title: Dosing de novo combinations of two targeted drugs: Towards a customized precision medicine approach to advanced cancers.
abstract: Metastatic cancers harbor complex genomic alterations. Thus, monotherapies are often suboptimal. Individualized combinations are needed in order to attenuate resistance. To help inform selection of safe starting doses for novel, two-agent, targeted drug combinations, we identified clinical trials in adult oncology patients who received targeted drug doublets (PubMed, January 1, 2010 through December 31, 2013). The dose percentage was calculated for each drug: (safe dose in combination divided by single agent full dose) X 100. Additive dose percentage represented the sum of the dose percentage for each drug. A total of 144 studies (N = 8568 patients; 95 combinations) were analyzed. In 51% of trials, each of the two drugs could be administered at 100% of their full dose. The lowest safe additive dose percentage was 60% if targets and/or class of drugs overlapped, or in the presence of mTor inhibitors, which sometimes compromised the combination dose. If neither class nor target overlapped and if mTor inhibitors were absent, the lowest safe additive dose percentage was 143%. The current observations contribute to the knowledge base that informs safe starting doses for new combinations of targeted drugs in the context of clinical trials or practice, hence facilitating customized combination therapies.
authors.affiliation: Department of Hematology-Oncology, Kaiser Permanente San Diego Medical Center, San Diego, CA, USA.
authors.forename: Sariah
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Mina
authors.initials: M
authors.lastname: Nikanjam
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D004359:Drug Therapy, Combination / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D057285:Precision Medicine / Q000379:methods*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: maximum tolerated dose; oncology; precision medicine; recommended phase 2 dose; targeted therapy
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