Iopofosine I-131 Under Further Investigation in CLOVER WaM Trial in Waldenström Macroglobulinemia

After progression following treatment with a BTK inhibitor, patients with Waldenström macroglobulinemia have limited treatment options. For a rare cancer, developing new and alternative treatment options has remained a challenge, according to Sikander Ailawadhi, MD, who added that the radiotherapeutic iopofosine I-131 (CLR 131) could represent a new option for heavily pretreated patients.

In the phase 2 CLOVER-1 trial (NCT02952508), iopofosine I-131 displayed safety and efficacy in heavily pretreated patients with various B-cell malignancies, including Waldenström macroglobulinemia. Results from the trial led to the pivotal expansion cohort of the trial, CLOVER WaM, specifically for patients with Waldenström macroglobulinemia.

“You can imagine that as a new class of drugs, initially, there may have been some questions or hesitation. However, as time goes on, this is becoming identified more and more as something that may have true benefits for patients,” Ailawadhi said. “Hopefully, this will help fill some of the unmet needs in Waldenström macroglobulinemia.”

In interviews with OncLive^®, Ailawadhi an oncologist in the Department of Hematology and the CAR T-Cell Therapy Program at the Mayo Clinic, and Jorge J. Castillo, MD, an associate professor of medicine at Harvard Medical School, and a senior physician and the clinical director of the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute, discussed early efficacy observed with iopofosine I-131, the rationale of investigating the agent in the CLOVER WaM trial in patients with Waldenström macroglobulinemia, and how the radiotherapeutic could affect the treatment paradigm.

OncLive^®: What is the mechanism of action for iopofosine I-131? What makes this agent unique from other therapies?

Ailawadhi: [Iopofosine I-131] is a radiopharmaceutical, or a radiotherapeutic. In cancer care, we have had drugs that have been developed in the past that were radiopharmaceuticals, where a molecule has some amount of radiation attached to it that is stabilized [and can] be given to the patients as an intravenous [IV] administration. That molecule is supposed to seek out specific types of cells—cancer cells—and deliver that payload of radiation to kill the cells. That is the mechanism of radiopharmaceuticals.

Radiopharmaceuticals have previously been used in cancer care, [particularly] in lymphoma. Some of [these products] were more successful than others, but due to certain challenges, or the way those drugs were developed or marketed, they did not really take off. However, there are also radiopharmaceuticals used in certain solid tumors, for example, prostate cancer. Iopofosine I-131 is basically a radiolabeled iodine that specifically goes and seeks certain kinds of lipid molecules, or lipid rafts, in cancer cells to deliver that radiation.

Castillo: The idea is the medication takes advantage of a specific construct in the membrane of the cancer cell called a lipid raft. Cancer cells, in general terms, have a higher density of these lipid rafts in them. This medication uses that specific construct, and it is then able to introduce radioisotopes within the malignant cells. Through that, it induces cell death. This is not a totally directed or targeted regimen; it is a broader [approach], and it has been shown to be active in different cell lines of different types of cancers. It seems to be especially effective in malignancies such as multiple myeloma, lymphomas, and Waldenström macroglobulinemia.

What were the initial efficacy findings reported with iopofosine I-131 in the CLOVER-1 trial?

Ailawadhi: CLOVER-1 allowed a broad selection of cancers to be included, and that is standard for many drugs that are being newly developed in cancer care, where a wider variety of diseases [that are expected to] benefit are included. The CLOVER-1 trial allowed certain kinds of lymphomas [like small lymphocytic lymphoma], even aggressive lymphomas, as well as mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, etc. They were all put together as different cohorts, so that we could better analyze the data.

The CLOVER-1 trial included many of these patients, and we got an extremely clear signal that the patients with some of these diseases were responding. In other disease areas, the drug was stabilizing the disease so that that upward trajectory of progression was stopped.

Castillo: In CLOVER-1, [which had] very few patients [with Waldenström macroglobulinemia] enrolled, we saw initial evidence of activity in most of these patients. [The majority] had a response, which was defined by a decrease in the serum levels of IgM, which is a classic protein secreted by malignant cells in patients with Waldenström macroglobulinemia. The decrease and increase of IgM levels tell us that diseases are responding to treatment or progressing, respectively. We saw IgM decreases in these patients [with this treatment].

What are the current unmet needs for patients with Waldenström macroglobulinemia?

