Phase 1/2 FELIX Trial to Determine Obe-Cel Potential in Adult Patients With ALL

Claire Roddie, MD, PhD

With promising efficacy previously shown with obecabtagene autoleucel (obe-cel; AUTO1) in heavily pretreated adult patients with acute lymphoblastic leukemia (ALL) in the phase 1 ALLCAR19 study (NCT02935257)¹, the phase 1/2 FELIX trial (NCT04404660) will now explore this CAR T-cell therapy even further in this population.

In FELIX, patients with relapsed/refractory ALL will receive obe-cel at 410 x 10⁶ CD19-positive CAR T cells as a split dose on day 1 and day 10 plus or minus 2 days.

The coprimary end points are the frequency and severity of adverse effects (AEs) and serious AEs following infusion, as well as overall response rate. Secondary outcome measures include duration of response, progression-free survival, overall survival, and safety.

“This FELIX study addresses lots of questions in ALL and adult ALL, and opens up the possibility of a CAR to populations who might not have been served in the past,” Claire Roddie, MD, PhD, said.

Adult patients with ALL have limited options, Roddie added, noting that the FELIX research aims to bring the promising results from pediatric and young adult patients into older age groups.

In an interview with OncLive^®, Roddie, hematologist at the University College London Hospital, discussed how the phase 1/2 FELIX trial could impact the treatment landscape for ALL, how CAR T-cell therapies have evolved, and what challenges remain in making these treatments more accessible for patients.

OncLive^®: How has the use of CAR T-cell therapy evolved within ALL?

Roddie: ALL is clinically challenging because the prognosis is poor. In terms of the patient population I look after, about 50% of those patients will relapse following standard therapies. When they relapse, it is difficult to get them back into remission. At that point, the only curative option for them is an allogeneic stem cell transplant.

CD19 CAR T cells are an attractive proposition in the absence of any other therapies, but we know from trials and other indications that CD19 CAR T cells are associated with significant toxicity. That is a problem when we consider the patient population that we are looking to treat, which is adult patients with comorbidities.

That has been one of the biggest Achilles' heels in terms of developing CAR T-cell therapy for adult ALL. [The goal is] trying to [match] up the toxicity [associated] with CD19-directed CAR T cells and the patients who may benefit. That is where this whole subject of [obe-cel] comes in as a potential solution to that problem.

What makes obe-cel unique from other CAR T-cell therapies?

There are licensed CAR T-cell therapies out there. For the pediatric and young adult population, we have tisagenlecleucel [Kymriah], which has transformed the relapsed/refractory space for those patients. All of those CAR T-cell therapies are high affinity CD19 binders. Effectively, what that means is the CAR T cell is in contact with the leukemia cell for these protracted periods of time. That lends itself to a lot of cytokine secretion and to T-cell exhaustion. The CAR T cells signal so much that they can stop being functional in the patient. That is where obe-cel comes in.

[Obe-cel] is a second-generation CD19 CAR T, but it has a different binding kinetic than all other CARs that we have been using and researching. It comes off CD19 quickly, and what that means is for each target interaction, the CAR T cells secrete less cytokines, which may have an effect on the risk of the kind of immune toxicities [such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)] that we see from CARs, because they are cytokine driven. It has the potential to reduce the toxicity that we see from CAR T-cell therapy. Because it is not in contact with the leukemia target cell for as long, the cell does not tend to exhaust itself as much.

What we see is a more proliferative cell, and a cell that lasts for considerably long periods of time within patients. Those are the 2 clear, potential, biological benefits of a simple tweak in the design of the CD19 CAR. That is what makes it unique.

Moreover, the phase 1 CARPALL trial [NCT02443831] looked at [obe-cel] in pediatric and young-adult patients with leukemia. [Investigators] saw exactly what they expected. There was very CRS, very little ICANS. When they followed [up with] those patients, they were detecting CAR T-cells in the peripheral blood, 3 years and more downstream. In a sense, you design the CAR with little tweaks and specifications, and it is gratifying when you then put it into the patient population and see that it is doing what you expected it to and more. That is the prelude to testing this in the adult population.

The phase 1/2 FELIX trial is exploring the use of this product in patients with relapsed/refractory B-cell ALL. What was the rationale and the key objectives of this study?

