What's Up With the Comparative Oncology Trials Consortium?
ACVIM 2008
Melissa C. Paoloni, DVM, DACVIM (Oncology)
Bethesda, MD, USA

Introduction

A central mission of the Center for Cancer Research (CCR), National Cancer Institute (NCI) is the development and delivery of novel cancer treatment strategies for cancer patients. A significant hurdle in the translation of information from the laboratory to the clinic is the availability of appropriate preclinical cancer models. Through a number of new initiatives created by the CCR, an essential infrastructure now exists to facilitate the translational research process. These efforts include the creation of the NCI Comparative Oncology Program (COP). The goal of this program is to include naturally occurring cancer seen in pet animals into studies of cancer biology and drug development.

Comparative Oncology Trial Consortium (COTC)

To facilitate the goals of the COP, NCI has developed a collaborative network of exemplary comparative oncology programs at numerous accredited schools of veterinary medicine, known as the Comparative Oncology Trial Consortium (COTC). Institutions whose focus is on excellent clinical care, innovative research programs and the goal of promoting both animal and human health. Current members of the COTC include:


 

 Auburn University

 Colorado State University

 Cornell University

 Michigan State University

 North Carolina State University

 Purdue University

 The Ohio State University

 Tufts University

 University of California at Davis

 University of Florida

 University of Georgia

 University of Illinois at Urbana-Champaign

 University of Missouri

 University of Pennsylvania

 University of Tennessee

 University of Wisconsin

 University of Minnesota

Clinical trials are conducted through the COTC in pet dogs with cancer and together, NCI and COTC members are able to leverage their respective research strengths to advance goals of the COP. Studies are designed to answer key questions of novel therapy pharmacokinetics and pharmacodynamics, to optimize delivery schedules or regimens, to validate innovate imaging techniques and correlate these biological endpoints to activity. They are generally small in patient number but biologically intensive.

How We Operate

The COP has agreements with each COTC member (Memorandum of Understanding, MOU) to allow the NCI to act uniformly in dealings with pharmaceutical companies and other institutions that have a desire to interact with the COTC in the conduct of clinical trials in veterinary oncology patients to inform the development path of novel anti-cancer agents. The NCI adds value to this interaction by supplying trial design, oversight and data management. The NCI does not fund the COTC, but in many instances operational costs are offset by funding obtained from outside sources. Trials that operate through the COTC are funded by sponsor groups, namely pharmaceutical or biotech companies, of whose agents are evaluated through this network. Trials can be initiated either centrally through the NCI or laterally from relationships via individual COTC member sites and their pharmaceutical company contacts and moved back into the COTC as a whole.

Cotc Trials

COTC001: Tumor Vasculature Targeted Delivery of Tumor Necrosis Factor (TNF-α) Using a Novel Targeted Vector (AAVP-TNF-α) to Treat Pet Dogs with Spontaneous Tumors

Summary of Two Studies, n=46 Dogs Treated at Five COTC Institutions

Recently, considerable efforts have been directed to antiangiogenic and antivascular therapies as approaches to treat cancer. RGD-4C targeted AAVP-TNF-α (RGD-A-TNF) is a novel vector designed to deliver TNF-α, a potent cytotoxic and antivascular cytokine, selectively to tumor endothelium. In a dose-escalation study design in dogs with cancer, a single intravenous dose of RGD-A-TNF was found to be well tolerated in all dosing cohorts evaluated. Systemic administration of RGD-A-TNF resulted in selective trafficking to tumor associated vasculature while sparing normal tissues. The safety, tumor-specific targeting and anti-tumor activity of weekly intravenous doses (up to 8 doses) of RGD-A-TNF was then confirmed in a subsequent cohort of 18 dogs. These dogs received a fixed dose of 5x1012 TU of RGD-A-TNF intravenously. Objective tumor regression, using RECIST criteria, was seen in 2 dogs (out of 14 evaluable dogs) receiving at least 4 doses of RGD-A-TNF. These results indicate that RGD-A-TNF can be safely administered, traffics selectively to tumor vasculature and results in objective tumor responses in large animals with spontaneous tumors.

COTC003: Evaluation of the mTOR Inhibitor Rapamycin in Dogs with Osteosarcoma

Summary of One Study, n-21 Dogs Treated at Five COTC Institutions

mTOR is a key signaling pathway that interprets both extracellular and intracellular growth and stress signals and transduces them to the cell's protein machinery. Thus it functions as the nutrient sensor of the cell controlling protein translation, integral in cancer development and progression. Both mTOR and its downstream effectors, S6K and 4EBP1, are upregulated in a variety of tumor histologies and are linked to aggressive phenotypes. The inhibition of mTOR is possible with the use of Rapamycin, initially developed as an immunosuppressant for transplant patients, and its novel analogues, known collectively as Rapalogs. Although there are currently many treatment trials evaluating Rapalogs, the correlation of dose, pharmacodynamic modulation, response and benefit as a combinational therapy are unknown. Thus this study in pet dogs with osteosarcoma was designed to address questions of Rapamycin pharmacokinetics and its relationship to tumoral and PBMC correlative pharmacodynamics. An initial dose escalation study was conducted and results of this work are currently being evaluated.

COTC005: Evaluation of NHS-IL12-IL2 Fusion Protein in Tumor Bearing Dogs

Currently Underway at 5 COTC Institutions

Strategies are currently being developed to evaluate the therapeutic value of cytokines in the clinic. At this time, IL-2 has been approved as a drug for melanoma and renal cancer in humans, but has significant systemic toxicities. IL-12 has been tested in numerous trials, but has not yet been approved as a therapy. A novel immunocytokine (i.e, NHS-IL12-IL2), in which human IL-2 is fused with human IL-12, has been generated as a hopeful potent immunotherapy. It is a humanized antibody targeted to necrotic DNA. To determine if the selective delivery of these dual cytokines into the tumor microenvironment by intratumoral injection will limit toxicity, two distinct pre-clinical trials in pet dogs with cancer have been designed. The first is a dose escalation and tolerability study, in which we expect to gain insight into the optimal dose and early indication of anti-tumor efficacy of this agent. A subsequent study will assess activity and tolerance to chronic NHS-IL12-IL2 with the best-chosen dose from study one.

Information about current trials may be found at: http://ccr.cancer.gov/resources/cop

Establishment of the COTC Pharmacodynamic (PD) Laboratory Core

One of the newest efforts of the COTC is the establishment of the Pharmacodynamic (PD) Core Laboratory. This virtual laboratory will provide assay services and scientific expertise that will contribute to preclinical studies needed for COTC clinical trial initiation and COTC trial pharmacodynamic and biological endpoints. The PD Core consists of multiple members prospectively identified to provide scientific service and guidance in a variety of experimental techniques and services including pathology, immunohistochemistry, immunocytochemistry, flow cytometry, genomics, proteomics, cell culture, pharmacokinetics and cell biology. Participating individuals and institutions were selected for inclusion based on demonstration of expertise, interest, and infrastructure sufficient to manage the needs of the COTC drug development efforts. A comprehensive assay/procedure service catalog was developed that outlines assay/procedure costs, time lines and sample needs for services available through the PD Core. This catalog is used to facilitate early discussions with potential COTC trial sponsors (pharmaceutical companies), lead to rapid implementation of preclinical studies needed to initiate a COTC study, and seamlessly allow interrogation of biological questions within COTC protocols. The PD Core is a dynamic entity that will be updated yearly to include new services/assays and institutions.

References

1.  Paoloni M, et al. Nat Rev Cancer 2008;8, 147.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Melissa Paoloni, DVM, DACVIM (Oncology)
Washington, DC


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