title: Dosing targeted and cytotoxic two-drug combinations: Lessons learned from analysis of 24,326 patients reported 2010 through 2013.
abstract: Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I-III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA-approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA-approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly-ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA-approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two-drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice.
authors.affiliation: Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA.
authors.forename: Mina
authors.initials: M
authors.lastname: Nikanjam
authors.affiliation: Department of Hematology-Oncology, Kaiser Permanente San Diego Medical Center, San Diego, CA.
authors.forename: Sariah
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, San Diego, CA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D056572:Histone Deacetylase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
keywords: cytotoxic chemotherapy; maximum tolerated dose; precision medicine; recommended Phase 2 dose; targeted therapy