A Phase I Dose-Escalation Study of Carfilzomib in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis
Authors: Cohen Adam D. , Scott Emma C. , Liedtke Michaela , Kaufman Jonathan L. , Landau Heather , Vesole David H. , Gomes Christina L. , Gasparetto Cristina , Lentzsch Suzanne , Rosenzweig Michael , Sanchorawala Vaishali , Smith David D. , Comenzo Raymond L. , Durie Brian G. M. 
Published: October 2019

Abstract
Background: The proteasome inhibitor (PI) bortezomib is active in AL amyloidosis. Carfilzomib (CFZ) is a novel irreversible PI approved for relapsed/refractory multiple myeloma, with less neurologic toxicity than bortezomib, but its safety and efficacy in AL amyloidosis is not known. We report the first results of a multi-center, Phase I, dose-finding study of CFZ in AL (NCT01789242).
Methods: Patients had relapsed AL after ≥1 prior therapy. Patients with advanced cardiac involvement (Mayo stage III, LVEF<40%, or NYHA Class III/IV) were excluded. A standard 3+3 dose escalation schedule was used, with planned cohorts of 27, 36, 45, and 56 mg/m2. CFZ was given as a 30-minute infusion on days 1, 2, 8, 9, 15, 16 of a 28-day cycle, starting at 20 mg/m2 on cycle 1, days 1,2, then escalating starting day 8. Primary objectives were safety, tolerability, and determination of MTD. DLTs were defined in Cycle 1 only. Adverse events (AEs) were graded by NCI-CTCAE v4. Serial echocardiograms were performed at baseline, after cycle 3, and every 4 cycles thereafter. Hematologic and organ responses were assessed by updated AL Consensus criteria. Dexamethasone 20mg with each CFZ dose was added for patients without VGPR after cycle 4. After 8 cycles, patients could continue on a reduced-frequency (day 1, 2, 15, 16) schedule at investigator discretion. Two expansion cohorts (PI-naïve and PI-exposed, n=12 each) are currently enrolling at MTD.
Results: As of 7/17/14, 12 patients have enrolled. Median age was 62 (range 58–81); 50% were male. Median time from diagnosis was 2.8 years, with median of 2 prior regimens (range 1-4). Eleven patients (92%) had prior bortezomib (5 were refractory); 50% prior IMiDs; 50% prior stem cell transplant. Median # of involved organs was 1 (range 1-2), including 5 patients with heart, 5 kidney, 1 liver, 2 GI tract, and 4 peripheral/autonomic nerve. Median NT-proBNP was 854 pg/ml (range 93 – 9702); 3 and 9 patients were Mayo cardiac stage I and II, respectively. Three patients each were treated at 20/27 and 20/36 mg/m2, with no DLTs. In the 20/45 mg/m2 cohort, there were 2 DLT's of grade 3 fatigue ≥7 days in 4 patients, establishing 20/36 mg/m2 as the MTD. Two additional patients have enrolled at MTD in the PI-exposed expansion cohort. Median number of cycles is 5 (range 1+-13+), with 7 patients still on study, and 5 discontinuing (3 AE, 2 patient withdrawal). Drug-related AEs occurring in >20% of patients (n=11 evaluable) included fatigue (45%), nausea (36%), anemia, dyspnea, and diarrhea (27% each). Seven patients had at least one Grade ≥3 AE (any cause), including cardiac events (n=4 patients), fatigue (n=3), diarrhea (n=2), and nausea, hypoalbuminemia, and pneumonia (n=1 each). There have been 3 cardiac events possibly related to drug: 1 grade 4 cardiac arrest due to ventricular tachycardia during cycle 5; 1 grade 4 restrictive cardiomyopathy and CHF after cycle 3 (with negative endomyocardial biopsy for amyloid); 1 grade 3 drop in ejection fraction after cycle 7. Rising NTproBNP levels correlated with clinical and/or echocardiographic manifestations of CHF in these latter 2 patients. A 4th patient had exacerbation of atrial fibrillation during pneumonia, deemed unrelated. No deaths have occurred. Of 9 evaluable patients, 7 have responded hematologically, including 6 VGPR (≥PR rate=78%; Table 1). Responses have been seen at all dose levels, with median response duration of 3.8 months (range 0.3+ –10.9+) and no hematologic progression. Two patients had dexamethasone added after cycle 4, both improving response to VGPR. With median follow-up of 5.1 months (range 0.2 to 12.3), no organ responses have yet been observed.
Conclusions: Carfilzomib monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Cardiac events are common in this population, and may be related to drug, underlying disease or both, suggesting a role for monitoring with cardiac biomarkers and serial echocardiograms. Preliminary hematologic response rates are promising in this bortezomib-exposed population, and organ assessments are ongoing. Further study is warranted.
Table 1: Preliminary response data Carfilzomib Dose Cohort Hematologic response 20/27 (n=3) 20/36 (n=5) 20/45 (n=4) Total (n=12) VGPR 2 1* 3** 6 PR 0 1 0 1 SD 1 0 1 2 Not evaluable/ too early 0 3 0 3
*Dex added. **1 had dex added. Never escalated above 20mg/m2

Disclosures
Cohen: Celgene: Member, Independent Response Adjudication Committee Other; Janssen: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Onyx Pharmaceuticals: Advisory Board, Advisory Board Other. Off Label Use: Carfilzomib treatment in amyloidosis . Scott:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Merck: Research Funding. Landau:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Onyx Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Gasparetto:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Rosenzweig:Celgene: Speakers Bureau. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Comenzo:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Durie:Millennium Pharmaceuticals: IRC, IRC Other; Onyx Pharmaceuticals: IRC Other.