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Proposal 924/1341

Title of the Proposed Research

Vol-PACT: Improving Volumetric CT Metrics for Precision Analysis of Clinical Trial Results

Lead Researcher

Geoffrey R. Oxnard

Affiliation

Dana-Farber Cancer Institute
Harvard Medical School

Funding Source

The Biomarkers Consortium at the Foundation for the National Institutes of Health (FNIH) will provide seed funding ($250,000) to complete Aim 1 (approximately 9 months). The remaining funds to support the project ($986,000) will be raise among interested parties, such as pharmaceutical companies.

Potential Conflicts of Interest

Lead Researcher: Ad hoc advisory board: Boehringer-Ingelheim; AVEO; Novartis; Genentech. Consulting: Astra-Zeneca

Researcher 1: I have no conflicts with this project. I do serve as an independent blinded reviewer and serve on Data and Safety Monitoring Board (DSMB) through BioClinica and ICON Medical Imaging.

Researcher 2: None

Researcher 3: None

Researcher 4: None

Researcher 5: I have no conflicts with this project. I do have research funding from Sanofi and Bayer. I am a paid consultant for Millennium. I have been an uncompensated consultant for Fujifilm and Bayer

Researcher 6: Research funding: GSK, Genentech/Roche

Management of Real or Potential Conflicts of Interest
The researchers do not believe that the research support or consulting activities reported by Lead Researcher (G.R.O.), Researcher 1 (L.H.S.), Researcher 5 (M.M.), and Researcher 6 (A.V.) will affect the researchers' objectivity in designing the study, conducting the research and/or interpreting results. The real or potential conflicts of interest will be managed through disclosure of interests when the research is presented and published.

Data Sharing Agreement Date

924 - 13 November 2014
1341 - 31 May 2016

Lay Summary

Currently drug activity in phase 2 clinical trials (typically 100–300 patients) in solid tumors is primarily assessed by computed tomography (CT) imaging-based Response Evaluation Criteria in Solid Tumors (RECIST) to determine response rate in single-arm trials where all patients are treated with the drug. Some trials compare drug activity between patients who receive the drug treatment and those who don’t. In such cases, other RECIST-based tumor assessment, such as time to tumor progression (TTP) and progression-free survival (PFS), is used as the endpoint to measure drug activity. Drugs that show promise in effectiveness warrant further evaluation in phase 3 clinical trials to confirm the effectiveness and overall benefit-risk relationship in a larger number of patients. In phase 3 trials, overall survival (OS) remains the gold standard for clinical benefit. It often requires a large number of patients (e.g., 1000 or more) and long observation time to demonstrate OS advantage of the new drug over available treatment. Surrogate endpoints are accepted for drug approval in certain situations, but clinical benefit is generally required to be confirmed in subsequent or ongoing trials. In reality, up to 60% of the drugs that showed promise in phase 2 trials later proved ineffective to treat the disease when the drug is tested in phase 3 trials.

This study aims to develop new analytical methods to improve the ability of imaging in phase 2 trials in predicting the effectiveness of new drugs and their potential for success in phase 3 trials. These methods can reduce the number of patients required in clinical trials, and shorten the observation time required by currently used methods of assessing clinical benefit to patients. As a result, they improve the efficiency in bringing new drugs to the market and patients.

To develop such methods, we will generate 1000 simulated phase 2 trials by sampling patient imaging and outcomes data from completed phase 3 clinical trials that supported regulatory approval of the drug. Changes in tumor burden will be assessed by tumor volume calculated from CT imaging data. This volume assessment more closely reflects true tumor burden than the line length of a tumor lesion as seen on a cross-sectional image according to RECIST. The study also proposes to analyze tumor response as a continuous variable rather than a categorical (progression=yes or no) variable as is used in RECIST.

We will study images donated by several pharmaceutical company-sponsored phase 3 drug trials from four common measurable cancers of solid tumors. By studying multiple agents used to treat different cancers, we hope to draw broad conclusions about improved strategies for effective trial analysis.

This research has value to a wide number of parties, including academic investigators, pharmaceutical companies, regulatory representatives, and ultimately cancer patients. Our results will be published, and the tools available to the public.

Study Data Provided

Study BI-1200.23: BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)
Study BI-1200.32: BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation
Study BI-1200.34: BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)
Study VEG105192: A Randomised, Double-blind, Placebo controlled, Multi-center Phase III Study to Evaluate the Efficacy and Safety of Pazopanib (GW786034) Compared to Placebo in Patients with Locally Advanced and/or Metastatic Renal Cell Carcinoma
Study VEG108844: Study VEG108844, A study of Pazopanib versus Sunitinib in the Treatment of Subjects with Locally Advanced and/or Metastatic Renal Cell Carcinoma

Statistical Analysis Plan

Publication Citation

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

Summary Results

Results summary or link will be posted when available.