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. 2010 Feb 15;16(4):1289-97.
doi: 10.1158/1078-0432.CCR-09-2684. Epub 2010 Feb 9.

Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse

Rajul K Jain  1 , J Jack Lee, David Hong, Maurie Markman, Jing Gong, Aung Naing, Jennifer Wheler, Razelle Kurzrock
Affiliations

Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse

Rajul K Jain et al. Clin Cancer Res. .

Abstract

Purpose: To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Because traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised about administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.

Experimental design: Twenty-four consecutive trials treating 683 patients between October 1, 2004, and June 30, 2008, at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (<or=25% MTD), medium-dose (25-75% MTD), or high-dose (>or=75% MTD) group, and groups were compared for response rate, time-to-treatment failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis, patients treated above the MTD were excluded (high-dose group, 75-100% MTD). Of the 683 patients, 97.7% received targeted agents.

Results: Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment failure, with 32.9% versus 25.2% of patients on therapy at 3 months (P = 0.08). In addition, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.

Conclusions: These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies.

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Conflict of interest statement

Disclosures:

None of the authors have any conflicts of interest relevant to the subject of this manuscript.

Figures

Figure 1
Figure 1
Response to Treatment 3–12 Months After Starting Study. A. Percentage of patients with a favorable response that stayed on study. B. Percentage off trial due to toxicity. C. Percentage off trial due to progressive disease or toxicity.
Figure 2
Figure 2
Kaplan-Meier Estimate of Time-to-Treament Failure. Tic marks represent censored patients (those still on study on June 30, 2008, the last date included in this analysis). p-values are for low, medium, and indicated high-dose group. Inset shows 3-year data.
Figure 3
Figure 3
Kaplan-Meier Estimate of PFS. Tic marks represent patients who started another treatment prior to disease progression or death, or who were on study on June 30, 2008. p-values are for low, medium, and indicated high-dose group. Inset shows 3-year data.
Figure 4
Figure 4
Kaplan-Meier analysis of OS. Overall survival for up to 3 years after starting phase I study.
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Comment in

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