The prelude to the FELIX study was the phase 1 ALLCAR19 trial, which I ran with Karl Peggs, MB, BCh, MA, MRCP, FRCPath, at University College London [UCL], and that was where the evidence for this receptor came into force in the adult population. We treated 20 patients with relapsed/refractory ALL, as well as heavily pretreated patients. [Moreover], 65% of patients previously had an [allogenic stem-cell transplant], and 50% had inotuzumab [Besponsa] and 25% had had blinatumomab [Blincyto]. These are patients who were heavily pretreated. When patients went in to have their CAR, 45% of them had more than 50% [bone marrow] blasts.

This was a high-risk population, particularly for toxicity. For CRS and ICANS, those risks correlate with disease burden. We were tentative going into [the ALLCAR19] study. [However], we were surprised because we did not see any grade 3 CRS in the study, and that was despite the disease burden. We saw [3 episodes of grade 3] ICANS, but [patients] responded quickly to steroid treatment. The toxicity, or the safety profile, was good.

In terms of efficacy, it was gratifying. We saw 85% of our patients achieve a complete response [CR] again. Compared [with] non-CAR therapeutics, it is impressive. At 12 months, approximately 50% of those were in ongoing CR. Like what they saw in the pediatric data, as we follow patients out to 2 or 3 years and more, we are seeing patients in ongoing remission, and for a subpopulation within the study, we have ongoing CAR T-cell engraftment. We saw a bit of what was going on in the CARPALL study. We have been able to replicate that in adults.

It was that ALLCAR19 study off which FELIX pivoted, because adult ALL had no licensed safe product [when FELIX was being designed]. That is where FELIX comes in. It has taken our UCL-centric CAR program and is now global. It is open in the United States, Spain, United Kingdom, and Scotland. Patients can come on this study and receive this CAR in a schedule similar to the phase 1 study.

What is more interesting about the phase 2 study is we have the conventional eligibility. [Patients] need 5% blasts or more in bone marrow. That is the conventional definition of relapsed/refractory B-cell ALL, which is cohort A.

However, you also have an additional cohort because we recognize that there is an unmet need in minimal residual disease. It may not be 5% blasts, but these patients will do poorly. [This population], at the current time, does not have a product that is licensed for them. They cannot access a CAR T, but we know those patients will end up relapsing. We can take [these patients] into the study, and they are a poor prognostic group anyway. We can take [patients with] extra medullary disease who would not necessarily be able to access a CAR, but they are also an unmet need.

This FELIX study addresses lots of questions in ALL and adult ALL, and opens up the possibility of a CAR to populations who might not have been served in the past.

What is the design and dosing strategy in the phase 2 FELIX trial?

It is a single-arm, non-randomized study. Moreover, the CAR is autologous, so they are patient-derived cells. We know the importance of lymphodepletion, fludarabine, and cyclophosphamide to CAR T-cell engraftment expansion and persistence. These patients all get fludarabine, and cyclophosphamide.

We have tweaked the delivery of the CAR with safety in mind. We have a split dose of CAR T-cell administration, [where] patients will get an initial dose on day 1, and then a second dose on day 10. [The rationale of that decision was] if anybody got immune toxicity in the meantime, you would have that window in which to decide if it was safe to proceed with dose 2. This is thinking of older patients and comorbidities.

We also titrated the initial dose, depending on what [a patient’s] bone marrow blast percentage. We see that more disease equals more immune toxicity risk. If [patients] have higher blasts, they will get a lower dose on day 1. If blasts are lower than 20%, [patients] will get a slightly higher dose. All of this [keeps the] patient population in mind in trying to make this as safe and tolerable as possible.

If these data turn out to be positive, how might this CAR T-cell therapy impact the treatment paradigm for ALL?

This is a registration study, and we want to vindicate the CAR design. We want to replicate what was seen in the phase 1 trial because this could effectively be a transformative therapy for adults with B-cell ALL. At the moment, there are no safe options for them. What this represents is something that, to date, has been well tolerated, and that is effective in that it delivers CRs.

In that proportion of patients, those are durable responses, around of 50% at 1 year, and I personally have patients who are in over 3 years in remission with this product. If we do see the same patterns emerging in FELIX, then you would hope that we will be able to take these to patients globally.

Are there any other efforts being made to investigate this agent? How else would you like to see the agent explored in terms of clinical trials?

CD19 is not unique to B-cell ALL. There is a whole [range] of CD19-expressing tumors that are preferentially seen in older, comorbid patients. Particularly with the favorable toxicity profile, we have already made inroads into that at UCL. We have a phase 1 study using [obe-cel] in CLL and high- and low-grade B-cell non-Hodgkin lymphoma. In the last 12 months, I [also] opened a study for primary central nervous system lymphoma.

