Dosing Three-Drug Combinations That Include Targeted Anti-Cancer Agents: Analysis of 37,763 Patients

Abstract

Background: Combining targeted and cytotoxic agents has the potential to improve efficacy and attenuate resistance for metastatic cancer. Information regarding safe starting doses for clinical trials of novel three-drug combinations is lacking.

Materials and methods: Published phase I-III adult oncology clinical trials of three-drug combinations involving a targeted agent were identified by PubMed search (January 1, 2010 to December 31, 2013). A dose percentage was calculated to compare the dose used in combination to the single agent recommended dose: (U.S. Food and Drug Administration-approved/recommended phase II dose/maximum tolerated dose). The additive dose percentage was the sum of the dose percentages for each drug in the combination.

Results: A total of 37,763 subjects and 243 drug combinations were included. Only 28% of studies could give each of the three agents at 100%. For combinations involving two targeted agents and a cytotoxic agent, the lowest starting additive dose percentage was 133%, which increased to 250% if two antibodies were included. For combinations of one targeted agent and two cytotoxic agents, the lowest additive safe dose percentage was 137%. When both cytotoxic agents were held at 100%, as occurred in 56% of studies (which generally used cytotoxic doublets with known combination safety dosing), the lowest safe dose percentage was 225% (providing that a histone deacetylase inhibitor was not the targeted agent).

Conclusion: These findings serve as a safe starting point for dosing novel three-drug combinations involving a targeted agent in clinical trials and practice. The Oncologist 2017;22:576-584 IMPLICATIONS FOR PRACTICE: Targeted and cytotoxic drug combinations can improve efficacy and overcome resistance. More knowledge of safe starting doses would facilitate use of combinations in clinical trials and practice. Analysis of 37,763 subjects (243 combinations) showed three drugs could be safely administered, but less than 30% of combinations could include all three drugs at full dose. Dose reductions to 45% of the dose of each single agent may be required. Combinations involving two antibodies required fewer dose reductions, and the use of established cytotoxic doublets made initial dose assignment easier.

Keywords: Cytotoxic chemotherapy; Maximum tolerated dose; Precision medicine; Recommended phase II dose; Targeted therapy.

Figure 1.

Consort diagram for three‐drug combinations. Articles identified from the PubMed search were screened to identify three‐drug combinations of cytotoxic and targeted agents that included at least one targeted agent. Studies including immunotherapy, radiation, organ dysfunction (renal and liver failure), pediatric patients, exclusively elderly patients, or those administering one drug of the combination at greater than the FDA‐approved/RP2D/MTD dose were excluded from the analysis.