Remember the days when meetings were held in person? The thing I looked forward to most about conferences was meeting new people. I always found it exciting to hear about physicians’ practices and ideas about medicine. With social media, it’s easy to stay in touch with new colleagues, too. This is how I came to meet Yaacov Lawrence, MA, MBBS, MRCP(UK). A mutual colleague introduced us at a conference, and I was fascinated to hear all about his radiation oncology practice and research in Israel. We kept in touch via a radiation oncology worldwide WhatsApp group. I interviewed Dr. Lawrence with the hope that others will be inspired by his groundbreaking work in international trial design.
MK: How did you conceive of this phase II study?
YL: Soon after the abdominal stereotactic body radiotherapy (SBRT) program was opened at our institution, I was referred a patient with a painful post-Whipple tumor bed recurrence. We delivered SBRT with the intent of obtaining local control. I remember asking him after three fractions how he was feeling, and was surprised to hear that his pain was resolved. However, this good palliative response was not typical. I brainstormed with my chair, Professor Zvi Symon, why the pain may have resolved, and how we could optimize this type of treatment. We hypothesized that perhaps our radiotherapy target for palliative treatment is not actually the pancreatic tumor, but rather the celiac nerve plexus that sits immediately behind the pancreas. Together with Dr. David Hausner from the palliative care service, we designed a phase I trial to deliver SBRT to the celiac plexus. In the phase I trial, we observed minimal toxicity and high patient-reported levels of pain relief. With these excellent results, we decided to open a larger multicenter phase II trial.
MK: Who is the study designed for?
YL: The study is designed for patients with cancer who have opioid-refractory celiac-style pain, i.e. upper abdominal/lower back pain that radiates in a belt like distribution. This is mostly patients with pancreatic cancer, but we have also enrolled a few patients with other malignancies metastatic to the celiac nodes with similar “pancreatic-style” pain. In addition, we require good performance status (ECOG 2 or higher).
MK: Where have patients been enrolling from?
YL: The study is now open at eight sites worldwide: three cancer centers in Tel Aviv, Israel; three cancer centers in North America: Princess Margaret Hospital in Toronto (PIs: Dr. Laura Dawson and Dr. Aisling Barry), The Ohio State University (PI: Dr. Alexandra Diaz), and Mount Sinai in New York (PI: Dr. Michael Buckstein); Portugal (PI: Dr. Artur Aguiar); and Poland (PI: Dr. Marcin Miszczyk). Additional centers are in the process of opening in Australia, South America, and North America.
MK: What was the process for opening up this study internationally?
YL: We employed a local academic contract research organization (CRO) to help us with the logistics: arranging trial insurance, setting up the electronic case report form (eCRF) system, and contracting. Ultimately finding the initial subsites was based upon my personal contacts. It goes without saying that all this costs money, and we were very fortunate to receive generous funding from Gateway for Cancer Research, a Chicago-based nonprofit organization that funds innovative phase I and phase II trials; without Gateway, none of this would have happened. We were not able to open in every country: the United Kingdom had strict rules about reimbursement for SBRT, France required us to work with a European-based CRO which was well beyond our budget, and there were problems obtaining insurance coverage for Russia.
MK: How has COVID-19 impacted your study?
YL: COVID-19 has slowed down accrual at some of the sites, and hampered the process of contracting with new centers. One center was closed to accrual for 2 months during the first wave, and another placed numerical limits on accrual to all clinical trials. For post-treatment follow-up we no longer mandate hospital visits; unfortunately, this means that we cannot clinically assess functional status by means of the 6-minute walking test and the hand grip strength. Conversely, these restrictions have encouraged us to introduce new technologies. For example, we now send our patients wearable fitness trackers to measure daily steps and sleep prior to and after treatment.
MK: What is your advice for researchers looking to open non-industry sponsored studies?
YL: There are a few important steps:
- You need a good, grantable idea that addresses an unmet need.
- Start small. We initially ran a proof-of-principal study within our department—this was essential. This small study showed us that our idea had potential and provided preliminary data for the grant. It also allowed us to tweak the idea before we went multi-institutional.
- Network at international meetings like ASCO and ASTRO. Most of the subsite coinvestigators are colleagues I have rubbed shoulders with over the years. Moreover, the relationship with Gateway for Cancer Research started with an unplanned meeting in the ASCO Annual Meeting Oncology Professionals Hall.
- Cultivate mentors. I am fortunate to have great teachers and mentors. For example, when planning the trial, I addressed my clinical questions to Professor Symon, my chair at Sheba Medical Center, and logistics questions about how to get the whole project up and running to Dr. Adam Dicker, chair of radiation oncology at Thomas Jefferson University in Philadelphia.
- You need a receptive host institution and lots of goodwill on all sides. Even with grant funding, the level of financial support we received is far less than what is typically provided by pharmaceutical companies. Without the support of the Sheba Medical Center’s senior leadership, this project would never have happened. Likewise, it is clear that the subsites’ physicians and support staff are all going the extra (unsalaried) mile to make this trial happen and improve outcomes for patients with terminal cancer.
MK: Did you have any prior experience running trials?
YL: From 2007 to 2010 I was a fellow, and later a junior faculty member, under Dr. Dicker. With his mentorship, I learned the logistics of clinical trials and wrote two clinical protocols. Since returning to Israel, I have opened (with local collaborators Dr. Talia Golan and Dr. Ofer Margalit) a number of phase I clinical trials with and without industrial support.
Dr. Lawrence graduated from Cambridge University and University College Hospital, London. He is board certified in internal medicine and radiation oncology. Between 2007-2010 he was a fellow and subsequently attending physician at Thomas Jefferson University, Philadelphia. In 2009, he was awarded an ASCO Young Investigator Award. Currently, Dr. Lawrence leads the gastrointestinal program within the Department of Radiation Oncology at Sheba Medical Center in Israel, and heads the research division within the department. He is a senior lecturer at Tel Aviv University. Dr. Lawrence has led numerous early-phase clinical trials, and was the lead author of the NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers. He has received funding from the Israel Cancer Association, European Union FP7 program, NATO, the Rosetrees Trust, the Israel Science Foundation, and Gateway for Cancer Research. Dr. Lawrence lives with his wife and six children in Jerusalem, Israel. Find more information about his study (NCT03323489 at clinicaltrials.gov) or contact Dr. Lawrence with questions. Disclosure.