Castillo: For patients [with Waldenström macroglobulinemia] who are progressing on BTK inhibitors, there is certainly an unmet need in terms of what potential treatments could be used in that specific setting; this is where exploring iopofosine I-131 could cover interesting ground in that sense.

Ailawadhi: Waldenström macroglobulinemia is a relatively rare disorder. Just about 1700 or so new patients are diagnosed in the United States every year [with this disease]. However, it is important to keep in mind that these rare cancers tend to be frequently neglected or ignored. We are in a good state, because 2 drugs are specifically FDA approved for Waldenström macroglobulinemia and several others are used.

BTK inhibitors do provide benefit [to these patients], but a lot of times, they do not provide a deep response. The disease may be stabilized, it may be improved, but the deep responses are not achieved, and sometimes the protein and the tumor markers go down, but the bone marrow burden may not change much. The unmet need, in my mind, is [that we need] to have something that can address the biology of the disease and the natural history of the disease [to] provide deeper responses without exposure to traditional chemotherapy. Preferably, [it should] not have many adverse effects [AEs] either.

What was the rationale for further exploring iopofosine I-131 specifically in patients with Waldenström macroglobulinemia?

Ailawadhi: [In CLOVER-1], we noticed that those patients with Waldenström macroglobulinemia had extremely deep responses. These were patients who were previously treated, had relapsed/refractory [disease], and they [achieved] complete responses [CRs]. The disease went away completely. We also noted that at least in 1 patient, this response lasted for a couple of years; she stayed free of disease. That gave the idea to specifically look [at iopofosine I-131in those with] Waldenström macroglobulinemia; [we wanted to address those] unmet needs and see whether there may be more impact or benefit we can provide there. Hence, CLOVER WaM was brought up for patients with Waldenström macroglobulinemia.

Castillo: Many of these patients don not have many other options left. When we consider the treatment paradigm for patients with Waldenström macroglobulinemia, we think about rituximab [Rituxan]-containing regimens, and BTK inhibitors. Now, some patients have been exposed to BCL-2 inhibitors. Beyond that, there are not too many other options. Iopofosine I-131 provides a novel mechanism of action in this specific setting.

What are the criteria for enrollment to CLOVER WaM?

Castillo: Patients with treatment-naïve disease will not be included. This is not a frontline treatment. Patients need to have received at least two lines of prior treatment that includes BTK inhibitor exposure. Another interesting part of the study is that this agent has penetration into the central nervous system [CNS], which is unique because not many agents can do that, besides BTK inhibitors and some chemotherapeutic agents.

There is a rare presentation in patients with Waldenström macroglobulinemia called Bing-Neel syndrome, in which there is CNS involvement. Patients with Bing-Neel syndrome are classically excluded from clinical trials. As such, it is important to note that in this study, these patients could be included as part of the enrollment.

What are the challenges of enrolling patients?

Ailawadhi: Waldenström macroglobulinemia is a rare diagnosis. If a patient is sitting somewhere far away in a geographic location where they do not have access to a larger [treatment] center, it is relatively easy for a physician to be able to prescribe a medication that is FDA approved, although it may have financial impact, it may have AEs, or it may have to be taken for the rest of the patient’s life. It is a little bit trickier for patients who have a rare disorder to be able to seek the right kind of trial and be able to accrue to that. That is clearly the challenge.

Castillo: Despite our enthusiasm, there are some potential issues. Iopofosine I-131 is a radioisotope, so institutions that would like to enroll patients will need to get in touch with a radiopharmacy, and they have specific policies that are distinctly different than what we do with classic chemotherapy, targeted agents, or other experimental agents. In addition to that, we need to get in touch with nuclear medicine and have nuclear medicine colleagues involved.

I see how these [challenges] might portend—at least for the initial investigation of the agent—some minor difficulties. I would say most academic centers would be well suited to be able to deal with these issues. Community centers, probably not so much maybe at the beginning, but once the data is out, if we are seeing continued activity, then maybe looking into how we translate this into clinical use in the community will be a next step.

Ailawadhi: If a patient otherwise qualifies, the sponsor will sometimes help the patient with resources so that they are able to come back and forth [for treatment]. Or importantly, once the patient gets on the study, they could even get labs [completed] locally. They do not have to sit in the clinical trial center away from home, without caregiver support. Patients could receive the treatment, come back for their study-related visits, but if they need labs in between, they could have them done locally and send the results [to us]. We can do some visits remotely. We can do some phone visits. The effort is to make it a very user-friendly, real-world study.

