Discoveries in CAEL-101 Trial for Patients with AL Amyloidosis
Jason Valent, MD, Director of the Multiple Myeloma Program and Co-Director of the Amyloidosis Program at Cleveland Clinic Cancer Center, joins the Cancer Advances podcast to discuss the developments of the CAEL-101 trial for patients with AL amyloidosis. Listen as Dr. Valent talks about the discoveries and changes in treatment in each phase of the trial.
Discoveries in CAEL-101 Trial for Patients with AL Amyloidosis
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Jason Valent, Director of the Multiple Myeloma and Amyloidosis Program here at Cleveland Clinic. He is here today to talk to us about research on the treatment of amyloidosis that he recently presented at the American Society of Hematology meeting. So welcome Jason.
Jason Valent, MD: Thank you Dr. Shepherd. It's good to be here. I'm very excited.
Dale Shepard, MD, PhD: Very nice. Tell us a little bit about your role here at Cleveland Clinic?
Jason Valent, MD: So I am the director of Multiple Myeloma Amyloidosis at Taussig Cancer Institute. And I also am the co-director of the Amyloidosis Center for the Cleveland Clinic. So with Dr. Mazen Hanna in cardiology, we serve as the co-directors for our Amyloidosis Program for the entire institution.
Dale Shepard, MD, PhD: Excellent. So I guess let's start very basic. What is amyloidosis?
Jason Valent, MD: So amyloidosis, in its simplest description, is the abnormal deposit of a protein made by your body in a place that it shouldn't be, generally being in vital organs, causing organ dysfunction and potentially death if left untreated. AL amyloidosis refers to the light-chain amyloidosis, or what's sometimes referred to as immunoglobulin light-chain amyloidosis. And Al amyloidosis is a disorder of the plasma cell whereby the defective plasma cell produces an abnormal light-chain portion of the antibody. And that light-chain portion of the antibody ultimately deposits in vital organs, again, causing organ dysfunction and death if left untreated. The most common organs that are affected are the heart, the kidney and the liver. But the disease often will affect the nervous system, potentially the bowel, but ultimately these deposits can occur anywhere, generally speaking, outside of the brain.
Dale Shepard, MD, PhD: How would people know that they might have amyloidosis?
Jason Valent, MD: It's difficult sometimes for patients, and even physicians, to ultimately make this diagnosis. The disease has somewhat nonspecific symptoms, but common symptoms that are seen in patients are, heart failure with preserved ejection fraction and nephrotic syndrome. So patients may experience swelling in their legs, belly, and those can be either from heart failure or kidney involvement from the amyloid causing a nephrotic syndrome.
Jason Valent, MD: Many patients will experience shortness of breath. Oftentimes patients will experience muscle loss and weight loss. With patients with nerve involvement, neuropathy can be very severe. And in the bowel, unexplained diarrhea or constipation can be an indication of amyloid involving the bowel. There are a number of different symptoms that can occur, but it's often not the first thing that patients or physicians think about in terms of a diagnosis.
Dale Shepard, MD, PhD: What are we doing currently to treat it?
Jason Valent, MD: So the standard of care is a combination of chemotherapy and immunotherapy. So there was a research trial that we were part of that basically utilized what was considered the standard of care chemotherapy, which was a combination of bortezomib, cyclophosphamide and dexamethasone, with or without daratumumab. And so this was a randomized trial of four drugs versus three drugs, with the addition of daratumumab potentially to the backbone of bortezomib, cyclophosphamide and dexamethasone. And the four-drug combination certainly showed superiority in that trial. The primary endpoint was a hematologic complete response, which is important in amyloidosis because that generally portends for better survival. So it's a very well recognized surrogate of survival in amyloidosis.
