Dataset Information

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.

SUBMITTER: Nikanjam M

PROVIDER: S-EPMC5423521 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Nikanjam Mina M Liu Sariah S Yang Jincheng J Kurzrock Razelle R

The oncologist 20170419 5

<h4>Background</h4>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.<h4>Materials and methods</h4>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 com ...[more]

PMID: 28424323

Similar Datasets

Project description:BackgroundThe diversity in the genomic landscape of advanced and metastatic tumors calls for combination therapies based on the genomic signature associated with each tumor. Determining safe and tolerable doses for novel combinations of oncology drugs is essential for a precision medicine approach, but can also require dose reductions. Trametinib, palbociclib, and everolimus are among the targeted therapies most often used in novel combinations at our precision medicine clinic.ObjectiveTo evaluate the safe, tolerable dosing of trametinib, palbociclib, and everolimus when used as part of novel combinations with other agents for the treatment of advanced or metastatic solid tumors.MethodsThis retrospective study included adult patients with advanced or metastatic solid tumors who received trametinib, everolimus, or palbociclib plus other therapies as a part of novel combinations between December 2011 and July 2018 at the University of California San Diego. Patients were excluded if they received trametinib, everolimus, or palbociclib in standard combinations, such as dabrafenib plus trametinib, everolimus plus fulvestrant, everolimus plus letrozole, and palbociclib plus letrozole. Dosing and adverse events were determined through a review of the electronic medical records. A safe, tolerable drug combination dose was defined as being tolerated for at least 1 month, with no clinically significant serious adverse events.ResultsA safe, tolerable dose was determined for 76% of the 71 patients who received trametinib, 88% of the 48 patients who received everolimus, and 73% of the 41 patients receiving palbociclib when used in combination with other therapies. For patients with clinically significant adverse events, dose reductions were attempted in 30% of the trametinib recipients, in 17% of everolimus recipients, and in 45% of palbociclib recipients. When used in combination with other therapies, the optimal dosing of trametinib, palbociclib, and everolimus was lower than the standard single-agent dosing: it was 1 mg daily for trametinib; 5 mg daily for everolimus; and 75 mg daily, for 3 weeks on and 1 week off for palbociclib. Of note, everolimus could not be given concomitantly with trametinib at these doses.ConclusionSafe and tolerable dosing of novel combination therapies that includes trametinib, everolimus, or palbociclib is feasible for a precision medicine approach. However, neither results from this study nor results from previous studies could support the use of everolimus in combination with trametinib, even at reduced doses.

Dataset Information

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

Background

Materials and methods

Results

Conclusion

Publications

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

Similar Datasets

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