Could you provide an overview of the methods being used in CLOVER WaM? What doses of iopofosine I-131 will be evaluated?

Ailawadhi: It is a single-arm study. There is no randomization. Everyone who [enrolls to] the trial will receive iopofosine I-131. The patients should have had any 2 prior lines of therapy, and [have] disease that is progressing, disease that is measurable, with an IgM spike that requires treatment, whether [for] clinical [symptoms] or progressive disease.

The study allows certain kinds of imaging or bone marrow testing that may have been done in the recent past but not necessarily on study. The study allows those results to be used so that patients do not have to undergo unnecessary testing. They must have adequate liver function, adequate kidney function, and adequate bloodwork, which are also relatively easy criteria.

Once the patient gets into [the trial], they get a consult with a radiation oncologist, because at most treatment centers, radiopharmaceuticals are administered by a radiation oncologist. The patient gets a consult with radiation oncology, and then a day is decided on when the drug can be manufactured and sent over.

Castillo: The study treatment involves IV infusions, and these IV infusions are relatively short. They’re not the several-hour IV infusions that we are used to. Rituximab, for example, is a classic agent that we use due to its shorter infusions. Given that this is not a biologic agent per se, we are not expecting infusion reactions in these patients. These will be given in series of two infusions about two months apart for a total of four infusions, and that’s it. There’s not going to be an indefinite duration of therapy. It’s going to be fixed-duration therapy with fast infusions.

As we have some experience with prior [AEs] in the past, cytopenias are probably going to be 1 of the complications that we’re going to see with this agent. I’m talking specifically about neutropenia, thrombocytopenia, and maybe some anemia. There has always been a concern of potential stem cell damage with these radiological agents. However, based on the safety data coming from the company [Cellectar], there does not seem to be an excess of myelodysplasia or acute myeloid neoplasms in patients who were exposed to this agent previously. But longer follow-up and a larger sample size can also help identify other potential AEs.

If data continue to be positive, what will be the next steps for researching this agent? What could the effect be on the treatment paradigm in Waldenström macroglobulinemia?

Ailawadhi: The data has been very interesting, intriguing, and exciting. We are continuing to enroll patients with Waldenström macroglobulinemia on this trial, nationally at various institutions—more institutions are now coming on board.

Castillo: The disease remains incurable. The CR rates are hard to [improve]. They are rare and low with any treatment. There’s a specific group of patients who do not respond very well to BTK inhibitors. These are patients with CXCR4 mutations. A lot of the treatments that we have currently, the oral agents specifically, are indefinite duration therapies in which patients get exposed to costly agents for several years. In all these aspects, iopofosine I-131 has the potential of addressing some of these unmet needs.

Is there any other ongoing research in Waldenström macroglobulinemia that you find intriguing?

Ailawadhi: We know that patients who get treatment with a BTK inhibitor have chronic AEs, or sometimes [the BTK inhibitors] can stop working or may not provide any deeper of a response. In that family, newer drugs are coming about which hopefully will be able to overcome some of those challenges.

The population with CXCR4 mutations, the tougher subcategory of disease, tends to respond less to treatment. There are some drugs that are being developed that will specifically focus on that subgroup.

Castillo: The next generation of clinical trials are going to include triplets. Most of these regimens are going to include BTK inhibitors, which is great because these are potent agents and are well tolerated. But they will be fixed-duration regimens, so they’re trying to address some of the unmet needs. Triplets and BTK inhibitor–containing regimens of fixed duration are probably the future.

How important are clinical trials for improving treatment options for patients with Waldenström macroglobulinemia?

Castillo: As we try to improve treatments, [elicit] deeper, longer responses, hopefully safer treatment options, the only way to do that is through clinical trials. To my colleagues, if you have a patient with Waldenström macroglobulinemia or any other disease who might be a candidate for a clinical trial or might be interested in participating in a clinical trial, I encourage you to get in touch with investigators, in touch with us, and to refer your patients so we can advance the field.

Ailawadhi: If the efficacy and safety [of iopofosine I-131] continues to pan out the way we are noticing right now, this may become an excellent opportunity for our patients. And if that is indeed true, logistic challenges, hurdles, or even barriers are a very minimal issue to overcome. We all deal with radiation oncology in our practice in various kinds of settings. So, it’s not difficult to set up the process [of trial treatment]. And that’s where centers such as Mayo Clinic and others that have participated in the trial and have worked on the study would be more than happy to help [other centers participate], especially if it turns out to be addressing the needs of the patient.