The results of a Phase I/IIa dose-escalation study for ChemGenex’s investigational cancer drug Quinamed sheds light on how pharmacogenomics may be used to determine the right dose for patients.
The Phase I/IIa dose escalation study was designed to identify a genotypically optimized dose of Quinamed in heavily pre-treated patients with solid carcinomas. ChemGenex presented the results at the American Society of Clinical Oncology’s annual meeting last week in Chicago.
According to the company, the study showed that patients had improved tolerance and evidence of anti-cancer activity when Quinamed dosing was based on their genotypes.
“The key outcomes from this study were (i) demonstration that dose level could be optimized according to patient genotype, (ii) the drug was well tolerated, with predictable and manageable side effects, and (iii) there was evidence of anticancer activity in several solid tumor types,” the company said in a statement.
In clinical trials, the genotype was established by PCR testing done at the University of Louisville. ChemGenex President Dennis Brown told Pharmacogenomics Reporter this week that the company is currently in discussion with diagnostic shops to develop a test that would help physicians genotypically dose Quinamed to patients.
“There are commercial corporations who have created similar types of assays for [the tuberculosis drug] isoniazid,” Brown said. “So, this will not be difficult in the commercial setting to have a kit or patient samples to be sent out for a diagnostic test. We have been speaking to groups who can do this for us but we haven’t gone into a formal relationship yet.”
ChemGenex’ product, if approved by the FDA, would advance the science of PGx-based dosing, an area of research that has made slow progress. According to the HHS draft report, Realizing the Promise of Pharmacogenomics: Opportunities and Challenges, current PGx-based testing can identify patients who are likely to respond differently to particular drugs and indicate the need for customized dosing, “but that testing does not necessarily translate into dosing instructions” [see PGx Reporter 03-28-2007].
Clinical History of Side Effects
The clinical activity of Quinamed against a “variety of cancers has long been recognized, but development has been hampered by the unpredictable side-effect profile for patients," lead investigator John Kuhn from the University of Texas Health Science Center in San Antonio said in a statement.
According to Brown, Quinamed, also known as amonafide dihydrochloride, is an isoquinoline analog that has been explored for anti-infective drugs, but never before in the cancer field. In a Phase I and a Phase II National Cancer Institute study, the drug showed promising activity in breast, prostate, non-small cell lung, and brain cancer.
“But in those studies the issue was that there seemed to be a less-predictable control over the side effects,” Brown said. “So pharmacologists worked on understanding the metabolic profile of the agent and found that one of the enzymes to first metabolize the compound after it was administered was an enzyme called N-Acetyltransferase (NAT).”
There are two types of such enzymes, NAT 1 and NAT2, and investigators linked the latter with Quinamed metabolism. The NAT2 enzyme adds an acetyl group to the chemical structure of the drug in an effort to remove it quickly from the body. “The enzymology of this drug allowed us to rethink how the drug might be better given to patients in today’s setting,” Brown explained.
“Our desire was to test if we knew the genotype of the patient could we get a better, or more precise dosing, for that patient,” Brown added. “This was the goal of the Phase I/IIa trial.”
The nature of cancer treatment, where adverse reactions are often taken as signals of a patient’s response to therapy, makes finding the right dose particularly difficult.
“In the cancer field … it is very difficult to have any kind of broad window of dosing for patients,” Brown said. “Usually you push the dose so high that the difference between a significant side effect and getting any kind of response for the patient is limited. The doses are very high to get a response and those with high responses have very significant side effects.
“A goal of personalized medicine and translational genomics to cancer is to try to broaden the therapeutic index, meaning have a better effect on the tumor and have [fewer] side effects,” he added.
“This will not be difficult in the commercial setting to have a kit or patient samples to be sent out for a diagnostic test. We have been speaking to groups who can do this for us but we haven’t gone into a formal relationship yet.”
According to ChemGenex, the study results confirmed that “genotyping patients [based on NAT2 genotype] prior to treatment allows for optimized personalized dosing and improved drug tolerance.”
In the first part of the study the researchers dose-escalated until patients experienced a dose-limiting toxicity. Then ChemGenex researchers collected biological samples from these patients with a cheek swab and sent them to the University of Louisville for PCR-based genotyping.
“It has been well established independently that there are two groups of people that can acetylize molecules like this: the fast and slow acetylators,” Brown said. There are identified SNPs that correspond to the fast, intermediate, and slow acetylation genotypes. Researchers used this information to separate the fast and intermediate acetylating patients into one group and the slow acetylating patients into another.
Patients with rapid and intermediate acetylator genotypes achieved a maximum tolerated weekly dose of 320 mg/m2. Slow acetylator patients achieved an MTD of 400 mg/m2 of Quinamed weekly. The weekly dosing schedule included three weeks on treatment followed by one week of rest.
With this dosing schedule, 64 percent of rapid and intermediate acetylators and 77 percent of slow acetylators showed no dose-limiting drug toxicities or dose-delay during treatment.
“If you were a slow acetylator you could take more of the drug. If you were a rapid acetylator you could take less drug and it was given in an IV,” Brown explained. In other words, “at an equally high dose, the slow acetylator group could tolerate the drug better than the high acetylator group.”
According to the company, the study showed Quinamed to be efficacious in a number of solid tumors in treatment-experienced cancer patients. “In a population of heavily pretreated patients who were refractory to multiple existing therapies and who had advanced tumors, there was evidence of antitumor activity in a range of tumor types,” ChemGenex said in a statement.
Three prostate cancer patients experienced a decline in prostate specific antigens; one patient achieved a partial response. Two patients with ovarian cancer achieved stable disease and saw a decline in the ovarian cancer biomarker CA125. One gastrointestinal stromal tumor patient reached stable disease and sustained in this state for more than 18 monthly cycles of Quinamed.
“We are encouraged by the signs of anticancer activity across a range of tumor types in patients who had failed multiple prior therapies, and look forward to progressing Quinamed into further development for indications where the clinical need and commercial potential is greatest,” ChemGenex CEO Greg Collier said in a statement.