Promising Early Clinical Trial Results Prompt Study Expansion to Include Patients with Mantle Cell Lymphoma

The CIRLL clinical trial will now be expanded to include additional patients with mantle cell lymphoma (MCL) after it showed promising results in patients with chronic lymphocytic leukemia and six patients with MCL.

In the phase 1 study, researchers combined two medications, cirmtuzumab and Imbruvica (ibrutinib), in patients who were heavily pretreated for their disease. They discovered that some patients had a complete response, or showed no signs of cancer, following treatment and the drugs were also well-tolerated.

CURE® recently spoke with Dr. Hun Ju Lee, an investigator on the trial and assistant professor of medicine in the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, about cirmtuzumab — a tyrosine-protein kinase transmembrane receptor-1 (ROR1) targeted antibody — and how it works in tandem with Imbruvica, offering hope for patients with MCL, a rare, aggressive form of non-Hodgkin lymphoma.

CURE®: How would you explain ROR1 and how it pertains to cancer treatment?

Lee: ROR1 is a safe target, and the antibody we’re investigating now (cirmtuzumab) was recently discovered a couple of years ago by Dr. Thomas James Kipps at the University of California, San Diego, as a novel and targeted therapy. We needed a target like CD20, which is a great target, however, it's expressed on normal B cells. So, when you do use rituximab (Rituxan), you will kill some normal CD20-positive B-cells, in what I call friendly fire.

So, this one (ROR1) is a very interesting target in that it’s expressed on abnormal cells and not expressed on normal cells, which is what you want, right? You don't want to shoot a missile and hit your own friendly targets. So, you have a target that is not expressed, and it is scientifically driving the disease. So if we blocked this pathway, this will have a negative impact on the disease, meaning a positive response to the patient.

That is key because if you look at all the targets that we have right now, they're all expressed on normal cells, which is why we get so many side effects. We always get carried away about the response rates, but you need to be very careful with the toxicities. We are hoping that this is a great target, but we first have to prove that this is safe to give to our patients.

That was what we did with phase 1 of this trial — trying to figure out what the dosing of the drug will be. It’s not looking for response, but safety. You need to learn how to crawl before you can walk and run. We have been part of the phase 1 process, finding the right dose of the ROR1 antibody, and we feel that we have not reached the maximally tolerated dose, meaning that at even the highest dose that we plan to use, we did not see any what we would call serious adverse events.

The expansion of the clinical trial examining this ROR1 inhibitor aims to include more patients with MCL. Can you explain what prompted the expansion and how the combination is being tolerated in these patients thus far?

MCL is fairly rare in the United States, and accounts for only about 5% of all lymphomas. It's a very small population. However, they have been very fortunate in the past five years to have been given a plethora of clinical trials, and this ROR1 trial will be one of those clinical trials that will be available to our patient population.

In phase 1, we found it to be very safe, and we saw good response rates. Two thirds of the patients with MCL responded, with one third of the patients achieving complete response. And now we're very excited to move forward with the phase 2 portion to really recruit at the highest dose level that we think will get the best response rate, because it is very well tolerated.

Remember, though, that this trial is not examining a single agent ROR1 antibody. We feel that it is a complimentary pathway with (Imbruvica), kind of like Batman and Robin. One by itself doesn’t work well, but when you combine them, they do very well. We hope that with (Imbruvica) and the addition of this ROR1 antibody, it will put the majority of the patients into complete remission. I may be wrong, and I don’t know if ROR1 is the perfect complimentary to ibrutinib, but we feel that it is very safe, and we are getting the signal so we will be moving forward with the trial.

What will this mean for patients with MCL?

For patients, I think this is another treatment option. With everything that’s out there now, where this ROR1 fits in is yet to be determined. However, it is a very, very good option for patients, especially in the elderly population who are not able to tolerate extensive toxicity.

The big question that many patients will ask is, is this the right treatment for me? No one is going to have the perfect answer, and decisions are usually driven mostly by response, but it should be determined by toxicity, and this could be a great fit.