PI3K与mTOR双重抑制剂XL765的相关信息

赛诺菲-安万特与Exelixis签署癌症药物合作协议

2009-5-31,赛诺菲-安万特与生物技术公司Exelixis签署了一项XL147与XL765的全球授权许可协议，同时建立了一项独家合作关系，旨在发现治疗恶性实体肿瘤的磷脂酰肌醇-3激酶（PI3K）抑制剂。

根据协议，赛诺菲-安万特将获得口服PI3K抑制剂XL147及口服PI3K与mTOR双重抑制剂XL765的全球授权。目前，这两种化合物均在进行Ⅰ期临床试验。赛诺菲-安万特将全权负责接下来的全部临床试验、监管审批、生产及销售活动。Exelixis将参加正在进行的及未来可能的临床试验。此外，两家公司将共同努力建立若干与PI3K选择性抑制剂相关的临床前项目。

对于现有及未来的项目，赛诺菲-安万特将支付Exelixis现金及开发和阶段性付款总计超过10亿美元。

赛诺菲-安万特高级研发副总裁MarcCluzel表示：“我们很高兴在我们的产品组合中加入这一具有高治疗潜力的新型靶向治疗药物。我们期待结合我们的努力与Exelixis开发出对癌症患者有利的创新药物。此次的合作符合我们通过战略合作伙伴关系提供新型治疗选择，创造价值的战略目标。”
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XL765是喹恶啉(quinoxaline)的衍生物,临床前试验表明,XL765能抑制PI3K和mTOR。
相关临床：
Ⅰ/Ⅱ期临床
SAR245409/ XL765
与替莫唑胺联用治疗多形性恶性胶质瘤
A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas
http://www.clinicaltrials.gov/ct ... m=xl-765&rank=5
与厄洛替尼联用治疗非小细胞肺癌
Safety Study of XL765 (SAR245409) in Combination With Erlotinib in Adults With Solid Tumors
http://www.clinicaltrials.gov/ct ... m=xl-765&rank=4
专利下载：

官方网站：
http://www.exelixis.com/pipeline/xl765
合成方案：
磷脂酰肌醇_3_激酶_PI3K_抑制剂XL765的合成.pdf (301.43 KB, 下载次数: 43)

2012-12-12 11:31 上传

点击文件名下载附件

这个副作用会不会很大。

A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors.
2010 ASCO Annual Meeting
Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mechanism of resistance to EGFR inhibitors. XL765 is an oral, selective inhibitor of Class I PI3Ks, TORC1, and TORC2. In preclinical studies, XL765 has demonstrated dose-dependent target modulation in tumor xenograft models. Methods: Pts with advanced solid tumors are enrolled in successive cohorts to receive escalating doses of XL765 in combination with E. After the preliminary MTD has been defined, 9-12 additional pts with NSCLC will be enrolled. Cycles consist of 28 days of XL765 qd or bid and E qd. Pts enrolled into the dose escalation cohorts have a 14-day E monotherapy run-in with PK sampling. Tumor response is evaluated every 8 weeks. Results: 21 pts with advanced solid tumors have been enrolled at four dose levels of XL765 (30, 50, and 70 mg qd and 20 mg bid) in combination with 100 mg E. Thirteen of the 14 NSCLC pts enrolled had prior treatment with E. No dose limiting toxicities have been reported. The most common (≥ 10%) treatment-related adverse events (AEs) were skin and subcutaneous tissue disorders (including rash) and diarrhea. Grade 3 AEs related to study treatment were observed in 1 pt: nausea, vomiting, anorexia and AST increased. No grade 4 events were reported. Based on comparison with historical single agent data, no major PK interaction between XL765 and E has been observed. In skin and tumor biopsies, substantial post-dose reductions were evident in phosphorylation of AKT, 4EBP1, ERK, and EGFR. For example, reductions in pAKT-T308 (57%), p4EBP1 (60%), pERK (61%), and pEGFR (38%) were evident in tumor biopsies from a NSCLC adenocarcinoma pt previously treated with E after administration of 30 mg qd XL765/100 mg E for 21 days. Four NSCLC pts with prior E (3 had progressed on E) have been on study for 16 to 45+ weeks. Conclusions: XL765 in combination with E is generally well tolerated at daily doses up to 50 mg XL765/100 mg E with no apparent PK interaction, and results in robust inhibition of PI3K and EGFR signaling in skin and tumor tissue. The MTD has not yet been determined.

A phase I safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with newly diagnosed malignant glioma.
2010 ASCO Annual Meeting
Background: PI3K pathway dysregulation has been implicated in resistance to TMZ in preclinical glioma models. XL765, a potent and selective inhibitor of class I PI3K isoforms and TORC1 and TORC2, has demonstrated dose-dependent target modulation in both tumor xenograft models and in normal brain tissue in preclinical studies. Methods: Pts with WHO grade III and IV astrocytic tumors who have received standard chemoradiation with TMZ followed by at least one cycle of maintenance TMZ (200 mg/m2/day × 5 q 28 days) are eligible. XL765 is dose escalated following a standard 3 + 3 design and administered in combination with a fixed dose of TMZ. Results: 18 pts have been treated with XL765 in combination with TMZ across 4 dose levels of XL765 (30, 40, 50, and 60 mg qd). The maximum administered dose (MAD) of XL765 is 60 mg for the qd schedule; 2 of 6 pts experienced DLTs. The most common (≥ 10%) treatment-related AEs were nausea, hyperglycemia, constipation, fatigue, thrombocytopenia, and skin disorders. Grade ≥ 3 treatment related AEs were observed in four pts: grade 3 brain edema and grade 4 thrombocytopenia (one pt, also reported as a DLT), grade 3 rash (one pt, also reported as a DLT), grade 3 thrombocytopenia (one pt), and grade 4 increased transaminases (one pt). Based on comparison with single agent data, no major PK interaction between XL765 and TMZ is evident. At the 30 and 40 mg qd XL765 dose levels, inhibition of PI3K pathway (pAKT-T308, pAKT-S473, and p4EBP1) signaling has been demonstrated in skin. Based on assessment of archival tumor material, the most common molecular alterations detected include MGMT promoter methylation, PTEN point mutations, and EGFR gene amplification. Of the first 18 pts enrolled, seven pts have remained on study for > 16 weeks, one of whom continued on study for 62 weeks. Conclusions: XL765 in combination with TMZ is generally well tolerated at doses up to 40 mg qd. There is no apparent PK interaction between XL765 and TMZ. MTD determinations for qd and bid schedules are ongoing.

