Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma
Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma
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依鲁替尼和替莫唑胺、依托泊苷、脂质体多柔比星、地塞米松、利妥昔单抗 (TEDDI-R) 与艾沙康唑递增剂量治疗复发性和难治性原发性中枢神经系统淋巴瘤的 1 期研究
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
W. Wilson
中科院分区：
文献类型：
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作者：
M. Roschewski;C. Melani;R. Lakhotia;S. Pittaluga;J. Phelan;C. Peer;M. Lionakis;L. L. Chou;M. Holdhoff;M. Glantz;J. Drappatz;Catherine Lai;J. Butman;A. Lucas;S. Steinberg;W. Figg;E. Jaffe;S. Ivy;R. Little;L. Staudt;W. Wilson
背景：CNS原发性DLBCL（PCNSL）依赖于慢性活性B细胞受体（BCR）信号传导。伊布替尼通过BTK抑制（BTKi）靶向BCR信号传导，这也可能损害先天免疫。我们发现，伊曲替尼和替莫唑胺，依托泊苷，脂质体阿霉素，地塞米松，利妥昔单抗（TEDDI-R）诱导复发性/难治性PCNSL的持久缓解，但7（39%）患者发生曲霉菌感染，无真菌预防。较新的三唑类药物对曲霉菌有效，但通过CYP 3A 4抑制伊鲁替尼清除。与伏立康唑相比，艾沙康唑对CYP 3A 4的影响较小，肝毒性较小。我们假设，在TEDDI-R中，伊曲替尼和艾沙康唑可以安全地联合给药，并在保持疗效的同时改善曲霉菌的风险。我们在TEDDI-R中研究了递增剂量的伊曲替尼与艾沙康唑，以确定其在复发性/难治性PCNSL中的安全性特征、伊曲替尼PK和临床活性。
方法：入选年龄≥18岁、ECOG PS ≤2、器官功能良好的复发性/难治性PCNSL患者。既往BTKi、HIV、EBV+和妊娠被排除。患者接受基线脑部MRI、FDG-PET脑部和身体检查、Ommaya放置检查、CSF流式细胞术检查和眼部检查。艾沙康唑200 mg BID x 3天在伊曲替尼给药前开始，然后每日200 mg。在每个周期中连续给予三个剂量水平的伊克替尼（280 mg、420 mg、560 mg）。患者接受多达6个周期的TEDDI-R联合IT阿糖胞苷治疗。没有人得到维持或巩固。如果在给定的伊布替尼剂量水平下，前3例患者发生DLT，则在递增剂量前再治疗3例患者。在两个剂量水平后，在递增前审查了完整的安全性和PK数据。计划在最高的伊布替尼剂量水平下扩展10例患者，以确认安全性和临床活性。真菌感染的监测包括第1周期中期和每个周期后的胸部CT沿着血液和CSF中的β-D葡聚糖和曲霉半乳甘露聚糖。在第1、2、4和6个周期后进行脑MRI，以确定缓解并筛查CNS曲霉菌。所有MRI缓解均经FDG-PET和CSF分析证实。监测脑MRI每3个月1次，每4个月1次，每6个月1次，然后每年一次。主要目的是确定在TEDDI-R中与艾沙康唑安全联合给药并达到足够PK浓度的最高剂量。
结果：2018年11月至2020年6月期间入组了13例复发性/难治性PCNSL患者。10例（77%）患者为男性，中位年龄为65岁（范围46-77岁），包括3例≥ 70岁的患者。13例（100%）患者既往接受过高剂量MTX，2例（15%）患者既往接受过自体干细胞移植（ASCT）。3例可评价患者接受了伊鲁替尼280 mg，3例患者接受了伊鲁替尼420 mg，6例患者接受了伊鲁替尼560 mg。280 mg队列中的1例患者不可评价。在49个周期的13例患者中评价了毒性，毒性主要是血液学毒性。G3和G4中性粒细胞减少分别发生在45%和37%的周期中，而发热性中性粒细胞减少发生在8%的周期中。中性粒细胞减少症的中位（范围）持续时间为4.5（1-12）天。1例既往接受过ASCT的患者在4个周期后因骨髓抑制而停止治疗。4个（8%）周期并发≥G3感染，但未观察到机会性感染（包括曲霉菌）。G3和G4血小板减少症分别发生在22%和8%的周期中，1例患者发生黑便，无明显GI出血。≥G3粘膜炎发生在6%的周期中，1例患者在5个周期后因复发性粘膜炎而停止治疗。掌跖红细胞感觉迟钝导致9例（69%）患者的多柔比星脂质体剂量降低，但仅发生1例G3事件。12例患者的缓解可评价，11例（92%）患者在仅接受1个周期治疗后缓解（图1）。完成至少4个周期的所有8例（100%）患者均达到CR，另外4例仍在接受治疗。6例（75%）达到CR的患者保持缓解，2例（25%）患者在停止治疗后3个月内复发。中位潜在随访时间为5.2个月后，1年PFS估计为60.0%（95% CI，12.6-88.2），OS为100%。
结论：在TEDDI-R中，伊布替尼560 mg与艾沙康唑联合给药治疗复发性/难治性PCNSL是安全的。未观察到DLT，未发生曲霉菌病例，也未出现新的安全性信号。前8例（100%）完成治疗的患者达到完全缓解。这项正在进行的研究（NCT 02203526）的更新临床结果将在会议上提交。
赖：艾伯维：咨询公司;阿吉奥斯：咨询公司;爵士：发言人局;宏观：咨询公司;安斯泰来：发言人局。
Background: Primary DLBCL of the CNS (PCNSL) relies on chronic active B-cell receptor (BCR) signaling. Ibrutinib targets BCR signaling through BTK inhibition (BTKi), which may also impair innate immunity. We showed that ibrutinib and temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL but 7 (39%) pts developed Aspergillus infections without fungal prophylaxis. Newer triazoles are effective against Aspergillus but inhibit ibrutinib clearance through CYP3A4. Isavuconazole has less effect on CYP3A4 and less hepatotoxicity than voriconazole. We hypothesized that ibrutinib and isavuconazole could be safely co-administered in TEDDI-R and ameliorate the risk of Aspergillus while maintaining efficacy. We studied escalating doses of ibrutinib in TEDDI-R with isavuconazole to determine the safety profile, ibrutinib PK, and clinical activity in relapsed/refractory PCNSL.
Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2, and adequate organ function were enrolled. Previous BTKi, HIV, EBV+, and pregnancy were excluded. Pts had baseline MRI brain, FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole 200mg BID x 3d started prior to ibrutinib then 200mg daily. Three dose levels of ibrutinib (280mg, 420mg, 560mg) were given continuously through each cycle. Pts received up to 6 cycles of TEDDI-R with IT cytarabine. No one received maintenance or consolidation. If a DLT occurred in the first 3 pts at a given ibrutinib dose level, 3 more pts were treated before escalating. Full safety and PK data was reviewed after two dose levels prior to escalating. An expansion of 10 pts was planned at the highest ibrutinib dose level to confirm safety and clinical activity. Surveillance for fungal infections included chest CT mid-cycle 1 and after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI was performed after cycles 1, 2, 4, and 6 to determine response and screen for CNS Aspergillus. All remissions by MRI were confirmed with FDG-PET and CSF analysis. Surveillance brain MRI were q3m for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the highest dose of ibrutinib safely co-administered with isavuconazole in TEDDI-R that achieves adequate PK concentrations.
Results: 13 relapsed/refractory PCNSL pts enrolled between 11/2018 and 06/2020. 10 (77%) pts were male and the median age was 65 (range 46-77), including 3 pts ≥age 70. 13 (100%) pts had prior high-dose MTX, and 2 (15%) pts had prior autologous stem cell transplant (ASCT). Three evaluable pts received ibrutinib 280mg, 3 pts received ibrutinib 420mg, and 6 pts received ibrutinib 560mg. One pt in the 280mg cohort was not evaluable. Toxicity was evaluated in 13 pts across 49 cycles and the toxicity was mainly hematologic. G3 and G4 neutropenia occurred in 45% and 37% of cycles, respectively, while febrile neutropenia occurred in 8% of cycles. The median (range) duration of neutropenia was 4.5 (1-12) days. One pt with prior ASCT stopped after 4 cycles due to myelosuppression. Four (8%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. G3 and G4 thrombocytopenia occurred in 22% and 8% of cycles, respectively, and 1 pt developed melena with no overt GI bleeding. ≥G3 mucositis occurred in 6% of cycles and 1 patient stopped therapy after 5 cycles due to recurrent mucositis. Palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 9 (69%) pts, but only 1 G3 event occurred. Twelve pts were evaluable for response, and 11 (92%) pts have responded and all after receiving only 1 cycle (Figure 1). All 8 (100%) pts who have completed at least 4 cycles have achieved CR and the other 4 remain on therapy. Six (75%) pts who achieved CR remain in remission while 2 (25%) pts relapsed within 3 months of stopping therapy. After a median potential f/u of 5.2 months, the 1-year PFS is estimated at 60.0% (95% CI, 12.6-88.2) and the OS is 100%.
Conclusions: Ibrutinib 560mg was safely co-administered with isavuconazole in TEDDI-R for relapsed/refractory PCNSL. No DLTs were observed, no cases of Aspergillus occurred, and no new safety signals. The first 8 (100%) patients who have completed therapy achieved complete response. Updated clinical results from this ongoing study (NCT02203526) will be presented at the meeting.
Lai: Abbvie: Consultancy; Agios: Consultancy; Jazz: Speakers Bureau; Macrogenics: Consultancy; Astellas: Speakers Bureau.