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Proposal 946

Title of the Proposed Research

Assessing models for changes in tumour size over time and how they relate to survival times

Lead Researcher

Raluca Eftimie, PhD

Affiliation

Division of Mathematics, University of Dundee
Dundee, UK

Funding Source

Northern Research Partnership Early Career Researcher Engagement and Exchanges with Business and Industry

Potential Conflicts of Interest

None

Data Sharing Agreement Date

28 May 2014

Lay Summary

The background to the research
• There are still many unanswered questions regarding how, or even if, changes in tumour size relate to patient survival. In addition, to our best knowledge most survival models in the existing literature have never been tested on independent data sets. Such a test is the main purpose of this study. The testing of survival models on independent data sets is vital to establishing the validity of the selected approach.
• Although melanoma is not the most prevalent skin cancer, it does have one of the highest mortality rates. In the US alone, it is estimated that 76,000 new cases will be diagnosed in 2014, and about 10,000 people will die this year. (http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics)

How the research will add to medical science or improve patient care?
• In assessing the relationship between tumour size changes and survival, this research should enable an earlier evaluation of how well a new treatment is likely to affect survival times for patients with metastatic melanoma.
• We will also address a key basic science question regarding growth laws applicable to clinical tumours. A recent article has highlighted that there remains considerable uncertainty regarding appropriate growth laws for human tumours (http://cancerres.aacrjournals.org/content/early/2013/02/07/0008-5472.CAN-12-4355).

The aims and objectives of the research
The overall aim of this project is to assess whether mechanistic models for tumour growth offer any functional advantage over empirical investigations of how changes in tumour size ( e.g. at week 8) relate to survival times .

Specific Objectives are:
• Build and test different mechanistic models of tumour growth.
• Assess if there is a relationship between empirical tumour size changes and survival.
• Assess if there is a relationship between parameter values from the different growth law models and survival.
• Also determine the prospective use of a survival model built using one drug and tested with data from other drugs within a similar diseases setting.

How the research will be conducted
• The research will be conducted using data from three drugs approved in the metastatic melanoma setting: Vemurafenib, Trametnib and Dabrafenib. The data from one of these studies will be used to select a tumour growth law model used to develop a survival model. The data from the other two drugs will be used as a validation set.


How the findings will be interpreted and communicated to patients and/or the public
• Publication in an open access format
• Summary available through a dedicated project webpage hosted by the main investigator.

Study Data Provided

Novartis Study BRF112680: A Phase I, Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the BRAF Inhibitor GSK2118436 in Subjects with Solid Tumors
Novartis Study BRF113710: A Phase II (BRF113710) single-arm, open-label study of GSK2118436 in BRAF mutant metastatic melanoma
Novartis Study BRF113683: A Phase III randomized, open-label study comparing GSK2118436 to Dacarbazine (DTIC) in previously untreated subjects with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma
Novartis Study MEK113583: An Open-Label, Multi-Center Study to Investigate the Objective Response Rate, Safety, and Pharmacokinetics of GSK1120212, a MEK Inhibitor, in BRAF Mutation-positive Melanoma Subjects Previously Treated with or without a BRAF Inhibitor
Novartis Study MEK114267: A Phase III randomized, open-label study comparing GSK1120212 to chemotherapy in subjects with advanced or metastatic BRAF V600E/K mutation-positive melanoma
Novaftis Study MEK111054: An Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor GSK1120212 in Subjects with Solid Tumors or Lymphoma
Roche Study NO25026: A randomized, open-label, controlled, multicenter, global study on progression-free and overall survival in previously untreated patients with unresectable stage IIIC or stage IV melanoma with V600E BRAF mutation receiving RO5185426 or dacarbazine
Roche Study NP22657: An open-label multicenter study on the efficacy of continuous oral dosing of RO5185426 on tumour response in previously treated patients with metastatic melanoma

Statistical Analysis Plan

Publication Citation

The publication citation will be added after the research is published.

Summary Results

The summary results are being finalized and will be posted after the research is published.