The Broadspec Clinical Trials are intended to validate the efficacy of tackling heterogenity in advanced cancers with personalized therapeutic protocols customized for an array of molecular targets unique to each patient. The approach leverages our understanding of the molecular biology of the hallmarks of cancer and combines it with the principles of precision medicine and network pharmacology. The goal now is to use genomic and proteomic information to provide physicians with complementary, low-toxicity protocols developed dynamically, individualized, and then used to support cancer patients who are already undergoing traditional modes of treatment.
Several challenges exist, and this approach will necessitate concurrently administered combinations of many agents using metronomic dosing regimens specifically designed and managed to ensure patient safety. But this is a logical next step forward in personalized cancer therapeutics that will help us take advantage of next generation sequencing information.
The first step taken towards the initiation of Broadspec Clinical Trials was the formation of an esteemed advisory board with expertise spanning the various aspects of the project. As a result, the current advisory board has experts in the molecular biology of the four types of advanced cancers mentioned, experts in cancer biology, and experts who have extensive clinical experience using NHPs and repurposed pharmaceuticals. The advisory board has been involved in the initial conceptual map for this project. Clinical trials that follow will start on a small scale and each trial will be managed by a single Principal Investigator and initiated only once an accompanying Institutional Review Board approval has been secured. Updates on our progress will be reported on this website.
Ethics
One of the biggest challenges in this project will be the challenge of getting ethics board approval for a series of case-studies using a common methodology that utilizes varying combinations of therapeutics (as opposed to a single therapeutic regimen for a single cancer type).
Historically, cancer therapeutics have been tested one at a time for individual efficacy before considering these an individual therapy as a potential constituent for a combination chemotherapy regimen. Also, because of toxicity constraints, combinations of substances have almost always consisted of a very limited number of chemicals. As well, cancer types in clinical trials are typically defined by cell type. They are sometimes further characterized by cancer stage, and occasionally refined further by dominant form of an important genetic mutation (e.g., ER-positive). So a broad-spectrum methodology (which is based on our current understanding of disease biology) will challenge several of these norms.
For example, we will focus on cancers that are defined by cell-type and cancer stage, but the genetic and proteomic information that will be gathered in each individual case will result in a substantial list of potential targets that will be unique to that particular patient. As the hallmarks of cancer disease framework suggests, some of these targets will be tumor specific while other relevant targets may be found in related systems and the tumor microenvironment (involving processes such as inflammation, angiogenesis, immune-evasion, tissue invasion and metastasis, etc.). As such, there will be a long roster of potential therapeutics to be considered (i.e., repurposed pharmaceuticals and NHPs which might have the potential to reach these targets).
These agents can be readily identified in the literature but the criteria by which they are chosen will need to be carefully defined. The standard of evidence for potential actions by an agent, combined with issues related to practical availability, and details on safety and tolerance, will all be critically important. This will result in unique combinations of dozens of common agents being combined to produce a personalized protocol for each patient. Each constituent that is selected will therefore need to have a very broad therapeutic index, and these constituents will need to be introduced individually and incrementally in the clinic (such that the number of agents being used in combination increases over time) with close monitoring by a physician to assess tolerance and quickly identify any adverse effects.
This idea of a personalized protocol of agents aimed at a broad-spectrum of targets represents a fundamental and paradigmatic shift (in comparison to single chemicals or static combinations that are put forward for general purpose use across a broad base of patients with the same cancer type). This approach recognizes that addressing the heterogeneity in most advances cancers is going to take more than a predictable action on a few key driver mechanisms. It also recognizes that some agents that have the potential to exert an action on a specific mechanism of relevance may not be potent enough to gain approval as an individual therapy but still serve a valuable support role in a combination approach.
Currently, Ethics Boards do not typically favor great numbers of chemicals in combination for cancer therapy, but the current situation is unsatisfactory. On the one hand, we have oncologists who understand the disease biology but ignore the potential value of additional actions and synergies that could be produced by complementary agents (because these agents have not been individually proven or approved as cancer therapies). Yet 20-90% of patients are using NHPs anyway (many of whom are not sharing this detail with their treating physician)1,2 and other physicians are supporting cancer patients with repurposed pharmaceuticals and NHPs without a thorough knowledge of disease biology. So the false wall that currently divides these practitioners is truly a fiction that should not be allowed to stand. It serves only as an impediment to a practice of supplementation that is already being widely employed.
What is now needed is a rigorous set of trials that can determine whether or not patients with advanced cancers who are undergoing conventional forms of treatment would benefit from a personalized, broad-spectrum protocol that has the potential to also act upon as many additional targets as possible. Currently these patients are trying to supplement themselves (i.e., without physician support) or they are working with physicians who are not using the best information available to make decisions related to the types of constituents that might work best given the genetic makeup of the cancer. As a result, these ‘experiments’ are not based on the best science available, and the patient outcomes from these efforts are not peer-reviewed or published. Our task is therefore to convince an Institutional Review Board that this situation is untenable. We need to explain why the current situation demands a much more rigorous form of systematized investigation.
The World Medical Association Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects) 2013 contains a new provision that addresses these circumstances. With respect to “Unproven Interventions in Clinical Practice”, clause 37 reads as follows:
- In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.
So our goal is to create the sort of support that is needed to provide the expert advice that physicians will need to offer protocols that are highly personalized to individual cancers using a rigorous, reproducible method and to cooperate with those physicians such that the progress of these patients can be carefully documented and the results published. Since every patient will have a tailored protocol, our goal will be to produce a case-series that can capture these results over time.
References
- Frenkel M, Sierpina V. The use of dietary supplements in oncology. Curr Oncol Rep. 2014;16(11):411.
- Le TQ, Smith L, Harnett J. A systematic review – Biologically-based complementary medicine use by people living with cancer – is a more clearly defined role for the pharmacist required? Res Social Adm Pharm. 2016.