Based on what we believe to be the favorable toxicity and reasonably low ICANS incidence, it might be a good choice for those patients. We are recruiting well into those studies, but it feels like this is a well-tolerated product in those settings.

How has the emergence of CAR T-cell therapy shifted treatment for various hematologic malignancies?

Within my clinical lifetime, this is the most transformative development since imatinib [Gleevec] for chronic myeloid leukemia. It has been incredible. The future feels like immunotherapy to me. In CD19 malignancies, there is room to improve. There is antigen loss and antigen escape that we need to address. There are T-cell exhaustion issues to address on whether allogeneic CAR may answer questions about getting patients to CAR sooner.

[There is a number] of research questions that seem to rapidly be translating into the clinic, which is great to see as a practicing clinician. But what is more fascinating beyond CD19 is what therapy offers more broadly in terms of cancer in general. That is the final frontier in some ways: taking a lot of the hard lessons that we have learned in hematology, and then applying them into solid tumors to see whether we can see the same benefits and the same inroads there. As far as immunotherapy and cell therapy goes, this is just the beginning.

Have there been other emerging CAR T-cell therapies in the ALL space?

What is great for patients in the United States is that brexucabtagene autoleucel [Tecartus] had its FDA approval. In a sense, we feel that at least patients in the United States will be able to access that in the adult ALL space soon. [There are] high remission rates there, [though] a more challenging toxicity profile, but that is to be expected with a CD28 endodomain CAR. These are patients who need a therapy now, so the emergence of that is a huge step forward for the field.

There are a lot of interesting data coming out of the adolescent and young adult B-cell ALL space, which will make its way into adult ALL. [This includes] the bispecific-targeting CARs trying to circumvent that CD19-negative escape mechanism. [Moreover], the immune rejection of CAR has seen a lot of work done at the University of Pennsylvania, where they have humanized their CAR, and Shannon L. Maude, MD, PhD, has been spearheading trials using that [method].

[Discussions from the 2020 ASH Annual Meeting evaluated] whether we could end up seeing response rates, which at the moment are sitting around 50% at 1 year, and bringing them closer to 70% or even 80%. [We are] incrementally improving outcomes every step of the way. Taking [pediatric] designs and therapeutics, and applying them in the adult space, is going to be exciting going forward.

When looking to the patient perspective on CAR T-cell therapy, what is the willingness of this population to undergo this treatment, as opposed to other options?

Patients on a whole are delighted to have a [new] option. There has been coverage in the media about what CAR T cells can do. In the United Kingdom, we have licensed CAR T cells for the pediatric and young adult population, and it is much chagrin to the adult population that they do not have the equivalent available to them. I never encounter any resistance to coming on to studies. Patients are hugely enthusiastic and willing to come on to the studies, and they recognize the value.

Patients and the advocacy groups are hammering down our doors to try and get access to these drugs. The sooner we can get these trials done, and the sooner we can make these broadly available to everybody, the better for our patients and their families.

From a practitioner standpoint, how do you consider CAR T-cell therapy as associated with cost and duration of time that it takes for patients to undergo therapy?

From the cost perspective, all new therapies are associated with costs. It is not exclusive to CAR T cells. While the cost issue does get discussed quite frequently, bispecifics and other options come with a cost. Downstream, optimization of manufacturing processes, streamlining the release, and testing [could] feed into a more budgeted CAR T-cell approach. With increased competition in the field, maybe we will see prices start to fall. But whenever you look at the potential patient benefit and the broader impact beyond the direct finances, there is no argument to be waged at all. We must push forward and make these available.

From a practical perspective, patients are committed to a reasonably long period in the hospital. They have lymphodepleting chemotherapy, then they have to be observed for a period of time for toxicity. But that is where low-toxicity CARs can come into their own. [If patients] can get a CAR that is so well tolerated that it can be delivered in an outpatient setting, you are addressing the patient satisfaction issue and the hospitalization costs.

If we could work with the design and technology side to get high-efficacy, low-toxicity products, who is to say they could not be delivered safely as outpatients? That is another challenge in the field to get that right.

Reference

1. Roddie C, Dias J, O’Reilly MA, et al. Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. J Clin Oncol. 2021;39(30):3352-3363. doi:10.1200/JCO.21.0091