Effect of Isavuconazole on Plasma and CSF Levels of Ibrutinib and Plasma Levels of Liposomal Doxorubicin Among Patients Receiving Teddi-R for CNS Lymphoma

Background: Ibrutinib is an oral BTK inhibitor that is highly effective for B-cell lymphomas and chronic graft versus host disease. Escalating doses of ibrutinib were highly active and achieved good CNS penetration when added to temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) in primary CNS lymphoma (PCNSL) but was associated with aspergillosis (Lionakis Cancer Cell 2017). To prevent aspergillosis, we added the antifungal agent isavuconazole (isa) to the TEDDI-R regimen, but it is a moderate inhibitor of CYP3A4 and inhibits ibrutinib clearance. We performed a new dose escalation study of ibrutinib with concomitant isavuconazole and TEDD-R in PCNSL with a dose expansion cohort. In a separate study, we tested fixed doses of ibrutinib with TEDD-R in secondary CNS lymphoma (SCNSL) with pharmacokinetic (PK) sampling from plasma and cerebrospinal fluid (CSF). Herein we present the PK of ibrutinib in plasma and CSF from both ongoing studies along with plasma PK of liposomal doxorubicin.

Methods: Patients with untreated and relapsed/refractory PCNSL enrolled onto the phase 1 trial of TEDDI-R with isa in a standard 3+3 fashion testing three dose levels of ibrutinib: DL1=280 mg, DL2=420 mg, and DL3=560 mg. Patients with untreated and relapsed/refractory SCNSL were enrolled onto a phase 2 trial of TEDDI-R with isa and a fixed dose of ibrutinib 560 mg. Isa was started ≥3 days before ibrutinib and continued throughout combination therapy of 4 to 6 cycles. At the first dose of ibrutinib, patients with PCNSL underwent plasma and CSF sampling at the following timepoints: pre-dose, then 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10-18 hr (one sample in this timeframe), and 24 hr post-dose. Patients with SCNSL underwent plasma sampling at pre-dose, 1 hr, and 10-18 hr (one sample in this timeframe) after the first ibrutinib dose. All patients also had steady-state (≥4 prior ibrutinib doses) plasma and CSF sampling at pre-dose and 2 hr post-dose. Plasma sampling for liposomal doxorubicin (dose range 30-50 mg/m²) occurred at pre-dose and at 5-8 hours post-dose. Concentrations were measured using LC-MS/MS (Frontage Laboratories and NCI). PK parameters were estimated using non-compartmental methods.

Results: 55 consecutive patients (30 PCNSL, 25 SCNSL) were included for analysis. Among the 30 patients with dense first-dose sampling, the T_max was 2.05 hr (SD 1.06, n=30), T_1/2 8.3 hr (median 6.2 hr, SD 6.4, n=26), volume of distribution 13121 L (median 10756, SD 11422, n=24), and clearance 1560 L/hr (median 1093, SD 1397, n=24) (patients with r²<0.9 excluded). There was wide interpatient variability in ibrutinib PK. In both the plasma and CSF, ibrutinib 560 mg + isa had a higher AUC, C_max, and steady-state peak concentration than 560 mg alone. Compared to 700 mg and 840 mg alone, 560 mg + isa had a similar AUC and C_max in the plasma, but a higher steady-state peak plasma concentration. In the CSF, 560 mg + isa had a similar AUC and C_max but higher steady-state peak concentration compared to 700 mg alone, and a higher AUC and C_max but similar steady-state peak concentration compared to 840 mg alone (Tables 1 and 2). Peak (5-8 hours post-dose) plasma concentrations of liposomal doxorubicin were not significantly different with isa versus without isa (dose-normalized geometric mean ratio 0.94, 95% CI 0.80-1.08, n=82 data points).

Conclusions: Isavuconazole increases the plasma and CSF exposure of ibrutinib approximately 2-fold, allowing for similar or improved CNS penetration at 560 mg compared to what was previously observed with ibrutinib 700 mg and 840 mg without isavuconazole. Further development of the TEDDI-R regimen utilizes ibrutinib 560 mg as the target dose along with isavuconazole. Plasma concentrations of liposomal doxorubicin were not significantly affected by isavuconazole.

No relevant conflicts of interest to declare.