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      An overview of precision oncology basket and umbrella trials for clinicians

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          Abstract

          With advancements in biomarkers and momentum in precision medicine, biomarker‐guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.

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          Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

          Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.
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            Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.

            HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.
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              Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols

              Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. Results We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. Conclusions We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology. Electronic supplementary material The online version of this article (10.1186/s13063-019-3664-1) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                edward.mills@cytel.com
                Journal
                CA Cancer J Clin
                CA Cancer J Clin
                10.3322/(ISSN)1542-4863
                CAAC
                Ca
                John Wiley and Sons Inc. (Hoboken )
                0007-9235
                1542-4863
                07 February 2020
                Mar-Apr 2020
                : 70
                : 2 ( doiID: 10.3322/caac.v70.2 )
                : 125-137
                Affiliations
                [ 1 ] Experimental Medicine, Department of Medicine University of British Columbia Vancouver British Columbia Canada
                [ 2 ] Department of Health Research Methodology, Evidence, and Impact McMaster University Hamilton Ontario Canada
                [ 3 ] Cytel Inc Vancouver British Columbia Canada
                Author notes
                [*] [* ] Corresponding Author: Edward J. Mills, FRCP(Edin), Department of Health Research Methodology, Evidence, and Impact, McMaster University, 777 West Broadway, Suite 802, Vancouver, BC V5Z 1J5, Canada ( edward.mills@ 123456cytel.com ).

                Author information
                https://orcid.org/0000-0003-3120-9694
                Article
                CAAC21600
                10.3322/caac.21600
                7187272
                32031692
                fe06d110-669d-4da1-b287-4b58ec272147
                © 2020 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals, Inc. on behalf of American Cancer Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Page count
                Figures: 2, Tables: 3, Pages: 13, Words: 21267
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                March/April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:28.04.2020

                basket trials,master protocols,precision medicine,precision oncology,umbrella trials

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