A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma: Final analysis of second dose‐expansion cohort

Abstract The maximum tolerated dose of the panobinostat and carfilzomib combination in patients with relapsed/refractory multiple myeloma (RRMM) was not reached in our previous dose‐escalation study. We report additional dose levels in the phase I/II, single‐arm, multicenter, standard 3 + 3 dose‐escalation expansion‐cohort study (NCT01496118). Patients with RRMM were treated with panobinostat 30 mg, carfilzomib 20/56 mg/m2 (N = 3), or panobinostat 20 mg, carfilzomib 20/56 mg/m2 (N = 33). Treatment cycles lasted 28 days; panobinostat: days 1, 3, 5, 15, 17, 19; carfilzomib: days 1, 2, 8, 9, 15, 16. For dose level 6 (DL 6), median age was 63 years (range, 49–91 years), 60.6% were male, 42.4% were high risk. Patients received a median of two prior therapies (range 1–7); proteasome inhibitors (PI; 100%), immunomodulatory imide drugs (IMiD; 78.8%), and stem cell transplant (36.4%); 48.5%, 51.1%, and 24.2% were refractory to prior PI or prior IMiD treatment or both, respectively. Patients completed a median of seven (range 1–40) treatment cycles. Overall response rate (primary endpoint) of evaluable patients in the expansion cohort (N = 32): 84.4%; clinical benefit rate: 90.6%. With a median follow‐up of 26.1 months (range, 0–72.5 months), median (95% CI) progression‐free survival, time‐to‐progression and overall survival of patients was 10.3 (6.1, 13.9), 11.7 (5.6, 14.5), and 44.6 (20.8, N/A) months, respectively. Common adverse events (AEs) included thrombocytopenia (78.8%), nausea (63.6%), fatigue (63.6%), diarrhea (51.5%), and vomiting (51.5%). Seven patients had serious treatment‐related AEs. There was one treatment‐related death. In conclusion, panobinostat plus carfilzomib is an effective steroid‐sparing regimen for RRMM.

majority of patients will eventually progress and more treatment options are needed. Panobinostat is a pan-histone deacetylase inhibitor (HDACi) that affects multiple cellular pathways, has the ability to resensitize refractory MM cells, and has demonstrated synergistic effects with PIs in preclinical studies. [4][5][6] The MM cells are highly dependent on the proteasome system to degrade proteins 7 ; however, chronic exposure to PIs can cause aggresome formation, which contributes to acquired resistance and results in a poor prognosis for patients. 8 Panobinostat enhances the anti-MM activity of PIs by inhibiting the aggresome protein degradation pathway via acetylation of proteins involved in multiple oncogenic pathways. 6 Panobinostat is approved for the treatment of relapsed/refractory MM (RRMM) in combination with bortezomib and dexamethasone in patients who have received ≥2 prior lines of therapy, including bortezomib and an IMiD. 9 This regimen was approved based on the results of the PANO-RAMA 1 study sub-group analysis, which demonstrated improved efficacy in refractory patients. 10 However, the study dosed bortezomib intravenously (IV), and high incidences of grade 3/4 hematological and gastrointestinal toxicities were reported. 10 Thus, new treatment combinations of agents with minimal overlapping toxicities are of great interest to reduce the treatment burden for patients. Carfilzomib is a second-generation PI approved as a single agent with or without dexamethasone, and in combination with lenalidomide and dexamethasone. 11 Carfilzomib has a toxicity profile different than the first-generation PI, bortezomib. 12,13 In particular, carfilzomib induces less peripheral neuropathy (PN) than bortezomib but is associated with an elevated risk of cardiovascular adverse events (AEs), including heart failure, hypertension, ischemia, and arrhythmia, as well as pulmonary, renal, and thromboembolic AEs, such as dyspnea, acute kidney injury, and deep vein thrombosis/pulmonary embolism. [13][14][15] We previously reported the results from our dose-escalation and doseexpansion study of the steroid-sparing combination of panobinostat and carfilzomib in 44 patients with RRMM. 16 In this study, the maximum tolerated dose (MTD) was not reached with the four initially planned dose levels.
The highest dose level used for the dose-expansion cohort in the phase II part of the study was panobinostat 30 mg administered three times weekly (TIW), and carfilzomib 20/45 mg/m 2 . However, the panobinostat dose was often reduced, resulting in an average dose delivery of 23.6 mg in patients starting at 30 mg. Since our phase II expansion cohort publication, studies have shown that higher carfilzomib doses are feasible on a twice-weekly schedule in the RRMM setting. 13 The phase III ENDEAVOR study led to the approval of carfilzomib at 56 mg/m 2 given twice weekly with dexamethasone in patients with RRMM. 11,13 Taking into account these data and our prior experience with panobinostat dose reductions, which suggested that carfilzomib dosing may be optimized by capping the dose of panobinostat at 20 mg TIW, our original study was extended. Here, we report the results of two additional dose levels and a subsequent dose-expansion cohort.