And in the patients that were treated on that study with a four-drug combination, including daratumumab, the hematologic complete response rates were over 50% compared with 19% for the three-drug combination of bortezomib, cyclophosphamide and dexamethasone. So, our standard of care is the four drugs, daratumumab, bortezomib, cyclophosphamide, dexamethasone. And patients tolerate that actually reasonably well. The cyclophosphamide dose that's used is lower than what is typically used to treat malignancy. And most patients will be able to tolerate the four-drug combination reasonably well. Obviously dose adjustments can be made for toxicity, but the toxicity as shown in the trial was relatively limited. And patients who had received the four-drug combination also had improved quality of life.
Dale Shepard, MD, PhD: So I guess response rate then primarily is what you'd be looking for as an improvement, right? So it sounds from a tolerance standpoint, things are in pretty good shape. So when we think about new therapies, we're primarily driving efficacy.
Jason Valent, MD: Correct.
Dale Shepard, MD, PhD: Now you mentioned hematologic complete response, and I'm a simple solid tumor guy. So I'm used to having a ruler and measuring things side to side. This being a disease that you have deposits in tissues, how does that play into assessing response?
Jason Valent, MD: Right. So we assess response in two ways. So the hematologic response is based upon reduction in the involved free light-chain, looking at the serum and urine immunofixation. So hematologic complete response is normalization of the free light-chain that was causing the amyloid in the first place, along with a negative result on the urine and serum immunofixation for that light-chain as well. The hematologic response is relatively easy to assess, so that's just with blood in urine tests. The organ response for the heart, generally the most accepted standard objective measurement, is a reduction in the NT-proBNP by at least 30%.
So we monitor patients with NT-proBNP assessments generally on a monthly basis and look for improvement in organ response. In the kidney, we use 24-hour urine protein. So generally speaking, a reduction in the 24-hour urine protein by 30% is considered an organ response in the kidney. In the liver we use alkaline phosphatase assessments. It's very difficult to objectively assess nerve response or bowel response, but the objective measurements of 24-hour urine protein and NT-proBNP, for the kidney and heart respectively, are used for organ response assessment.
Dale Shepard, MD, PhD: So more biologic measures, no need biopsies or things like that?
Jason Valent, MD: Correct. The biopsies... It's interesting, even when you see improvement by these markers, oftentimes you will still see amyloid in the organs because, and this kind of leads into why this trial is being done, even though patients will have some organ function improvement hopefully. Oftentimes that's incomplete and patients are still left with symptoms related to the prior amyloid deposition, despite the fact they may clinically improve to some degree.
Although the other problem is some patients do not see improvements in these organ response parameters. And so, for lack of a better term, the holy grail of amyloid treatment and research would be to find a drug or substance that is able to effectively remove amyloid deposits that are in the organs. We're very good at being able to reduce or kill the plasma cells that are making the amyloid, but what we really need is a drug or a substance that is able to effectively remove amyloid from organs.
Dale Shepard, MD, PhD: So you did a trial, was a compound, still letters and numbers, CAEL-101. And you reported on some data at the recent ASH meeting. So give us a little idea, what was the background for that trial and what did you find?
Jason Valent, MD: So the CAEL-101 was formally known as 11-1F4, and it was developed by Alan Solomon, he was at the University of Tennessee. And he was able to synthesize basically a fully human monoclonal antibody against amyloid fibers. And basically this was shown in preclinical activity to be able to find an amyloid fibro and attach to it. So there was a Phase I study done by Suzanne Lentzsch several years ago, looking at previously treated patients who had persistent organ dysfunction. And the patients in that study got four doses, once a week for four doses, of what turned out to be CAEL-101 eventually, it was still called 11-1F4 then. And this was 27 patients in the Phase I. There was 10 dose levels starting at 0.5 milligrams per meter squared up to 500 milligrams per meter squared.
And the organ response rates were 67%. So it was a sign of improvement. And these were patients again who were previously treated, so there was no confounding factor of effective treatment just leading to organ function improvement. So it was a certainly a proof of concept that there was some activity with this drug. The safety in that study seemed to prove that the drug was also very safe.
