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抑制PI3K或JAK-STAT通路可能治疗B细胞恶性淋巴瘤，因为它们促进肿瘤生长和存活，作用于肿瘤微环境。阻塞这两个通路可能具有协同作用，因为JAK-STAT增强NFκB通路的BCR活化。
【方法】
这项正在进行的剂量递增研究扩展患者群纳入复发/难治（r/r）B细胞恶性肿瘤。INCB040093单药给药剂量为100-300mg，一天一次（QD）或两次（BID），或给药150-300mg，QD或BID加INCB039110剂量400-600mg，QD。评估药物的安全性，有效性和药物动力学。
【结果】
研究共纳入83名患者：FL n =19；cHL n =17；DLBCL n= 15；CLL/SLLn = 13；其它 n = 19。中位年龄为61岁，70%为男性。先前疗法中位数为4，而且24%的患者接受过HSCT。INCB040093单药和INCB040093+ INCB039110的中位治疗时间分别为185天（范围：5 - 491+）和99天（范围：6 - 337+）。
最常见的不良反应为疲劳（28%），
根据INCB040093剂量较高，肝酶增加，INCB040093+ INCB039110较高剂量时发生血细胞减少，INCB040093 100 mg BID和INCB040093 100 mg BID + INCB039110 400 mg QD被定为扩展患者组剂量。在选定的剂量治疗中，INCB040093最小剂量时，pAKT降低~90%，基于INCB039110，IL6诱导的pSTAT3平均降低65%。75名评估缓解的患者中报道了28名。值得注意的是，r/r cHL患者的ORR为60%（3例CRs），非GCB亚型DLBCL患者发生CRs。
【结论】
INCB040093± INCB039110疗法治疗经大量处理的r/r B细胞恶性肿瘤患者耐受性良好，并能产生缓解，包括CRs。鉴于其疗效，这项研究扩展纳入额外的r/r B细胞恶性肿瘤患者，比如DLBCL和cHL，开始进行r/r cHL患者的II期研究。
英文摘要
Interim analysis of a phase I study of INCB040093, a PI3Kδ inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor, in patients (pts) with relapsed or refractory (r/r) B-cell malignancies.（Abstract No: 8520）
Session Type: Poster Discussion Session
Background:Inhibiting the PI3K or JAK-STAT pathways may be therapeutic in B-cell malignancies due to their contribution to tumor growth and survival and effects on the tumor microenvironment. Blocking both pathways may be synergistic due toJAK-STAT augmentation of BCR activation of the NFκB pathway.
Methods:This ongoing dose escalation study with expansion cohorts enrolled adult pts with r/r B-cell malignancies. INCB040093 was given at doses between 100–300 mg QD or BID alone or 150–300 mg QD or BID with INCB039110 at 400–600 mg QD. Safety, efficacy, and pharmacodynamics were evaluated.
Results:A total of 83 pts have been enrolled: FL n = 19; cHL n = 17; DLBCL n = 15;CLL/SLL n = 13; others n = 19. Median age was 61 years and 70% were men. The median number of prior regimens was 4 and 24% underwent HSCT. Median exposure was 185 days (range: 5 – 491+ [ongoing]) for INCB040093 alone and 99 days(range: 6 – 337+ [ongoing]) for INCB040093 + INCB039110. The most common AEs were fatigue (28%), headache (19%), pyrexia (19%) and the most common grade ≥ 3 AE was pneumonia (6%). The most common laboratory abnormalities were liver enzyme elevations and cytopenias. One pt had a DLT on INCB040093 100 mg BID (GI bleed secondary to gastric DLBCL regression). Doses of INCB040093 100 mg BID and INCB040093 100 mg BID + INCB039110 400 mg QD were selected for expansion cohorts based on the incidence of liver enzyme elevations with INCB040093 and cytopenias with INCB040093 + INCB039110 at higher doses. At the selected doses, pAKT was decreased by ~90% at trough on INCB040093 and IL6-induced pSTAT3 was decreased an average of 65% on INCB039110. Of 75 pts thus far evaluated for a response,28 responses have been reported. Notably, ORR was 60% (3 CRs) for r/r cHL and both pts with the non-GCB subtype of DLBCL had CRs.
Conclusions:Treatment with INCB040093 ± INCB039110 was tolerable and produced responses, including CRs, in pts with heavily pretreated r/r B-cell malignancies. Given this activity, the study was expanded to enroll additional cohorts of pts with r/r B-cell malignancies such as DLBCL and cHL, and a phaseII study in pts with r/r cHL was initiated.
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