, response and toxicity to many therapies is highly unpredictable. For example, many eligible patients do not respond to Anti–vascular endothelial growth factor (anti-VEGF) targeted therapy when used in the treatment of advanced gastrointestinal cancers. Thus, more research is required to confirm and explore novel predictive markers of therapeutic and adverse effects of medicines used in the treatment of gastrointestinal cancers.
This project seeks to enable improved prediction of the therapeutic and adverse outcomes of patients using medicines in the treatment of gastrointestinal cancers. 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 these medicines.
Available data from various gastrointestinal cancers patients treated with relevant contemporary treatment options will be analysed to identify and validate predictors of the most important adverse effects, and clinical/biological/patient predictors of therapeutic outcomes such as response, tumor shrinkage, PFS and survival.
Study design:
A pooled observational cohort design will be used to conduct a meta-analysis of transparently shared clinical trials data.
Population:
Gastrointestinal cancers patients treated with contemporary treatment options.
Rationale for Study Selection and Selection of Populations/Participants:
To precisely and validly determine the relationship between potential predictors and outcomes of interest it is important to have the maximum sample size possible across a range of different study populations (an increased number of studies increases the population diversity, and is thus more comparable to standard clinical practice). Therefore, all studies collecting baseline and follow-up clinical characteristic data, as well as adverse event or therapeutic outcome data for patients with gastrointestinal cancers (gastric, colorectal, liver and pancreatic cancers) have been selected (model building will use the per-protocol populations).
How the data you have requested will help you answer the hypothesis:
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 univariable 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. 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.
Statistical Analysis Plan:
Population:
Gastrointestinal cancers patients treated with contemporary treatment options.
Study design:
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 tumours (RECIST), duration of response, progression, overall and progression-free survival).
Data:
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:
o Basic patient characteristics – e.g. age, sex, race / ethnicity, body mass index (BMI), weight, weight loss prior to diagnosis and therapy initiation, smoking status, alcohol consumption, family history of disorders, and measures of performance status
o Laboratory data – e.g. levels of lactate dehydrogenase (LDH), alkaline phosphatase, albumin, bilirubin, leucocyte and leucocyte subtype counts (e.g. total white blood cell (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
o 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. Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)), line of therapy, pathological features of tumour cells, tumour infiltrating lymphocytes, number of nodes with tumour, cancer antigen levels
o 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 gastrointestinal cancers patients treated with contemporary treatment options with transparently shared data.
Software:
The R Software (R Core Team) will be used for data preparation, modelling and graphical output.
Covariate analyses:
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 minimse 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.
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 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.
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 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.
Requested Studies:
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
Sponsor: Eli Lilly and Company
Study ID: NCT01183780
Sponsor ID: 13856
A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Capecitabine and Cisplatin With or Without Ramucirumab as First-line Therapy in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (RAINFALL)
Sponsor: Eli Lilly and Company
Study ID: NCT02314117
Sponsor ID: 15372
A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study of Weekly Paclitaxel With or Without Ramucirumab (IMC-1121B) Drug Product in Patients With Metastatic Gastric Adenocarcinoma, Refractory to or Progressive After First-Line Therapy With Platinum and Fluoropyrimidine
Sponsor: Eli Lilly and Company
Study ID: NCT01170663
Sponsor ID: 13894
A Phase 3, Randomized, Double-Blinded Study of IMC-1121B and Best Supportive Care (BSC) Versus Placebo and BSC in the Treatment of Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Following Disease Progression on First-Line Platinum- or Fluoropyrimidine-Containing Combination Therapy
Sponsor: Eli Lilly and Company
Study ID: NCT00917384
Sponsor ID: 13893
A Randomized, Open-label Study of the Effect of First-line Herceptin in Combination With a Fluoropyrimidine and Cisplatin Versus Chemotherapy Alone on Overall Survival in Patients With HER2-positive Advanced Gastric Cancer
Sponsor: Roche
Study ID: NCT01041404
Sponsor ID: BO18255
A Double-blind, Randomised, Multicenter, Phase III Study of Bevacizumab in Combination With Capecitabine and Cisplatin Versus Placebo in Combination With Capecitabine and Cisplatin, as First-line Therapy in Patients With Advanced Gastric Cancer
Sponsor: Roche
Study ID: NCT00548548
Sponsor ID: AVF4200g
A Randomized, Open-label, Dose-escalation to Rash Study to Assess the Effect of Tarceva in Combination With Gemcitabine on Overall Survival in Patients With Metastatic Pancreatic Cancer.
