START Dublin – the need, the science, and the pure serendipity of it all

Reference:

How the cutting-edge early phase oncology trials programme, START Dublin, came about and what it strives to achieve for cancer patients

It all started with a cup of coffee. Five years on and that simple fact continues to astound me. It was the ASCO-SITC [American Society of Clinical Oncology-Society for Immunotherapy of Cancer] conference in January 2020, just before Covid-19 hit, and I found myself deep in the gaudily carpeted underworld of an enormous Orlando hotel. Like a Vegas casino it could have been any time of the day or night, but it was the mid-morning coffee break and for once at these sort of events I decided to be sociable. Coffee in hand, I wandered into the thicket of chirpy networkers and proceeded to have a conversation that was to change my career, maybe even my life. Nehal Lakhani is a medical oncologist who I knew only slightly, having overlapped briefly with him at the National Cancer Institute (NCI) in Bethesda, Maryland. Not much of a networker either, Nehal and I grappled with the small talk of where life had taken us since leaving the NCI.

Superficially at least, my story might have seemed the more dramatic. At this point I had been back in Ireland just over two years and returning there after more than a decade in the US was fraught, but also, strangely, exhilarating. A little confounding too though because after a few years of hard slog helping my friend and mentor Tim Greten get an immunotherapy programme off the ground at the NCI, opportunities were beginning to present themselves in the US that I might have been expected to pursue. But instead, my American wife and I decided – and only partially because our son was reaching school age – to move back to Ireland. Nehal listened politely as I no doubt egged up the shock of the transition, exaggerating the whiplash of the abrupt career change away from the protected environment of US academia, though in truth I never regretted it. What about Nehal, what was his story? He told me that after the NCI he had ended up in Michigan, not so unusual perhaps given that he had done his residency in Grand Rapids, and was now working with an organisation called START, which specialised in phase 1 cancer trials. I’d never heard of them, but Nehal told me they were a physician-led company who had emerged from San Antonio, Texas, at a time when it was a sort of Silicon Valley for drug development. His mentor in Michigan, Tim O’Rourke, had spent the earlier part of his career in San Antonio and was friends with Lon Smith, one of the founders of START. Through this personal connection Nehal opened START Midwest in 2015.

I listened as he told me how START had collaborated with his practice to invest in him and build and support a team that brought genuinely cutting-edge new cancer drugs to his community, as opposed to obliging patients to travel to large academic centres far from their home in order to access them. Nehal told me he started off lean, with a staff of six people, taking over five infusion chairs in a small corner of their oncology infusion suite, but at the end of year one had already treated 55 patients. They doubled that by the end of year two and at five years, the time of our conversation, had become the largest phase 1 oncology site in the entire US midwest with five investigators and a staff of 50 people. More importantly, they had a roster of about 100 or so open studies at any one time and were treating over 200 patients a year.

As Nehal was speaking, it dawned on me that the conversation we were having was not mere small talk. He was intimating a different world and the path towards it which, though not entirely clear to me at that moment, seemed somehow right there. Jesus, I remember saying to him, we need to get you guys to Dublin. And just shy of five years later, this recent 14 October to be precise, we did exactly that.

Context and need

Before I explain what exactly START does, I should first explain the context and the need. When I returned to Dublin in 2017 I was struck by the lack of treatment options for Irish patients compared to their counterparts in the US. A lot of this was understandable. We have a socialised health system and cannot fund everything. An expensive cancer drug being reimbursed might mean less funding for scoliosis surgeries or community care. Besides, many of these unavailable cancer drugs were just ok, honestly pretty marginal in terms of the added benefit they brought, many of them not worth the cost. But it was harder to be philosophical about the genuinely effective medicines that were not available here; the ones that not only made a massive clinical difference – sometimes dramatically so – but were also cost-effective. The glaring example for me was the case of immunotherapy for MSI-high cancer, which could not in any way be described as a marginal treatment, but rather made all the difference in the world, being potentially curative. It was distressing not to be able to prescribe it and increasingly my day-to-day was taken up with navigating the complicated path of obtaining compassionate access and, even when successful, negotiating the legal and regulatory hurdles that followed.

But the poor access to new medicines also extended to experimental options. There were many good and important trials being done by organisations such as Cancer Trials Ireland, but I found that they were weighted more towards the later stage of drug development, namely phase 3 trials.

These types of trials have been crucial for Ireland over the past two decades, bringing life-saving drugs into the country (eg, herceptin), while also establishing a research infrastructure, training a generation of staff, and changing the mindset around research, demonstrating its utility and impact. But these studies come with a number of disadvantages. For starters, phase 3 studies tend to be geared towards the recently diagnosed, those who are untreated, or those in the post-surgery adjuvant setting. They also tend to involve patients with common cancers and – infuriatingly for patients – usually contain a placebo arm. The other problem is that it takes an average of eight years for a drug to reach the phase 3 stage, which means that by the time it gets there it is likely to no longer be best-in-class. And, given the pace of drug development, which may well be exponential at this point, it is highly likely that this trend will only accelerate with Irish patients falling further behind.

What START does

So what is START and what do they bring to the table? Is it just money, investment? And if so, could the Government not have done that, or a charity or philanthropy? START (which stands for South Texas Accelerated Research Therapeutics) was founded in 2007 by a physician group in San Antonio with the relatively pragmatic mission of accelerating the development of new cancer drugs by providing more community access to phase 1 trials. They grew rapidly and are now the largest early-phase oncology clinical trials network globally with over 10,000 patients treated, a current roster of over 500 active studies, partnering with over 150 pharmaceutical companies. START sites – of which we at the Mater are the eighth – have conducted more than a thousand clinical trials, leading the development of 43 agents subsequently approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) (including the banner achievement of having given – on 27 April, 2011 – the first human in the world the very first dose of pembrolizumab). In terms of what they bring to the table, yes, there was the financial investment in terms of capital, staff hiring, IT purchasing, and purchasing of other specialised equipment, such as isolators, centrifuges, and monitoring systems. But this only tells a small part of the story and the truth is that money alone would be insufficient. As a START centre we avail on a daily basis of the central supports and institutional expertise relating to not just the proper running and monitoring of these complicated studies, but also the aspects of study start-up that replicate across the network, ensuring efficiency: Centralised budgeting and contracting, robust information technology (including various bespoke software programmes which enhance safety), pharmacokinetics processing, pharmacy support, and regulatory and data monitoring services, all of which have been honed over a long period of time and embedded within a company-wide culture of staff development, education, and process improvement. Specifically for Ireland though, perhaps the main advantage of the partnership with START has been the association with their hard-earned reputation among pharmaceutical sponsors. Being part of the START brand has been powerful enough to confer instant legitimacy, convincing a number of sponsors in our pipeline to open in Ireland – in many cases for the first time – despite the lack of a track record in this space. And all of this with no cost to the patient, the hospital, or the taxpayer. In fact, the programme will bring in revenue, save on drug costs, and create jobs. We strive to be different only in terms of scale; specifically the number of studies we can open and the number of patients we can treat and this will be the ultimate arbiter of success, determinant of the programme’s rise or fall, to what extent it is able to meet the needs of patients and their doctors. Achieve that and it will have been worth it, to mirror START’s original pragmatic aim here in Ireland, offering access to emerging medicines and the latest science has to offer to those who can’t get them, in the hope that they might provide real benefit to patients with advanced cancer or, failing that and despite our best efforts, at least hold it out as a realistic possibility.

Author: Dr Austin Duffy, Director of Research and Principal Investigator, START Dublin, Consultant Medical Oncologist, Mater Misericordiae University Hospital, and Associate Professor of Translational Oncology, University College Dublin