Infusion-Schedule Challenges Halt Exploration of Carfilzomib/Ibrutinib in R/R MCL

Hun Ju Lee, MD

Findings from a recent phase I study show the combination of carfilzomib (Kyprolis) and ibrutinib (Imbruvica) is well tolerated among patients with relapsed/refractory mantle cell lymphoma (MCL), said lead investigator Hun Ju Lee, MD. However, scheduling concerns related to carfilzomib infusions significantly undermine the safety benefit.

The majority of adverse events (AEs) observed in this study were grade 1 or 2. Grade 3 or 4 AEs were easily managed and were largely hematologic in nature, such as thrombocytopenia and anemia.

There was 1 instance of grade 5 fungal pneumonia noted in 1 of the 8 patients enrolled; however, it is unclear if the death was treatment related, explained Lee.

Despite the intriguing results, the burdensome dosing schedule of carfilzomib infusions on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle has led investigators to shift their attention to the oral agent ixazomib (Ninlaro) in combination with ibrutinib.

"Proteasome inhibition has worked well as a strategy to treat MCL," said Lee. "It has been hindered by peripheral neuropathy associated with bortezomib (Velcade) and dosing-schedule challenges associated with carfilzomib. I feel ixazomib may be a [game-changer] to bring a reasonable proteasome inhibitor strategy to MCL as a combination therapy or as maintenance treatment. That could be a good option that may be introduced into the treatment paradigm."

In an interview with OncLive, Lee, an assistant professor of medicine in the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center, discussed the implications of the phase I results regarding the combination of carfilzomib and ibrutinib in relapsed/refractory MCL.

OncLive: What was the rationale for combining ibrutinib and carfilzomib for patients with MCL?

Lee: We know that proteasome inhibition is a rational way to treat MCL based on the approval of bortezomib for relapsed/refractory disease. It was a natural step to look at carfilzomib, which has a softer toxicity profile than bortezomib—particularly concerning peripheral neuropathy.

It made sense to add carfilzomib to a superstar like ibrutinib. Single-agent ibrutinib offers [a complete response (CR) rate] of about 23% according to a study published in Blood by Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center.

[In this study, we began to ask the question if] carfilzomib could improve upon CR rates without running into the trouble of peripheral neuropathy that was hindering bortezomib.

Mechanistically, combining these agents made sense. Patients who are refractory to/relapse on ibrutinib have overexpression of the nuclear-factor kappa-B (NF-kB) signaling pathway. That can be blocked with carfilzomib. Combining these agents made clinical sense and they do not have overlapping toxicities.

How was this trial designed?

This was a phase I study. Previously, we had published data looking at single-agent carfilzomib that did not show any significant toxicity for patients. This combination was a logical step up.

We knew ibrutinib was active in MCL and carfilzomib was mechanistically sound. By blocking the NF-kB pathway, we could potentially prevent relapses.

We started off with 5 dose levels. The full 28-day cycle course consisted of once-daily at 560 mg plus [56] mg/m2 of intravenous (IV) carfilzomib given on days 1, 2, 8, 9, 15, and 16 for 12 cycles.

[In order to ramp up dosing], we watched for any toxicities. If patients did not have any dose-concerning toxicities, such as grade 3 or 4 nonhematologic adverse events (AEs), we would increase to the next dosing level.

We planned to enroll approximately 30 patients, but due to enrollment difficulties, we were not able to. We enrolled 8 patients.

Patients did not experience any significant toxicities from the combination, but we did have 1 death on the trial. We believe it was related to an infection, but it is unclear whether [or not] it was treatment related.

Could you expand on the enrollment difficulties you faced?

Infusions on days 1, 2, 8, 9, 15, and 16 mean a lot of visits to MD Anderson for our patients. Carfilzomib is given via IV, so patients have to come to the hospital to receive infusions.

The median age of patients who signed up for this trial was approximately 70, which means these patients typically require a caregiver to bring them for treatment. This would be a full-time job for that caregiver. Many of our patients were traveling hundreds of miles for treatment. After 1 or 2 months, it became difficult for caregivers to bring patients to and from the institution.

Additionally, this trial took place during a time when many newer [treatment modalities] like CAR T-cell therapy were coming out. We had a landscape that was getting crowded with other exciting competitors who were fighting for space.

What were the findings of this study?

In terms of toxicities, this was a very well-tolerated regimen. Initially, we were worried about cardiac toxicities. However, we did not see any increases in congestive heart failure or atrial fibrillation in this study.

More than 85% of adverse events noted were grade 1 or 2. Grade 3 toxicities were mostly hematologic in nature, so we were familiar with treating them. Other than the infection, which can occur in many of our relapsed/refractory patients, it was a very well-tolerated combination.

What was the significance of including patients with prior BTK inhibitor therapy?

We felt that this combination won't be able to overcome many of the problems of single-agent [drugs]. As such, we did not want to exclude [patients previously treated with BTK inhibitors]. Many trials investigating ibrutinib or acalabrutinib (Calquence) do exclude patients who previously received BTK inhibitor therapy.

We wanted to see if the combination of ibrutinib and carfilzomib was more powerful than the single agents. We enrolled 5 patients with prior ibrutinib exposure. Of that group, 4 patients responded to the combination. That tells us that the regimen does have an impact for patients who had clinical progression on prior ibrutinib.

That was fairly exciting because by adding carfilzomib we may be able to re-sensitize cells to overcome some ibrutinib resistance the cells may have.

What are the next steps regarding this combination?

This combination is not built into an ecosystem where the patients will actually use it. The 1, 2, 8, 9, 15, and 16—day infusion schedule of carfilzomib is difficult for many patients. That is 6 of 28 days a patient would spend at MD Anderson.

We ran into a lot of difficulties trying to get patients into the hospital to adhere to the program.

[Rather than continue exploring this combination], we are moving on to ixazomib, which is an oral regimen that does not require patients to come into the hospital for infusions. We have a trial that is currently enrolling that is looking at ixazomib plus rituximab (Rituxan) for BTK inhibitor—refractory patients.

We recognize that carfilzomib is a great drug, but many of our patients understand they have many treatment options right now. We need to ensure the delivery of the treatment is reasonable.

We have another trial that will read out fairly soon looking at the combination of carfilzomib, lenalidomide (Revlimid), and rituximab.

Lee HJ, Schmelz JL, Cramer F, et al. A phase I study of carfilzomib in combination with ibrutinib for relapsed refractory mantle cell lymphoma. [published online March 12, 2020]. Br J Haematol. doi: 10.1111/bjh.16378