https://www.ajmc.com/compendium/hematology/study-summary-ibrutinib-plus-carfilzomib-for-relapsed-or-relapsedrefractory-multiple-myeloma
Study Summary: Ibrutinib Plus Carfilzomib for Relapsed or Relapsed/Refractory Multiple Myeloma

Chari A, Larson S, Holkova B, et al. Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma [published online April 4, 2018]. Leuk Lymphoma. 2018:1-7. doi: 10.1080/10428194.2018.1443337.

Background
Patients with multiple myeloma (MM) commonly experience relapsed disease; these patients are often older and may have decreased performance status, comorbidities, and toxicities from prior therapies or the disease itself. Additionally, relapse is frequently characterized by more aggressive disease. Optimal treatment for relapsed MM is uncertain.1

Myeloma cells are reliant on signal transduction pathways within the bone marrow microenvironment to grow and survive. Bruton’s tyrosine kinase (BTK), which is expressed in more than 85% of MM cells, may contribute to the development of drug resistance. Preclinical work using malignant plasma cells from patients with MM showed that ibrutinib, a first-in-class BTK inhibitor, had synergistic effects when given with bortezomib and lenalidomide. Treatment with ibrutinib in a mouse model resulted in a decrease in the number and activity of osteoclasts and a suppression of tumor growth. The combination of ibrutinib with dexamethasone in human patients has also demonstrated durable clinical activity.1

This phase 1 trial evaluated the combination of ibrutinib with carfilzomib, a next-generation, selective, and irreversible proteasome inhibitor (PI) that is approved for patients with MM who have been treated with multiple lines of therapy.1

Study Design
This open-label, multicenter study evaluated the use of ibrutinib in combination with carfilzomib, with or without dexamethasone, in patients with relapsed or refractory MM. Participants were required to have measurable disease and symptomatic relapsed and refractory MM; they also had to have received ≥2 prior lines of therapy (bortezomib and immunomodulatory agent [IMiD]). This phase 1 study followed a 3 + 3 dose escalation design. There were 4 cohorts: cohort 1 (dose escalation), cohort 2a (dose escalation), cohort 2b (dose expansion), and cohort 3b (dose expansion).1

Treatment was administered in 28-day cycles. Ibrutinib was administered orally once daily at 560 mg or 840 mg starting on day 8 of cycle 1. Carfilzomib was administered intravenously on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle through cycle 12; in subsequent cycles, carfilzomib was given on days 1, 2, 15, and 16. On days 1 and 2 of cycle 1, carfilzomib was dosed at 20 mg/m2. If tolerated, the dose was increased to 27 mg/m2 or 36 mg/m2 at day 8 and beyond. Oral dexamethasone was administered in cohorts 2b and 3b on days 1, 2, 8, 9, 15, 16, 22, and 23 at a dose of 20 mg for patients younger than 75 years and 10 mg for patients 75 years and older.1

The primary objective was to determine the maximum tolerated dose (MTD) of combination therapy, toxicities associated with combination therapy, and the recommended dose for phase 2 studies. Secondary objectives included assessment of objective response rate (ORR: complete responses plus partial responses) and duration of response (DoR).1

Results
Baseline Patient Characteristics
Across all dose cohorts, baseline patient characteristics were similar; the median age was 63 years and the median time from diagnosis was 4.2 years. Patients had received a median of 3 prior lines of therapy. All patients were refractory to previous therapies (bortezomib, 74%; lenalidomide, 72%; pomalidomide, 28%; both PI and IMiD, 60%). The great majority of patients (88%) were refractory to their most recent treatment line, which included bortezomib approximately half of the time (53%). All patients who were refractory to their most recent treatment line with bortezomib were actively progressing.1

Efficacy
Forty-three patients were enrolled in 4 cohorts: cohort 1 (n = 3), cohort 2a (n = 5), cohort 2b (n = 17), and cohort 3b (n = 18). One patient in cohort 3b discontinued treatment prematurely, leaving 42 patients evaluable for response. Patients spent a median of 20.5 months on the study.1

Overall Population: Among the 42 patients evaluated, ORR was 67% and the clinical benefit rate was 76%. Best overall responses include: stringent complete response (2%), very good partial response (21%), partial response (43%), and minimal response (10%). Twenty-eight patients achieved at least a partial response, with a median DoR of 12.9 months. The median follow-up was 20.5 months and the median progression-free survival (PFS) was 7.2 months. The estimated 1-year PFS rate was 35%. A total of 29% of patients having at least a partial response were alive without progressive disease. The median overall survival for all patients was not reached.1

Patients Refractory to Both PI and IMiD: ORR was 70% and median DoR was 6.4 months. Median PFS was 6.4 months, with an estimated 1-year PFS of 33%.1

High-Risk (del17p and/or t4;14) Patients: ORR was 78% and median DoR was 9.1 months. Median PFS was 8.1 months, with an estimated 1-year PFS of 30%.1

Expansion Cohorts: Median DoR was 9.1 months in cohort 2b and 7.2 months in cohort 3b. In patients who were refractory to bortezomib in cohorts 2b and 3b, ORR was 73% with a median DoR of 9.1 months. Median PFS was 8.1 months in cohort 2b and 6.4 months in cohort 3b. Estimated 1-year PFS was 33% in both cohorts.1

Safety
Forty-three patients were included in the safety population. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 37 patients experienced grade ≥3 TEAEs. During dose escalation, no dose-limiting toxicities were observed. Hematologic adverse events (AEs) included anemia (any grade, 35%; grade ≥3, 19%), thrombocytopenia (any grade, 28%; grade ≥3, 12%), and neutropenia (any grade, 9%; grade ≥3, 7%). Hypertension (23%), pneumonia (19%), fatigue (16%), and diarrhea (14%) were the most commonly reported nonhematologic grade ≥3 AEs. Grade 3 peripheral neuropathy (n = 2), renal events (n = 3), and rash (n = 3) were also reported.1

There were 13 dose reductions in the study (ibrutinib, n = 5; carfilzomib, n = 8). One patient was still receiving study treatment at the time of this analysis. Treatment was discontinued in 29 patients due to progressive disease (n = 18), AEs (n = 13; grade ≥3 pneumonia and cardiac events were the most common), investigator decision (n = 5), and patient withdrawal (n = 6). Thirteen patients died.1

Pharmacokinetics/Pharmacodynamics
Rapid absorption and elimination were observed after ibrutinib was administered. When coadministered with carfilzomib and dexamethasone, systemic exposure of ibrutinib trended higher than when administered with dexamethasone only.1

Conclusion
The results of this study demonstrated that ibrutinib in combination with a PI and dexamethasone had a manageable safety profile. Neither dose-limiting toxicities nor new safety signals were identified in the study. The MTDs for combination therapy were established as ibrutinib 840 mg and carfilzomib 36 mg/m2, with dexamethasone dosing being adjusted for age.1












Reference
1. Chari A, Larson S, Holkova B, et al. Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma [published online April 4, 2018]. Leuk Lymphoma. 2018:1-7. doi: 10.1080/10428194.2018.1443337.

 
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