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International Clinical Trials

Special Treatment

Not all therapies have the same effect on each patient. Yet, until recently, drugs have been developed with a ‘one-size-fitsall’ approach. Pharmacogenomics uses information about a person’s genetic makeup, or genome, to help determine the most effective treatment for a patient with a specific disease (1).

A key benefit of pharmacogenomics to clinical studies is that it potentially reduces the size and duration of trials because the right patients are identified sooner. Studying a drug only in those likely to benefit from it could speed up and streamline its development, while maximising its therapeutic benefit to patients.

Pharmacogenetic testing provides information about a patient’s likelihood to have a therapeutic response and/or an adverse reaction to a medication, enabling the potential for a tailored and personalised approach to medication therapy. Genetics has been estimated to account for anywhere between 20-95% of the variation in individual responses to medications (2). When it comes to chemotherapy, the potential for complications is very high and must be carefully weighed against the benefit and overall outcome for each patient. Thus, a treatment regimen should be tailored to the tumour’s genotype in order to optimise the patient’s response. To minimise potential side effects in patients, their genetic profile can help to identify how they will metabolise and respond to the treatment.

Evolving Trial Designs

The traditional treatment path for cancer has been tumour biopsy, histologic diagnosis and a standard chemotherapy regimen. However, when it comes to treating cancer, ‘one size does not fit all’. The traditional approach does not account for the variability between tumours or between patients, and the oncology community is recognising the need for these treatments to evolve.

Considerable progress is being made in genotyping to determine if a given regimen is appropriate for a specific tumour. Examples include the identification of human epidermal growth factor receptor 2 (HER2) in the selection of transtuzumab as treatment for breast cancer, receptor tyrosine kinase (RTK) molecules when selecting erlotinib to treat lung cancer, or cetuximab for metastatic colorectal cancer. These RTK molecules may either be overexpressed or mutated. Inhibition of the defective RTK can aid in the initial complete remission induction and, in some cases, prevention or delay of relapse.

The fundamental – and often overlooked – step is to make the necessary linkages between specific biomarkers and their underlying genotypes, then tailor drug treatments to achieve optimal patient outcomes and minimise adverse reactions.

For example, it was recently discovered that a mutation in the protein phosphatase and tensin homolog (PTEN) has been identified as an important biomarker in many tumours. PTEN is an enzyme that modulates phosphoinositide 3-kinase (PI3K), an enzyme that causes a tumour to grow. PTEN actually inactivates PI3K by removing a phosphate group. Identification of the PTEN mutation suggests that treating patients with an inhibitor of PI3K can do what the mutated PTEN cannot: inhibit tumour growth.

While such discoveries are remarkable, it is important to emphasise that there may be more than one mutation, which means that a single therapy may not be curative. Furthermore, the genotype may evolve with new mutations, or different genotypes may emerge in different cell lines. Identification of reliable tumour biomarkers can provide an early likelihood of treatment response to a specific drug regimen and/or indicate patient prognosis.

Radical Change

The manner in which clinical trials are currently being conducted is undergoing radical change in an effort to identify appropriate molecular targets. For example, the traditional strategy used in Phase 1 trials to determine the maximum tolerated dose of a new oncolytic agent is being modified. Pharmacogenomics allows for a genome-wide analysis to identify particular biomarkers in specific tumour types, so that targeted, molecular drugs can be developed. Therefore, a different approach to clinical trials is evolving to provide the required information for development of both new diagnostics and new therapies.

‘Umbrella’ and ‘bucket’ (also called ‘basket’) trials are examples of new clinical trial structures designed to enrich the study population with specific tumour-genetic attributes. In this manner, information on the genetic drivers for a specific tumour type may be targeted. Examples of these types of studies include the US Department of Defense BATTLE (3) and NCI MATCH (4) trials. Such research can generate a huge amount of information. Special statistical methodologies are being developed to mine these rich data, in order to identify relevant signals appropriate to a specific tumour and a specific patient.

Safety and Toxicity Profiles

Unfortunately, most chemotherapy drugs have significant toxicities. It is important to identify at-risk patients, so that their doctor can decide if the expected toxicities are acceptable. For example, will a patient be at a higher risk for side effects like severe mucositis, diarrhoea, nausea and vomiting?

Genomic technology (single-nucleotide polymorphism (SNP) profiling) is evolving as a predictive tool to identify patients who are at risk for these toxicities – prior to treatment. Severe, and even fatal, toxicities can occur in patients with certain polymorphisms in enzymes that metabolise chemotherapy drugs. A polymorphism is defined as a normal variation in a particular enzymatic gene, usually an SNP, which can lead to modification of its function. Several classic examples of polymorphisms that involve the metabolism of common chemotherapy drugs include 5-flurouracil (5FU), Irinotecan and 6-mercaptopurine. Fortunately, polymorphisms that contribute to these toxicities are not common. In the case of 5FU, an enzyme – dihydropyrimidine dehydrogenase (DPD) – that metabolises 80- 90% of 5FU to an inactive form is critical. If DPD is not normally functional, or is absent, lethal levels of 5FU can accumulate in the patient. Partial deficiency of this enzyme occurs in 3-5% of the population.

