In this Q&A, Govindarajan Narayanan, MD, talks with Interventional Oncology 360 about the NanoKnife System and a recently approved investigational device exemption (IDE). Dr. Narayanan is coprincipal investigator of the DIRECT clinical study.
The FDA recently approved an IDE application for the NanoKnife® Irreversible Electroporation “Direct IRE Cancer Treatment” clinical study (DIRECT). Can you tell me more about the NanoKnife and the clinical need it hopes to meet?
The NanoKnife System is used for the ablation of soft tissue by a process known as irreversible electroporation (IRE). A NanoKnife procedure involves the delivery of a series of high voltage direct current electrical pulses between two electrodes placed within a target area of tissue. The delivery of the electrical pulses causes cells surrounding the electrodes to be irreversibly damaged due to the formation of nanoscale defects in the lipid bilayer leading to a loss of homeostasis and subsequent cell death. The major advantage of IRE-induced cell death, as compared to other ablation methods, is that the treatment zone can traverse across large blood vessels and bile ducts without damaging these vital structures. The NanoKnife System has a 510(k) clearance from the FDA for ablation in soft tissue, and the use of the device in organs is considered an off-label use. A growing body of scientific evidence is available to support the use of NanoKnife IRE to successfully treat tumors in the pancreas, liver, prostate. and several other organs.
Statistics from the American Cancer Society indicate that pancreatic cancer is one of the deadliest cancers, with a 1-year relative survival rate of 20% and 5-year rate of about 8%. The overall survival of patients on the current standard of care – the FOLFIRINOX regimen (combination chemotherapy using fluorouracil, leucovorin [folinic acid], irinotecan, and oxaliplatin) – is just 11.1 months. There is an urgent need to explore new therapies that can improve outcomes for Stage III pancreatic cancer patients. Results from previous clinical studies indicate that the use of the NanoKnife System to treat patients with Stage III pancreatic tumors, including both borderline resectable and unresectable tumors, leads to significant improvement in median overall survival from 15.3 to 27 months following treatment.
The DIRECT clinical study is an important step to show patients, regulators, and payors the potential benefit of the technology.
What is the study’s hypothesis?
The DIRECT clinical study is comprised of two protocols. The first is a Randomized Controlled Trial (RCT) and the second includes a Real World Evidence (RWE) Controlled Registry. The primary objective of the RCT is to test the hypothesis that IRE with the NanoKnife System plus FOLFIRINOX improves overall survival in unresectable Stage III pancreatic cancer patients as compared with the FOLFIRINOX regimen alone, which is the current standard of care. The assessment of safety of NanoKnife IRE treatments is part of the study’s primary objective.
Other objectives of the study include examination of progression-free survival and pain in subjects following NanoKnife IRE treatment as compared with FOLFIRINOX treatment.
The RWE Controlled Registry component of the DIRECT clinical study tests overall survival and safety but is more inclusive of other chemotherapy regimens and individualized treatment plans.
Tell me about the study’s design and why this particular design was chosen.
The study design is state-of-the-art. The IDE includes both the traditional RCT and a RWE Controlled Registry. The RCT was chosen to provide the highest level of evidence in a controlled fashion combined with the gold-standard of chemotherapy. The RWE Controlled Registry was designed to complement, augment, and expand our understanding of how the NanoKnife improves overall survival coupled with standard of care chemotherapy outside the artificial confines of the RCT.
How will data be collected as part of the study?
In addition to a state-of-the-art design, the study is unique in that it directly harvests data from electronic health records (with the appropriate protections in place) decreasing the burden on the hospital and doctor. From a regulatory standpoint, this design ensures consecutive enrollment, increases data accuracy, and reduces the amount of missing data. It is an exciting time to see next-generation clinical trial methodologies being used for a disease that has burdened many patients and families for far too long.
What type of research and other preliminary work led up to the Breakthrough Device Designation and IDE for the clinical study?
The concept and technique of utilizing electric pulses to create pores in the membrane of cells to introduce nucleic acids, proteins, and other molecules by reversible electroporation, or to ablate tissue by permanent cell damage from irreversible electroporation (IRE) has been around for many decades in the biomedical research community. It has also been well documented in scientific literature that IRE has the unique ability to safely ablate soft tissue without damaging critical structures such as blood vessels, nerves, and ducts. There is a heavy involvement of these critical structures in stage III pancreatic tumors, rendering it unresectable. Apart from chemotherapy, treatment options are very limited for stage III pancreatic cancer patients, and the prognosis tends to be dismal. Over the last 10 years, NanoKnife IRE has emerged as a promising option to fulfill the unmet needs for Stage III pancreatic cancer treatment as a large number of published studies in reputable peer-reviewed journals have documented successful treatments. The clinical evidence shows that there is a strong recognition in the medical community that NanoKnife IRE can be a safe and effective treatment for Stage III pancreatic cancer.
While the NanoKnife system had previously received 510(k) clearance for surgical ablation of soft tissue, it had not been approved by the FDA to treat a specific condition. In January 2018, the FDA granted the NanoKnife System a Breakthrough Device Designation under the 21st Century Cures Act for the treatment of stage III pancreatic cancer. The FDA’s approval of the investigational device exemption (IDE) application announced in April 2019 makes it possible to initiate the DIRECT clinical study to demonstrate the effectiveness of NanoKnife IRE technology as a treatment option for advanced pancreatic cancer patients.
What is the time frame for recruitment/completion of the study? Are there any expected announcements of interim data?
As part of the DIRECT clinical study, the study sponsor, AngioDynamics, Inc., launched angioDIRECT.com. Additionally, to facilitate enrollment, the Sponsor partnered with a patient recruitment firm and professional and patient advocacy societies. Overall, the Sponsor is targeting 18-24 months for enrollment, with one interim analysis, although it’s common for studies to take longer than anticipated for a variety of reasons. Study results are expected to be published following its conclusion.
Disclosures: Dr. Narayanan reports that he is a consultant with Angiodynamics.