Product Releases

Therapy Dose Management During Clinical Development of Oncology Products

Tue, 01/24/2012 - 5:47am
Salvatore J. Salamone, PhD, Founder & Chief Scientific Officer; Edward L. Erickson, President & Chief Executive Officer; Saladax Biomedical Inc., Bethlehem, Pa.; Jack DeForrest, PhD, President; JDF PharmaConsulting LLC, Wycombe, Pa.

Data from animal studies in 1910 showed that the ratio of blood volume to body weight decreased with increasing body weight, but that the relationship between blood volume and body surface area (BSA) was constant.1 In time, these findings were extended to humans. BSA has long been the gold standard for determining the appropriate dose of chemotherapeutic agents because it was assumed that BSA would better reduce patient blood level variability than body weight—improving efficacy and reducing toxicity. Numerous studies, however, have shown that the use of BSA to determine the proper dose of chemotherapeutics still results in large patient variability, most likely due to variations in drug biodistribution, genetic variation, metabolism, and clearance.

Examining patient pharmokinetic variability, Baker and colleagues studied the relationship between BSA and drug clearance alone in a retrospective analysis of 33 cancer agents that underwent clinical development between the years 1991-2001; a total of 1,650 patients were employed. In this study, only 5 of 33 chemotherapeutic agents demonstrated a positive correlation between BSA and drug clearance. The relative improvement in variability of these 5 drugs was between 15% and 35% suggesting that BSA can improve variability by one third at best. 2 The authors concluded that alternate dosing strategies based on exposure should be evaluated when determining the proper dose of chemotherapeutic agents.

Finding a more effective algorithm to optimize drug dose should be viewed favorably by regulatory agencies as there is increasing emphasis placed on tailoring medical treatment based on the specific biology/pathology of each patient, i.e., personalized medicine. Indeed, a recent publication in The New England Journal of Medicine, Margaret Hamburg and Francis Collins, the respective heads of the FDA and NIH, noted that scientists are developing and using diagnostic tests to better predict patient responses to therapy.3 The authors share the vision that the FDA and NIH need to support personalized medicine as the agencies plan to move forward on several fronts. One such effort will be the forthcoming guidance on the co-development of a therapeutic with a companion diagnostic test, where a companion diagnostic might include a genetic test, an assay for a protein biomarker, or an assay for therapeutic dose management (TDM). Drs. Hamburg and Collins recognize that one key to treating patients is having the proper diagnostic tools to steer them to the right dose of the right drug at the right time. To date, only trastuzumab, denileukin diftitox, lapatinib, panitumumab, and cetuximab are FDA-approved with mandatory companion diagnostic tests to identify the subset of patients most likely to have a favorable clinical outcome; 11 other oncology drugs have mention of biomarkers in the label.4

As regulatory agencies push the use of companion diagnostics in personalized medicine, it appears the pharmaceutical and biotechnology industries are getting the message. As of 2008, only Roche and Novartis had invested in internal companion diagnostic research. Other companies decided to partner for diagnostic expertise and as of that time, there were 7 pharmaceutical/diagnostic partnerships. However, this number more than doubled by 2010, and in a report from the Tufts Center for the Study of Drug Development in that same year, 94% of companies surveyed stated they were investing in personalized medicine research and that 12% to 50% of their pipelines are personalized medicines.5 

One reason for relatively late entry by the industry into personalized medicine might be the hesitancy of some companies to invest in internal expertise or to form partnerships, both of which take time and internal resources. Some companies undoubtedly waited since they did not want to stratify the patient population and thus reduce market size. Others may not have wanted to complicate clinical development by co-developing a companion diagnostic with their therapeutic. Still others may just not have appreciated the significance of using a companion diagnostic.

Regardless, the FDA’s refusal to approve ChemGenex’s Omapro for chronic myeloid leukemia (CML) without a validated companion diagnostic should be a wake-up call to those companies. It is critical to pursue a companion diagnostic test in parallel with the clinical development of drugs that will only be safe and effective in a specific patient population, or drugs where TDM is critical.6 

As already mentioned, having an assay that can measure levels of the drug in a patient’s blood is considered a companion diagnostic. Whereas a genetic test or protein assay will (in theory) ensure the right patient receives the right drug by providing information on the state of the disease, the right dose of the drug will still need to be optimized. A comprehensive review article on the importance of TDM found that when fixed doses of chemotherapeutic agents were administered based on BSA, plasma blood levels varied as much as 100-fold from patient-to-patient—as in the case of 5-fluorouracil (5-FU)7—presumably because of the high variability of pharmacokinetics with chemotherapeutic agents mentioned above.8 Given these data, one can argue that the reasons for conducting TDM during the development of a therapeutic is just as important as genetic testing or protein assays.

A study of 186 patients with metastatic colorectal cancer (CRC) highlights the importance of TDM in patients with cancer.9 All patients were treated with 5-FU. One arm of the study received the approved dose of 1500 mg/m2 during a continuous 8-hour infusion once weekly while the second had their doses adjusted weekly based on 5-FU plasma concentrations. The authors found that only 15% of the patients were receiving a dose of the drug in the therapeutic range, 68% of the patients were underdosed and 17% overdosed.

The clinical outcomes were equally compelling. Overall response rates for the BSA and dose-adjusted groups were 18.3% and 33.6%, respectively. For these two groups, survival was 16 months for the BSA group and 22 months for the dose-adjusted group.

In a similar study of 115 patients with CRC, patients receiving too little 5-FU had a 40% chance of disease-free survival, whereas the group receiving a dose in the therapeutic range had a 65% chance of disease-free survival.10

This issue is not unique to 5-FU. papers on the use of the kinase inhibitor imatinib in chronic myeloid leukemia (CML)11,12 and gastrointestinal stromal tumors (GISTs)13 have demonstrated that patients with higher trough blood levels of the drug responded better than those in the lowest quartile of blood trough levels. In the CML papers, patients in the lowest quartile were more likely to be discontinued, primarily because of unsatisfactory therapeutic effect. Both papers also suggested that the efficient plasma trough levels for imatinib should be above ~1000 ng/mL. Similar results were observed in GIST patients, i.e. those with plasma trough levels below 1000 ng/mL had a shorter time to progression and lower rate of positive clinical outcome.

Results from the study of 5-FU in CRC patients beg the question: how many drugs have failed in clinical trials because the pharmacokinetic variability was such that the incorrect dose was administered to some patients, or how many trials had to recruit a larger number of patients because of exposure variability?

There are examples where failure to co-develop a companion diagnostic resulted in either restricted labeling or non-approval by regulatory agencies. AstraZeneca’s Iressa is one such example. Originally approved by the FDA in 2003 as third-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the FDA placed very restrictive labeling on the drug when the ISEL7 study19 failed to show an overall survival benefit. Benefit, however, was observed in patients of Asian descent and non-smokers. Given this data, further research by scientists at AstraZeneca led to the discovery that only patients with a mutation of EGFR tyrosine kinase (TK) responded to the drug. AstraZeneca partnered with DxS Ltd (now Qiagen) to make the assay for EGFRTK mutation widely available and reapplied for regulatory approval. Sales of Iressa turned around when it gained EMA approval in 2009 for advanced metastatic NSCLC in patients expressing the EGFRTK mutation. Worldwide sales in 2010 hit $393 million, a 28% increase over 2009.14

The failure to recognize that a specific therapeutic is only going to be effective in a specific subset of patients, as in the case of Iressa, or to develop a companion diagnostic in parallel—as in the case of Omapro—highlights just two examples why relatively few therapeutics have been approved with a companion diagnostic. This issue is also true for TDM. Cyclosporin and warfarin are just two examples where TDM is required by regulatory agencies. Unfortunately, most oncology practices do not have the pharmacy capabilities, expertise, or even the tools needed to collect and process blood samples for TDM. All of this is complicated by the need to collect and process the samples in a relatively short period of time.

Still, given the high cost of drug development and the risk of failure if the wrong dose is given during clinical development, it seems intuitive that companies should invest the time and money needed during clinical development to have the best chance of observing a positive clinical outcome, regardless if the effort is internal or via a partnership. Having an assay that can measure drug exposure early in clinical development will increase the chances of understanding early on whether or not the drug will work. If the proper dose of the drug is administered and it fails to meet its primary and/or secondary endpoint, then it has failed because of reasons other than the dosing regimen. In this instance, the sponsor will be able to kill the project early and divert resources to other projects. If results from early development are positive, the sponsor can move very quickly to efficacy trials. It is reasonable to assume that fewer patients will be needed to show efficacy if every patient receives a therapeutic and non-toxic dose of the drug. It is also reasonable to assume that the need to study fewer patients will lead to corresponding decreases in development costs and time.

Considering findings that show capitalized clinical costs per new drug approval averaged $467 million and the average development time was 90.3 months, i.e., $5 million per month, using new technologies such as TDM to decrease either or both should be embraced by the pharmaceutical industry. Furthermore, decreasing development time has the added benefit of getting to the market sooner and of extending patent life. In the case of Iressa, had the EMA approved the drug in 2005 for NSCLC patients expressing the EGFRTK mutation, one can calculate that AstraZeneca may have saved $60 million per year in clinical development costs and that cumulative sales of the drug may have been increased by more than $1 billion by the end of 2010.15 

As mentioned above, having a TDM assay that meets the needs of the clinical community may be key to the success of a chemotherapeutic—or any drug where exposure is critical. In order to have wide applicability in the clinical field, the TDM assay needs to run on routine clinical instruments that are present in hospital and reference laboratories. It needs to be easy to use, robust, and provide a throughput where results can be reported back to the physician in a timely manner. The assays must also be cost effective. Immunoassays for TDM are able to provide such characteristics and have been used routinely in several indication areas in medicine since the 1970’s.

Saladax Biomedical is currently partnered with Myriad Genetics to market such an assay for 5-FU in the United States, and its pipeline includes more than a dozen other chemotherapeutics with known wide variability in BSA-based dosing.16 Saladax has established a broad intellectual property portfolio in the field of oncology TDM and is the leading company in the world in this space.

Personalized medicine is here to stay and TDM will be as much a part of it as genetic testing or using a companion diagnostic to identify a disease specific biomarker. Identifying the right patient population for the right drug is only part of the equation managing the right dose is just as important. Dose management is important for all therapeutics where exposure is variable, but especially for oncology products which also often have a narrow therapeutic window and dose-limiting toxicity. Regulatory agencies will increasingly demand that personalized medicine components are measured during clinical development and approval of the therapeutic will be linked to approval of a companion diagnostic.

Those companies not embracing this development strategy will be left behind. Regardless of the type of companion diagnostic, the assay must be robust, stable, and available for routine use.

1. Dreyer and Ray. The blood volume of mammals as determined by experiments upon rabbits, guinea pigs and mice and its relationship to the body weight and to the surface area expressed as a formula. Phil Trans Royal Soc London. 201:133-60, 1910.

2. Baker et al. Role of Body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J. Nat. Cancer Inst. 94, (24): 1883-1886.

3. Hamburg and Collins. The Path to personalized medicine. N Engl J med 363 (4) 301-304.

4. FDA, Pharmacogenomic Biomarkers in Drug Labels,

5. Personalized Medicine is Playing a Growing Role in Biopharmaceutial Development Pipelines.

6. ChemGenex press release, July 2010.

7. de Jonge et al, Individualized cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation. Clin. Pharmacokinet 2005: 44(2): 147-173.

8. Fety et al. Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced hand and neck carcinomas. Clin Cancer Res. 1998; 4(9): 2039-2045.

9. Gamelin et al. Individual 5-fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial in patients with metastatic colorectal cancer. J. Clin Oncol. 2008; 26(13):2099-2105.

10. Di Paolo et al. 5-Fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer. Clin Cancer Res. 2008; 14(9):2749-2755.

11. Picard et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood, 2007; 109(8):3496-3499.

12. Larson et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008; 111(8):4022-4028.

13. Demetri et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J. Clin. Oncol. 2009;27:3141-3147.

14. Case Study: Personalized cancer therapy. DATAMONITOR March, 2011.

15. AstraZeneca 2010 year-end financial report (



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