In some cases, an enzyme polymorphism may be present that fails the critical activation step of a prodrug; such is the case with clopidogrel. 30% of the population has a mutation in one of the P450 cytochromes, CYP 2C19, required to activate the prodrug. If the patient has this allele, or a mutated form of the enzyme, clopidogrel is not activated. Therefore, in these patients, clopidogrel provides no platelet inhibition to protect from strokes or heart attacks.

Dose targeting is another important advancement in minimising toxicity and improving efficacy. One example is busulfan in stem cell transplant. Prior to the initiation of treatment, the patient is given a small test dose of busulfan. Blood levels of the drug are then monitored to provide the peak drug level and the rate of drug clearance. From these data, an individual patient dose of busulfan can be determined to ensure that treatment efficacy is optimised and toxicity reduced.

Informed Decisions

An additional aspect in genomic applications to cancer diagnosis, classification, treatment and monitoring is its use in assessing treatment efficacy. Companion diagnostics – the use of medical devices to determine the risks and benefits of a particular therapy to a patient – can be used to monitor a patient’s response to a given therapy. With the information gathered, the doctor can make an informed, immediate decision regarding therapy or dosage adjustments.

Take, for example, HER2 in breast cancer and FMS-related tyrosine kinase 3 in acute myeloid leukemia. As the tumour is treated, the biomarker abates, and a companion diagnostic tracks the progress. Thus, the rate and extent of successful treatment can be determined. Likewise, the recurrence of the biomarker can indicate recurrence of the cancer. Faster, personalised and more informed treatments are possible with the right information.

Economic Impact

The impact of pharmacogenomics has critical downstream effects on its implementation – not only on the fields of haematology and oncology, but also on other areas of medicine.

Identification of a regimen that can effectively target a specific molecular defect in a tumour represents, of course, a major medical breakthrough – one that has the potential to positively impact pharmacoeconomics. First, for any given tumour, pharmacogenomics has the potential to reduce the number of tried-and-failed therapies, lessening the accumulated toxicities from exposure to multiple ineffective regimens, minimising the number of adverse events, and so on. The implications are farreaching when it is possible to identify the right therapy for the right patient early in treatment.

Additionally, by enriching the treatment population with appropriate patients, and by reducing the size and duration of clinical trials, the path for new drug development and time to market is being accelerated. Specific study subjects are identified and screened to maximise potential efficacy, and to exclude patients whose SNP profile may indicate prohibitive serious adverse events. All of these aspects are important in risk management during the drug development process.

The ability to improve overall patient outcomes and reduce toxicities, while enhancing the pharmacoeconomic impact of the correct regimen for specific cancers in a particular patient is critical – and has now become possible. Of course, the expense of developing companion diagnostic tests is still significant, and new approaches to curb these costs are imperative. SNP analysis, cell surface epitope identification and tumour micro particle diagnostics all offer real potential to lessen the economic burden of companion diagnostics and enhance outcomes for patients and payers in the future.

Caregiver and Payer Education

A significant barrier to the rapid implementation of pharmacogenomics to all oncology patients derives from the fact that not all haematologists and oncologists are wellversed in the importance of pharmacogenomics. Education for all healthcare providers and students is therefore mandatory. Practicing providers may need educational tools offered by pharma and CROs. The encouraging news is that most clinical centres are now adopting genotyping and phenotyping (observing interaction of an organism’s genotype and environment) as a standard of practice.

Success of these new approaches to drug and protocol development in the world of personalised medicine depends on early identification of toxicity and efficacy of treatment. These elements are necessary to avoid more severe toxicity, or continuing with a therapy that is ineffective. Patients, payers and providers all benefit from avoiding ineffective and unnecessary toxic therapies that, in principle, can be prevented by pharmacogenomics screening.

To capture these emerging data, consistent patient and nurse involvement is essential. The patient must be educated in what is important in their care and treatment regimen, so he or she is able to document and report important events. Clinical trial and marketed product nurses, through doctor and patient services, can effectively participate in this process by acquiring, organising and communicating relevant information. Nurses, whether onsite or in call centres, are able to obtain and record critical data, which is then brought to the doctor’s attention.

Oncology and Beyond

Even in these early stages, pharmacogenomics is redefining the approach to new drug development; clinical evaluation of new molecules; diagnosis and classification of cancer diagnosis; treatment regimen selection; and post-treatment monitoring of patients. Further maturation in all of these areas will be important, and requires continued education at all levels of participation.

1. National Human Genome Research Institute. Visit:
2. Wang L et al, Genomics and drug response, N Engl J Med 364: pp1,144-1,153, 2011
3. Visit:
4. Visit:

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Dr Don Gabriel serves as United BioSource Corporation’s Consultant Senior Director for Medical Oncology and Scientific Strategy. With more than 30 years of experience in the healthcare industry, he directs the company’s oncology programme design and development. Don is also responsible for developing strategic and fully integrated pre- and postmarketing oncology programmes for pharma and biotech manufacturers. He is a nationally recognised oncology haematologist in stem cell transplant for liquid tumours.
Dr Don Gabriel
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