Phase I Trial Of Cisplatin And KML-001 In Advanced Non-Small Cell Lung Cancer and Other Platinum Responsive Malignancies
Telomerase is the enzyme synthesizing the specific DNA sequences found at the telomeres in
the body's chromosomes. It is thus responsible for maintaining the length of telomeres.
Telomerase has been detected in human cancer cells and is found to be 10-20 times more
active than in normal body cells. This provides a selective growth advantage to many types
of tumors. If telomerase activity was to be turned off, then telomeres in cancer cells would
shorten, just like they do in normal body cells. This would prevent the cancer cells from
dividing uncontrollably in their early stages of development. In the event that a tumor has
already thoroughly developed, it may be removed and anti-telomerase therapy could be
administered to prevent relapse.
This study is being offered to patients with advanced cancer which has either no standard
therapy or which has progressed after treatment with one or more standard treatments.
The primary objective of this study :
To determine the maximum tolerated dose of KML001 in combination with cisplatin in patients
with advanced malignancy. This objective has been met. The study will be reopened with
expansion cohorts in advanced small cell lung cancer and non-small cell lung cancer to
better assess the activity of the combination, pending IRB approval.
Secondary Objectives of the study:
To determine the pharmacokinetics of KML001 and cisplatin in this combination. To assess the
response rate, disease-free survival and survival associated with this regimen.
To correlate indications of patient benefit (response or stable disease) with pretreatment
The highest safest doses are determined by increasing the doses of cisplatin and KML001 in
successive groups of patients until at least some of them have serious side effects. All
patients on this study will receive the same dose of cisplatin, which is known to have
antitumor effects. The doses of KML001 will be increased in successive groups of patients.
It is possible that those entering the study early may receive suboptimal doses of KML001.
At the end of the study we hope to determine the appropriate dose of the KML001 in
combination with cisplatin, learn about its side effects and understand how the body
metabolizes the drug.
Laboratory data from the UMGCC has demonstrated that the combination of KML001 and cisplatin
is synergistic in lung cancer cell lines. Cisplatin is the best established agent for the
treatment of lung cancer and most treatment regimens have been established with cisplatin
(or its congener, carboplatin). This synergism is particularly interesting given that there
is an anti-telomere effect for cisplatin.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the maximum tolerated dose of KML001 in combination with cisplatin
When dose limiting toxicities are established
Martin Edelman, MD
University of Maryland
United States: Food and Drug Administration
|University of Maryland Greenebaum Cancer Center||Baltimore, Maryland 21201|