Sponsor: Roche
Study ID: NCT00652366
Sponsor ID: BO21128
A Randomized, Open-label Phase III Intergroup Study: Effect of Adding Bevacizumab to Cross Over Fluoropyrimidine Based Chemotherapy (CTx) in Patients With Metastatic Colorectal Cancer and Disease Progression Under First-line Standard CTx/Bevacizumab Combination
Sponsor: Roche
Study ID: NCT00700102
Sponsor ID: ML18147
A Randomized, Three Arm Multinational Phase III Study to Investigate Bevacizumab (q3w or q2w) in Combination With Either Intermittent Capecitabine Plus Oxaliplatin (XELOX) (q3w) or Fluorouracil/Leucovorin With Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 Regimen Alone as Adjuvant Chemotherapy in Colon Carcinoma: The AVANT Study
Sponsor: Roche
Study ID: NCT00112918
Sponsor ID: CDR0000427299
A Randomized, Multicenter, Adaptive Phase II/III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine (T-DM1) Versus Taxane (Docetaxel Or Paclitaxel) In Patients With Previously Treated Locally Advanced Or Metastatic HER2-Positive Gastric Cancer, Including Adenocarcinoma Of The Gastroesophageal Junction
Sponsor: Roche
Study ID: NCT01641939
Sponsor ID: BO27952
A Randomized, Double-blind Study of the Effect of Avastin Plus Gemcitabine and Erlotinib Compared With Placebo Plus Gemcitabine and Erlotinib on Overall Survival in Patients With Metastatic Pancreatic Cancer
Sponsor: Roche
Study ID: NCT01214720
Sponsor ID: BO17706
An Open-Label Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) (“XELOX”) Versus Fluorouracil/Leucovorin as Adjuvant Therapy for Patients Who Have Undergone Surgery for Colon Carcinoma, AJCC/UICC Stage III (Dukes Stage C)
Sponsor: Roche
Study ID: NCT00069121
Sponsor ID: NO16968
An Open-Label Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) (“XELOX”) Versus Bolus and Continuous Infusion Fluorouracil/ Intravenous Leucovorin With Intravenous Oxaliplatin (Q2W) (“FOLFOX4”) as Treatment for Patients With Metastatic Colorectal Cancer Who Have Received Prior Treatment With CPT-11 in Combination With 5-FU/LV as First Line Therapy
Sponsor: Roche
Study ID: NCT00069108
Sponsor ID: NO16967
A 2×2 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
Sponsor: Roche
Study ID: NCT00069095
Sponsor ID: NO16966
A Double-Blind, Randomized, Multicenter, Phase III Study of Bevacizumab in Combination With Capecitabine and Cisplatin Versus Placebo in Combination With Capecitabine and Cisplatin, as First-Line Therapy in Patients With Advanced Gastric Cancer.
Sponsor: Roche
Study ID: NCT00887822
Sponsor ID: ML22367
An Observational Study of Avastin (Bevacizumab) in Combination With Chemotherapy for Treatment of Metastatic or Locally Advanced and Unresectable Colorectal Cancer and Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Excluding Predominant Squamous Cell Histology)
Sponsor: Roche
Study ID: NCT00388206
Sponsor ID: AVF3991n
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
Sponsor: Roche
Study ID: NCT00109226
Sponsor ID: AVF2192g
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
Sponsor: Roche
Study ID: NCT00109070
Sponsor ID: AVF2107g
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.
Sponsor: Roche
Sponsor ID: MO18458
A Multicenter, Open Label, Phase I /Randomised Phase II Study to Evaluate Safety, Pharmacokinetics and Efficacy of BIBF 1120 in Comparison With Oral Sorafenib for Advanced Hepatocellular Carcinoma Patients.
Sponsor: Boehringer Ingelheim
Study ID: NCT01004003
Sponsor ID: 1199.37
A Multicenter, Open Label, Phase I/Randomized II Study to Evaluate Safety, Pharmacokinetics and Efficacy of BIBF 1120 in Comparison With Sorafenib for Advanced Hepatocellular Carcinoma Patients in Asia.
Sponsor: Boehringer Ingelheim
Study ID: NCT00987935
Sponsor ID: 1199.39
A Randomized, Multi-Center, Blinded, Placebo-Controlled Study Of Mapatumumab ([HGS1012], A Fully Monoclonal Antibody To TRAIL-R1) In Combination With Sorafenib As A First-Line Therapy In Subjects With Advanced Hepatocellular Carcinoma
Sponsor: GlaxoSmithKline
Study ID: NCT01258608
Sponsor ID: 200149
A Phase II Biomarker Identification Trial for Erlotinib (Tarceva®) in Patients With Advanced Pancreatic Carcinoma
Sponsor: Roche
Study ID: NCT00674973
Sponsor ID: BO21129
A Double-blind, Randomised, Placebo Controlled Phase III Study of Nintedanib Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Patients With Metastatic Colorectal Cancer Refractory to Standard Therapies.
Sponsor: Boehringer Ingelheim
Study ID: NCT02149108
Sponsor ID: 1199.52
Trial of rhuMAb VEGF Antibody Combined With 5 Fluourouracil and Leucovorin in Subjects With Locally Advanced or Metastatic Colorectal Cancer
Sponsor: Roche
Sponsor ID: AVF0780G
Public Disclosures:
Summary of Results
This request was initiated as a transfer and continuance of the clinicalstudydatarequest.com (CSDR) project ID 1741 and data accessed via the project data sphere (PDS) portal when Roche and Lilly became Vivli data contributors. Publications (achieved with work conducted on CSDR and PDS) related to this research program identifying predictors of therapeutic and adverse effects of medicines used in the treatment of gastrointestinal cancers included:
- Lim HH, Hopkins AM, Rowland A, Yuen HY, Karapetis CS, Sorich MJ. Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab. Target Oncol. 2019 Dec;14(6):743-748. doi: 10.1007/s11523-019-00683-z. PMID: 31676953.
- Kichenadasse, G., Miners, J. O., Mangoni, A. A., Karapetis, C. S., Hopkins, A. M., & Sorich, M. J. (2021). Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy, Journal of the National Comprehensive Cancer Network, 19(9), 1037-1044.
Co-aligned and integral to the validity of this Vivli project transfer, the research team was trying to organize access to in-scope for sharing trials on the medicine panitumumab (NCT00115765, NCT01001377, NCT01412957, NCT00364013, NCT00113763, NCT00339183). The request to access these trials was submitted to the appropriate data contributor on an external portal at 20/02/2020. Unfrequently, as of 08/11/2022 we have not yet been able to organize access to the data, and there have been no further publications achieved from the project on the Vivli portal. The research team are closing this Vivli request and the request to panitumumab data at this stage.