A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies.
2010 ASCO Annual Meeting
Background: XL765 is a potent and selective inhibitor of class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 twice daily (bid) or daily (qd) for 28-day cycles. Dose escalation follows a standard 3 + 3 design. PK and pharmacodynamic biomarker analyses are performed. Tumor response is assessed by RECIST every 8 weeks. A cohort of lymphoma pts will be enrolled to explore the potential utility of combined inhibition of PI3K and TORC1/2 in this disease setting. Results: 79 pts have been dosed with XL765; 52 pts on a bid regimen (30-240 mg/day) and 27 pts on a qd regimen (70-100 mg/day). On the bid schedule, 25 subjects have been treated at the established maximum tolerated dose (MTD) of 50 mg bid. The maximum administered dose (MAD) is 120 mg bid. On the qd schedule, the MAD is 100 mg and the preliminary MTD is 90 mg. The most common related adverse events (> 10% of pts) were nausea, diarrhea, anorexia, elevated liver enzymes, skin disorders, and vomiting. Drug-related ≥ grade 3 AST/ALT elevation occurred in four pts (three pts initially dosed at 120 mg bid and one pt initially dosed at 50 mg bid). XL765 exposure increased with increasing doses on bid and qd schedules. Median tmax was 1-3 hours post-dose. Mean t1/2,z ranged from 3 to 9 hours at steady-state. Robust pharmacodynamic modulation of PI3K and ERK pathway signaling was evident in tumors and surrogate tissues following repeat-dose administration of XL765. For example, post-dose reductions in pAKT-T308 (57-76%), p4EBP1 (62-80%), and pERK (53-80%) were seen in paired biopsies of diverse solid tumors from five pts administered XL765 at 50 mg bid. Eleven pts have been on study for ≥ 16 weeks and seven pts on treatment for ≥ 24 weeks. Conclusions: In this phase I study, the MTD for single-agent XL765 is 50 mg bid. XL765 exhibited potent pharmacodynamic activity in solid tumors and surrogate tissues at generally well tolerated doses.

A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors.
2008 ASCO Annual Meeting
Background: XL765 is a selective dual oral inhibitor of Class I PI3K isoforms and mTOR. XL765 is a potent in vivo inhibitor of PI3K pathway signaling leading to tumor growth inhibition or tumor shrinkage in a dose dependent manner in multiple human xenograft tumor models exhibiting dysregulated PI3K pathway signaling. Methods: Pts with advanced solid malignancies are enrolled in successive cohorts of 3 to receive XL765 orally bid for cycles of 28 days. Cycle 1 safety data determine dose-limiting toxicities (DLT). Pharmacodynamic samples are collected. Tumor response is assessed by RECIST criteria every 8 weeks. Results: To date, a total of thirteen pts have been treated with XL765 across four dose levels up to 120 mg bid. There have been no DLTs. One grade 4 transaminitis possibly related to XL765 (120 mg bid) has been reported. Of the 9 pts enrolled into cohorts 1 to 3, 6 have completed >3 cycles of treatment. One patient (30 mg bid) with NSCLC has stable disease after 6 cycles and another patient (120 mg bid) with testicular carcinoma that had progressed under multiple chemotherapy regimes has a clinically significant reduction in alfa-fetoprotein from 11,000 to 7,000 U/L and radiological stable disease after 1 cycle. Plasma PK analyses indicated exposure increased less than dose-proportionally with increasing XL765 dose (range: 15-120 mg bid). Median Tmax occurred at 1-3 hrs post-dose. Mean terminal plasma half life ranged from 3-9 hours at steady state, which was reached by Dosing Day 8. No to moderate drug accumulation was evident following repeat daily bid dosing. Preliminary results suggest that XL765 administration augments food-induced changes in plasma insulin in an exposure dependent fashion. There are signs of pharmacodynamic modulation of PI3K and mTOR in patient hair bulbs as determined by reductions in phosphorylation of AKT, the AKT substrate PRAS40, and 4E- BP1. Conclusions: In this Phase 1 study, XL765 has been generally well tolerated at doses up to 120 mg bid. The MTD has not yet been established and dose escalation is ongoing. XL765 demonstrates biologic activity, as assessed by pharmacodynamic read-outs.

Hypokalemia:低钾血症
Hypophosphatemia:低磷血症
↑ GGT:γ-谷氨酰转肽酶升高
Abdominal Distension:腹胀
Peripheral Edema:外周性水肿
Fatigue:疲劳
Anorexia:厌食
Diarrhea:腹泻
Transaminitis:转氨酶升高
Hyperglycemia:高血糖
Mucositis:黏膜炎

好象还没有严重的感染。

这个能治疗NSCLC吗 不知道有没有一些数据出来？