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


METHODS
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.
Department of Investigational Cancer Therapeutics, Phase I Program, MD Anderson Cancer Center, Houston, Texas 77030-4009, USA. rjain@mdanderson.org
Rajul K
RK
Jain
J Jack
JJ
Lee
David
D
Hong
Maurie
M
Markman
Jing
J
Gong
Aung
A
Naing
Jennifer
J
Wheler
Razelle
R
Kurzrock
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents