--- title: "Targeted Therapy Efficacious Dose Finding: The Case for Agile Design" description: Why is the Palladia dose used at the clinic often different from the one on the FDA-approved label? Over 100 human targeted therapies have been approved, yet many doses were found to be incorrect in the post market stage. Why is that? image: https://blog.fidocure.com/hubfs/Imported_Blog_Media/Dog1-2071x1381-2.png --- [![FidoCure](https://blog.fidocure.com/hs-fs/hubfs/fidocure_logo.png?width=296&height=68&name=fidocure_logo.png "FidoCure")](https://www.fidocure.com/) - [Veterinarians](https://fidocure.com/for-veterinarians/) - [Portal Login](https://dvm.fidocure.com/) - [Veterinary Blog](https://blog.fidocure.com/fidocure-blog/tag/vet) - [Case Studies](https://blog.fidocure.com/fidocure-blog/tag/case-studies) - [Webinars](https://blog.fidocure.com/fidocure-blog/tag/webinars) - [Pet Parents](https://fidocure.com/pet-parents/) - [About Us](https://fidocure.com/about-us/) - [How it works](https://fidocure.com/how-it-works/) - [Find a Clinic](https://fidocure.com/find-a-clinic/) - [Contact Us](https://fidocure.com/contact-us/) # Targeted Therapy Efficacious Dose Finding: The Case for Agile Design [Dr. Gerry Post](https://blog.fidocure.com/fidocure-blog/author/dr-gerry-post) [Share this blog post on Twitter](https://twitter.com/intent/tweet?text=I+found+this+interesting+blog+post&url=https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/targeted-therapy-efficacious-dose-finding-the-case-for-agile-design/amp) [Share this blog post on Facebook](http://www.facebook.com/share.php?u=https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/targeted-therapy-efficacious-dose-finding-the-case-for-agile-design/amp) [Share this blog post on LinkedIn](http://www.linkedin.com/shareArticle?mini=true&url=https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/targeted-therapy-efficacious-dose-finding-the-case-for-agile-design/amp) The following medical brief espouses how ordinary clinical trial design is rendered less than perfect for targeted therapies, and suggests how the following 3 interrelated Agile Trial Design principles should be considered: 1. find the efficacious dose range rather than the single dose; 2. leverage tumor size and biomarker information to arrive at the efficacious dose; 3. use an adaptive or Bayesian approach to identify doses Our context: The dose for the most commonly used chemotherapies in veterinary medicine were most likely arrived at through trials using a 3 + 3 design. Put simply, this type of trial is a rules based trial that treats the first cohort of patients with a low dose of a drug. Dose is then escalated or de-escalated based upon the observation of dose limiting toxicities. These phase I clinical trials are familiar to most oncologists and have certain advantages. They are simple, robust, and easily understood by clinicians and investigators. However, this historical approach of selecting the maximum tolerated dose may no longer be appropriate for the new more targeted chemotherapeutic agents being used today. These drugs often don’t need to be given at the maximum tolerated doses, but instead can be given at a biologically relevant dose. A 2016 [article](https://pubmed.ncbi.nlm.nih.gov/27250933/) in Clinical Cancer Research discussed the rationale behind advocating for a different method for determining drug dose in the current age of chemotherapy – as the 3+3 approach was designed for evaluating cytotoxic chemotherapy agents (1). The authors go on to state that when this approach is used for targeted therapies, many non-optimal doses are taken into late stage development or to market. This results in frequent postmarket requirements to study lower doses or alternate regimens for these drugs. These postmarket trials are often quite challenging to complete in a timely manner. The experience of bringing Palladia® (toceranib phosphate) to the veterinary market illustrates the problem of bringing a targeted therapy drug to market with the optimal dose. Many oncologists now use this drug at a dosage different from that on the label. They use a lower dose (2.4-2.75 mg/kg rather than 3.25 mg/kg) and a longer interval (MWF instead of every other day) based upon their experience with both efficacy and tolerability of the drug. The authors then make a few recommendations about how to adjust the current trial design for targeted therapies and what methods may be appropriate to find doses for these new anticancer medications. One of their first recommendations is that investigators focus on determining an efficacious dose range rather than a single dose. This efficacious dose range can be based upon biomarkers and/or tumor size. This dose range may be incredibly wide, 5-fold or greater, encompassing both a minimally effective dose and a maximum tolerated dose (MTD). Figure 1 from: Nie L;Rubin EH;Mehrotra N;Pinheiro J;Fernandes LL;Roy A;Bailey S;de Alwis DP;. (n.d.). Rendering the 3 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy. Clinical Cancer Research. 22. 2623-2629. DOI: 10.1158/1078-0432. CCR-15-2644. The authors also recommend an adaptive or Bayesian approach to identify an appropriate dose of drug. There is a very real tension between speeding up drug development and taking the time needed to determine the most appropriate dose (or dose range). To address this issue, the authors recommend integrating non-clinical, preclinical and clinical data to both increase the speed and accuracy of the trial. The use of clinical data is exactly what the Real World Evidence and Real World Data “movement” spearheaded by FDA is really all about ([see our previous blog post](https://fidocu.re/rwe-uses)). Importantly, the authors also state that where there is significant unmet medical need, dose optimization could be carried out in the post-approval setting. A situation, I believe after 30 years of practice, exists in veterinary oncology. Agile dose finding design principles depart from ordinary dose finding trials. These principles may be used to accelerate the finding of efficacious doses of targeted therapies. Certainly the clinical experience with Palladia and post-market research show that lower doses of Palladia are likely still effective while minimizing the adverse event profile (2). --- 1. Nie, Lei & Rubin, Eric & Mehrotra, Nitin & Pinheiro, José & Fernandes, Laura & Roy, Amit & Bailey, Stuart & Alwis, Dinesh. (2016). Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy. Clinical Cancer Research. 22. 2623-2629. DOI: 10.1158/1078-0432. CCR-15-2644. 2. Bernabe, L.F., Portela, R., Nguyen, S. *et al.* Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose. *BMC Vet Res* 9, 190 (2013). [https://doi.org/10.1186/1746-6148-9-190](https://doi.org/10.1186/1746-6148-9-190) ## Related Articles [![](https://blog.fidocure.com/hubfs/Imported_Blog_Media/real_world_evidence.png)](https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/real-world-evidence-what-is-it-from-human-cancer-care-to-veterinary-cancer-care) ### [Real World Evidence: What is it? From Human Cancer Care to Veterinary Cancer Care](https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/real-world-evidence-what-is-it-from-human-cancer-care-to-veterinary-cancer-care) In veterinary cancer care, it’s common to come across tough clinical questions where there is no known right answer. A few examples include: [Dr. Gerry Post](https://blog.fidocure.com/fidocure-blog/author/dr-gerry-post) [Read More](https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/real-world-evidence-what-is-it-from-human-cancer-care-to-veterinary-cancer-care) [![](https://blog.fidocure.com/hubfs/petonc.png)](https://blog.fidocure.com/fidocure-blog/the-future-of-pet-oncology-how-ai-driven-targeted-therapies-are-revolutionizing-cancer-treatment-for-dogs) ### [The Future of Pet Oncology: How AI-Driven Targeted Therapies are Revolutionizing Cancer Treatment for Dogs](https://blog.fidocure.com/fidocure-blog/the-future-of-pet-oncology-how-ai-driven-targeted-therapies-are-revolutionizing-cancer-treatment-for-dogs) The global veterinary oncology market has been experiencing remarkable growth, reaching a valuation of [$259.4B](https://www.skyquestt.com/report/veterinary-oncology-market) in 2023. This surge reflects a significant shift in how... ![FidoCure](https://blog.fidocure.com/hs-fs/hubfs/Screen%20Shot%202023-05-08%20at%2011.54.38%20AM.png?width=45&name=Screen%20Shot%202023-05-08%20at%2011.54.38%20AM.png) [FidoCure](https://blog.fidocure.com/fidocure-blog/author/fidocure) [Read More](https://blog.fidocure.com/fidocure-blog/the-future-of-pet-oncology-how-ai-driven-targeted-therapies-are-revolutionizing-cancer-treatment-for-dogs) ![fc_portal_logo_bw](https://blog.fidocure.com/hubfs/fc_portal_logo_bw.svg) - [How it Works](https://fidocure.com/how-it-works/) - [FAQ](https://fidocure.com/faq/) - [Contact Us](https://fidocurestg.wpengine.com/contact-us/) - [For Vets](https://fidocure.com/for-veterinarians/) - [About Us](https://fidocure.com/about-us/) - [Terms of Service](https://fidocure.com/terms-of-service/) - [Blog](https://blog.fidocure.com/fidocure-blog) - [Careers](https://fidocure.com/careers/) - [Privacy Policy](https://fidocure.com/privacy-policy/) - - - - **FidoCure® is an advanced cancer-care service for dogs, developed by One Health Company**. DISCLAIMER: All patients are enrolled in FidoCure® by a veterinarian with a valid veterinarian-client-patient relationship (VCPR). We use best efforts to inform the veterinarian on available targeted therapy options for patients. FidoCure® does not prescribe therapy. The targeted therapies that veterinarians may prescribe and order from compounding pharmacies, after receiving genetic test results from FidoCure®, may constitute extra-label uses of those drugs. FidoCure® makes no claims that every patient will have genetic test results that lead to targeted therapy options. FidoCure® makes no claims or guarantees about the effectiveness of the diagnostic and targeted therapy selected by the veterinarian for an individual patient. Like most cancer care approaches, the services provided by FidoCure® are not a guarantee of a cure. FidoCure® is not a pharmacy and does not supply drugs directly. By ordering any medication via one of our pharmacy partners, you agree that the pharmacy, not FidoCure®, is solely responsible and liable for any and all issues relating to the preparation, dispensation and fulfillment of the medication. The lifetime offer is subject to the commercially reasonable availability of any medication(s) and/or active pharmaceutical ingredient(s) necessary for the selected therapy.  © Copyright 2018-2026 One Health Company, All rights reserved ```json { "@context" : "https://schema.org", "@type" : "BlogPosting", "author" : { "@type" : "Person", "name" : "Dr. Gerry Post", "url" : "https://blog.fidocure.com/fidocure-blog/author/dr-gerry-post" }, "dateModified" : "2023-04-05T18:57:06.538Z", "datePublished" : "2020-08-29T04:00:00.000Z", "headline" : "Targeted Therapy Efficacious Dose Finding: The Case for Agile Design", "image" : [ "https://blog.fidocure.com/hubfs/Imported_Blog_Media/Dog1-2071x1381-2.png" ], "mainEntityOfPage" : { "@id" : "https://blog.fidocure.com/fidocure-blog/veterinary-oncology/blog/targeted-therapy-efficacious-dose-finding-the-case-for-agile-design/amp", "@type" : "WebPage" }, "publisher" : { "@type" : "Organization", "logo" : { "@type" : "ImageObject", "url" : "https://blog.fidocure.com/hubfs/fidocure_logo.png" }, "name" : "FidoCure" } } ```