Expert insight: ACT clinical trials—The long road
Martin Lachs & Brandon Fletcher of ICON Clinical Research
Whilst there are two marketed products currently, the excitement and investment generated in adoptive cell transfer (ACT) products are leading to a steep increase in the number and now the diversity of ACT products in clinical development.
No longer the domain of autologous CD19 or BCMA constructs for blood cancers, we are in the world of tumor-infiltrating lyphocytes (TILs), allogeneic T cells, natural killer cells and other possible approaches in both blood and solid tumors.
Why the need for long-term follow-up trials?
Do we need long-term follow-up trials and is it really an issue? Well, although we are developing technologies that would allow for multiple infusion treatment regimens, most current technology is limited to a single or maybe just one secondary infusion.
Durability as well as response rates in the first wave of (potential) products have been impressive, but we know it is not the panacea yet, and some recent results with other large antibodies targeting CD19 are giving pause for thought when cost and logistical demands of ACT therapies are considered. However, the need to look at the long-term risks and benefits for patients who participate in ACT trials is paramount.
The fact is that with ACT therapy, the patient effectively becomes a genetically modified organism after administration, which in and of itself necessitates the length of follow up. It is often required by health authority regulatory guidelines per country, Germany being one example.
Study objectives are to demonstrate long-term safety and efficacy of subjects exposed to gene therapy medicinal products which are made with viral vectors, through monitoring of delayed adverse events related to ACT therapy including: persistence of the virus used in the manufature of the product in the patient’s tissues (known as replication-competent lentivirus or RCL) or other viruses used to modify cells; peristence of ACT cells in the patient (we measure something called persistent vector sequences or PVS); and date of relapse, progression or death, if applicable.
All patients who have received an ACT infusion under a protocol should be asked to roll over upon either premature discontinuation from or completion of a study and participate in a separate long-term follow-up (LTFU) protocol for up to 15 years after their ACT infusion.
The data garnered from LTFU studies will likely be invaluable, but there are challenges which arise, along with some pointers to addressing those challenges, as addressed below.
The challenges faced
So, what are the main challenges posed by LTFU studies in ACT development?
Patient retention is the first difficulty to countenance. Time is always of the essence. Cancer clinical trial patients commonly fall into the “previously failed prior therapy” category already; thus. they are primed and ready to quickly change direction if they are not responding to their current regimen and there are other treatment opportunities available.
This is certainly not unique to ACT studies but we are in risky waters, as more treatment options become available—especially in the ACT setting, we are seeing the reality of the challenge in real time. With patients needing to move on to other therapies as quickly as possible if they fail to respond to the investigational treatment and/or they have disease relapse, when a further experimental infusion is not possible, patients quickly remove themselves from one study in favor of another trial or other treatment, blurring the lines regarding safety profile and long-term effects.
With ACT there are real gaps in data sets for patient safety, tracking, patient outcomes/endpoint parameters resulting from, availability and quality of that data. For example, recognition of ACT associated toxicities such as B‐cell aplasia (a condition that exposes the patients to infections) which might persist for up to one year. If one experimental therapy bleeds into another, both likely with limited safety data, there is the serious potential for blurred ACT data.
As mentioned earlier, LTFU data reporting is required by agencies so protocol compliance is key and yet difficult to achieve if, for example, physicians are looking to the next possible treatment for their patients.
Then there are the ethics of it all. Patients’ needs for new medical treatments quickly are forces ranged against participation and compliance in LTFU studies. In addition there are complications in reconciling the requirement to track patients with. patient privacy concerns at sites.
Plugging the holes
So, given that we need to plug holes in data gaps and agencies are demanding it, what are the possible solutions for patient retention and protocol compliance, and how do we begin to deal with these factors?
We can discuss possible means of addressing challenges in the context of sponsors, contract research organizations (CROs) and sites. Sponsors and CROs need to engage regulators on this topic now, as this is not a protocol- or sponsor-specific risk. Obviously we need to secure commitment from investigative sites at research centers to adhere to protocol requirements at time of patient discontinuation by emphasizing the regulatory expectations, data needs and benefit to the wider patient community by collecting long-term data.
There are some smart things we can do, paying it forward by avoiding restrictions in LTFU protocols that prohibit patients’ participation on another clinical trial. We can also build and encourage the use of patient reported outcomes to help assess the impact of a new therapy on symptom burden and health-related quality of life (HRQoL) even in the long-term setting. Overall, ACT trial data are lacking on patient-reported toxicity and impact on HRQoL regardless. The National Institutes of Health, for example, offers some excellent guidance on constructing appropriate instruments to gather these data.
Speaking purely from a CRO perspective, we have a constructive part to play in championing the messaging to sites through site enrollment specialists, clinical research associates and conducting webinars, as well as providing easy-to-use tools (patient rollover trackers). This is not rocket science, but having a coordinated and highly informed team is not just a “nice to have” but rather is essential to the future success in developing cell therapies.
Conclusion
We must openly recognize and do our best to manage to the reality that emerging ACT clinical developments are rapidly expanding our investigational portfolio, yet our ability to capture the most critical data, safety and long-term outcomes is hindered by the very same topic;. specifically, in the rush to move to the next best development, we risk failing to follow up on really important data from the last trial we ran.
Thus, we must exercise patience and diligence in timeline expectations for true confidence in such data. Along the way, we as clinical researchers must play our part, remain attentive and nimble to best manage such long-term data collection to reach our ultimate goal of bringing safe and effective therapies to cancer patients.
Martin Lachs is vice president of project management for oncology and cell therapeutics at ICON Clinical Research and Brandon Fletcher is program manager and ACT principal at ICON Clinical Research.