One of the concerns with giving a monoclonal antibody, trying to stimulate the immune system to remove amyloid in the heart, would potentially be inflammation, and then leading to heart arrhythmias, and that was not seen. So the Phase II study was designed, and the Phase II is a little bit of the misnomer because it was kind of a part Phase I, part Phase II. So there was an additional dose escalation, but the other part of this that was more Phase I is, it was the first time that CAEL-101 was given with standard of care chemotherapy or chemoimmunotherapy for amyloidosis.
And so the dose escalation portion was successful. We dose escalated from 500 milligrams per meter squared up to a thousand milligrams per meter squared. Based on some PK data that the sponsor had, they thought that higher doses would produce better drug levels. And that was actually found to be true. With the higher doses there did not seem to be any additional safety concerns. We have not seen cardiac arrhythmias. The common toxicities were nausea, diarrhea, constipation, and rash.
It's a little bit interesting because on the Phase I study, they also showed a rash that developed and they biopsied the rash and they actually had an antibody to the antibody, the 11-1F4 where they showed the 11-1F4 was attacking amyloid in the skin. So it was almost a proof of concept up to the drug hit its target. The Phase II that we did initially used bortezomib, cyclophosphamide and dexamethasone in combination with CAEL-101. There was a second part of the study that was added, a part B for lack of a better term, when we realized that daratumumab, bortezomib, cyclophosphamide and dexamethasone was going to be the standard of care.
And so the part B patients were treated with the five-drug combination of daratumumab, bortezomib, cyclophosphamide dexamethasone and CAEL-101. Even with the addition of a second antibody, the daratumumab being another monoclonal antibody, the drug levels of CAEL-101 were very similar. And again, no new toxicity was found. In terms of effectiveness, we did measure cardiac and renal responses with NT-proBNP and 24-hour urine collections. So in the patients with renal involvement, eight of the nine patients had organ response in the kidney, and that's pretty spectacular. Historically, with just chemotherapy alone, you'd expect that number to be about 50%. So the renal responses, in addition to that, were very robust. There were some patients that had very deep and durable improvement in their protein area.
The cardiac responses were a bit less. So there was technically a 45% organ response in the heart. So nine patients had an organ response, ten patients had stable disease and one patient had progressive disease by NT-proBNP criteria. It's interesting because the one patient that had the progression by NT-proBNP actually had an organ response in her kidney. So I think the responses would indicate that the drug works and, at a minimum, it is very non-toxic. The Phase II results have led to now the opening of the Phase III trial. The Phase III trial is actually two different Phase III trials. The unique aspect to the Phase III is it includes the absolute sickest of the sick heart involvement patients.
So these are patients who have NT-proBNP at baseline that's over 8,500 and a troponin T that is over 0.035, which equates to basically a high sensitivity troponin of 50 or greater. It is very unique. No amyloid study that has ever been done has included this population of patients. This is the patient population that absolutely needs rapid reversal of damage that has been done. These patients have life expectancies that can be very short, even with effective treatment. And so the sickest of the sick patients are being included in this study, which is very unique and has never been done before in an amyloid study.
Dale Shepard, MD, PhD: You mentioned two phase IIIs, is there a more of a traditional marathon run of Phase III, and then a sort of cardiac, I need treatment Phase III?
Jason Valent, MD: Yeah. So it's not the marathon runners. That's the other one. So the there's a staging system called the Mayo staging system that divides patients into Mayo stage III A and Mayo stage III B, based upon the NT-proBNP and troponin values. So all of these patients have a troponin T that's over 0.035 or a high sensitivity troponin over 50. And the only delineation is the NT-proBNP value. So if your NT-proBNP is between, I think it's 660 and 8500, that's the three A population.
And if the NT-proBNP is over 8500, that's the Mayo stage III B population. So they're specifically looking at, honestly, the highest risk cardiac patients. And the primary outcome measure for the Phase III is going to be overall survival. So the design in both studies is to give the standard of care chemotherapy, and that a two to one randomization of CAEL-101 to placebo. So it's not a classic Phase III with a one to one randomization, the FDA permitted it two to one randomization so the patients will have a 66.666% chance of getting CAEL-101 on the study.
Dale Shepard, MD, PhD: Is there an allowable crossover?
