Speeding up the Evaluation of New Agents in Cancer

Abstract

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

“…[12][13][14]22 Full details are provided in the protocol. In summary, eligible patients had prostate cancer that was newly diagnosed and metastatic, node-positive, or high-risk locally advanced (with at least two of following: a tumor stage of T3 or T4, a Gleason score of 8 to 10, and a PSA level ≥40 ng per milliliter) or disease that was previously treated with radical surgery or radiotherapy and was now relapsing with high-risk features (in men no longer receiving therapy, a PSA level >4 ng per milliliter with a doubling time of <6 months, a PSA level >20 ng per milliliter, nodal or metastatic relapse, or <12 months of total ADT with an interval of >12 months without treatment).…”

“…It uses intermediate activity analyses, based on failure-free survival, to cease randomization to research groups that are insufficiently active. [12][13][14] We have previously reported that treatment with docetaxel at the inception of ADT increased median survival from 71 months to 81 months as well as overall survival (hazard ratio for death, 0.76). 15,16 These results, along with those of a systematic review that included other trials [17][18][19] and of a meta-analysis, 16 led to docetaxel becoming a part of the standard of care for suitable patients with prostate cancer who had not received previous hormone therapy.…”

“…The STAMPEDE trial uses a novel multigroup, multistage (also called multiarm, multistage [MAMS]) platform design [12][13][14] to test whether the addition of further treatments to ADT improves overall survival if used in the first-line setting. It uses intermediate activity analyses, based on failure-free survival, to cease randomization to research groups that are insufficiently active.…”

Applications for Oncologic Drugs: A Descriptive Analysis of the Oncologic Drugs Advisory Committee Reviews

“…Over the last decade, significant advances in cancer research have been made based on sequencing of the human genome, identification of driving growth factors and receptors, and signaling pathways [1]. From 2007 to 2010, research innovations led to an estimated 1,884 phase I, 3,436 phase II, and 1,025 phase III oncology clinical trials [2].…”

“…It is estimated that pharmaceutical companies spend an average of $1.7 billion dollars per drug from development to market approval [7]. Despite these investments, only 40% of drug applications submitted for consideration are approved [1,8,9].…”