| Study design
The primary study design, enrollment criteria, study procedures, and assessments have been reported previously. 16  participating sites and patients were enrolled following written informed consent.

| Patients
As reported previously, 16

| Treatment procedures
Two dose-escalation levels were planned (  19 Note, TTP was defined as the interval between first administration of study treatment and tumor progression or last adequate tumor assessment. So, PFS was defined as the interval between first administration of study treatment and disease progression or last assessment/follow-up, or death due to any cause. Overall survival was defined as the interval from first study treatment until last assessment/follow-up, or death.

| Statistical analyses
The efficacy analysis included all patients who received one or more dose(s) of both carfilzomib and panobinostat and underwent one or more response assessment. The remaining patients did not receive any steroids as part of their treatment or as premedication.

| Efficacy outcomes
All reported efficacy data below refer to the DL 6 cohort (N = 33).
However, one patient in the DL 6 cohort was not evaluable for efficacy outcomes as he or she did not receive a dose of carfilzomib before discontinuing treatment.

| Overall safety outcomes
All patients in DL 6 cohort (N = 33) were evaluable for safety outcomes.  16 In our previous study of the combination using lower doses of carfilzomib, the ORR for all patients was 67%, and after a median follow up of 17 months, median PFS was 7.7 months, median TTP was 7.7 months, and the median OS had not been reached. 16 Although the two studies were initiated at similar times, compared with the initial study, 16 the patient population in the expansion cohort presented here was not as heavily pretreated (median number of prior therapies: five vs two), but a higher proportion of patients were refractory to their prior treatments (either PI or IMiD: 52% vs 75.8%; both PI and IMiD: 14% vs 24.2%). Due to changes in standard of care, more complex combination regimens are being used as first-line and second-line therapy, and maintenance treatment is frequently used in the frontline setting. As such, patients are likely to receive fewer prior lines of therapy before developing refractory disease and requiring novel combinations such as panobinostat and carfilzomib. However, together these data suggest that the panobinostat and carfilzomib combination has the potential to be used before or after the many combination regimens available today, regardless of the number of prior treatment lines.
Although approximately 20% of the population in the current study were over 75 years old, and as such may have been more frail and susceptible to AEs, grade 3/4 AEs were infrequently reported. The most common grade 3/4 AEs in the current study included thrombocytopenia (60.6%), fatigue (18.2%), anemia (12.1%), and dyspnea (12.1%). With the exception of thrombocytopenia, grade 3/4 AE incidences appear to be similar to those we reported previously and in the ENDEAVOR study, and less frequent than those reported with other PI combinations. 16  The majority of patients on this trial were carfilzomib-naïve and thus the efficacy of this combination in carfilzomib-exposed or refractory patient is unknown. This could limit the utility of this combination especially considering recent data from the CANDOR and IKEMA trials with carfilzomib and anti-CD38 antibody combinations. 27 Early studies have produced limited data but nothing conclusive. 29

| CONCLUSION
The combination of panobinostat and carfilzomib is an effective steroid-sparing regimen with a reasonable safety profile in this relapsed/refractory population. Further evaluation of this combination and as a backbone to triplet/quadruplet therapies is warranted.

ACKNOWLEDGMENTS
The authors thank all patients involved in the study, as well as investi-

AUTHOR CONTRIBUTIONS
All authors contributed to patient enrolment and data collection; interpretation of data; manuscript review, and approval.

DATA AVAILABILITY STATEMENT
All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.