Jason Valent, MD: There is not.
Dale Shepard, MD, PhD: And are they getting immunotherapy as well?
Jason Valent, MD: They are. So the standard of care for at least North America... Well, I guess I should say the United States right now, is the daratumumab, bortezomib, cyclophosphamide and dexamethasone, so that'll be with or without CAEL-101.
Dale Shepard, MD, PhD: Well, I find it in encouraging that they're actually doing the study in people that can benefit most, because too often drug development happens in populations that are really not real world.
Jason Valent, MD: Not representative of the... Yes.
Dale Shepard, MD, PhD: And then you'll get an approval, but then you have to scratch your head and say, "well, but does it matter?"
Jason Valent, MD: Yeah, this was impress. I give a lot of credit to the sponsors of the trial for doing this. There is some background as to why it's being looked at. There was another monoclonal antibody called bertilimumab which we're also studying, which is also a monoclonal antibody against amyloid fibers. And while their primary outcome measure in their original Phase III trial was not met, there was a subgroup analysis that looked at these sickest of the sick patients showing a 50% benefit in overall survival. And so that part of the reason why these studies were designed this way. But again, it's a very difficult patient population to study at times because these patients will have mortality for non-treatment related issues, just related to their underlying significant heart involvement.
Dale Shepard, MD, PhD: A lot of credit for running that difficult trials.
Jason Valent, MD: I'll just say, we're kind of in a unique position here because we have the best of the best in terms of heart failure support from our cardiologists. And unfortunately we see a lot of patients who are presenting to us with very late stage disease based on just, it's a hard diagnosis for physicians to make. The one thing I'll always advocate for is, if you have a patient that you don't know why they're swelling, check a serum, free light-chain assay. But we're in a very unique position here because our cardiologists are very good at making this diagnosis. But unfortunately, a lot of patients who are presenting here have been seen other places and nobody could make the diagnosis. And so we see these patients with advanced heart failure and now we have, I think, a very viable, good clinical trial to treat them on.
Dale Shepard, MD, PhD: That's great. So doing fairly well from a hematologic control, have trials now looking at organ function and how we can restore that. What are the next steps? What's the biggest gap that remains?
Jason Valent, MD: I think that this is going to be potentially in terms of a therapy solving one of the biggest gaps that's left. If we can find an effective drug to move amyloid from organs in a rapid manner with limited toxicity, again, that's going to be the holy grail of amyloid treatment. The whole missing piece still is the early diagnosis of Al amyloidosis, and that's where I come back to the serum free light chain. Historically, when we're concerned about a plasma cell disorder, we order an SPEP and a UPEP, and that's not the test to order. We want doctors ordering serum free light chains and serum immunofixation, and urine immunofixation as a screening test for plasma cell disorders. 50% of patients with Al amyloidosis will not have a monoclonal protein detected on an SPEP. The only way you find it is with the serum free light chain assay.
And so my biggest ask to physicians, again, if you have someone and you don't know what's wrong with them, at a minimum, just check the serum free light chains. If they're abnormal, refer them to someone who does plasma cell disorders. And the key to amyloidosis and survival is early diagnosis. And so it is absolutely essential that we get the word out about how to test for this disease, appropriate referral to a hematologist, preferably someone who has experience with amyloidosis, and making a diagnosis as soon as possible. Because if we find these patients with early stage disease, their outcomes are exceptional.
The number of treatments that are available now with the four-drug combination. In addition to that, I apologize to my stem cell transplant colleagues for not mentioning high dose melphalan and autologous stem cell transplant as a potential treatment. But that is also a potential treatment for patients with less severe heart involvement in the patients that we're studying on these trials. The major limitation to high dose melphalan is severe cardiac involvement. So if we can make this diagnosis early, that opens up more therapy windows. And so I think that's still the biggest missing piece of amyloid, is early diagnosis.
Dale Shepard, MD, PhD: Outstanding. Jason, thanks for being with us. Thanks for your insights.
Jason Valent, MD: Dale, thank you very much for having me.
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