新药讨论：Sorafenib(多吉美)

多吉美（Sorafenib, 索拉菲尼）适应症是肝癌和肾癌。由于其广谱的靶点，因此在很多类型的癌症中都在做相关的临床性研究。这个贴子主要用来跟踪多吉美在肠癌方面的临床研究。

Final results of a multicenter phase II trial assessing sorafenib (S) in combination with irinotecan (i) as second- or later-line treatment in metastatic colorectal cancer (mCRC) patients (pts) with KRAS-mutated tumors (mt; NEXIRI).

Background: The raf kinase inhibitor S is the lead compound in a series of raf signalling pathway inhibitors that could inhibit cell growth and proliferation of pts in KRAS mt pts. The aim of this phase II trial was to evaluate the disease control rate (DCR) of i combined with S as second- or later line treatment (tt) in mCRC pts with KRAS mt. Methods: In the previous phase I, the recommended dose of I was 180 mg/m2 in a bi-weekly regimen with a fixed dose of S (400 mg twice daily) (1 cycle= 2 courses of I). In the phase II, pts received this combination until progression or toxicity. Eligibility criteria included: measurable and unresectable mCRC, age > 18 years, PS ≤ 2, progression after I-based chemotherapy, one or more previous lines and centralized confirmation of KRAS mt in codons 12 or 13 in the primary tumour (PT) or metastases. Primary endpoint was DCR according to RECIST criteria with independent review of CT-scan. Secondary were toxicity, PFS and OS. Tt regimen was considered promising if at least 14 out of 54 pts had DC in a two-stage Simon design. Pharmacokinetic, pharmacogenetic and pathologic studies were also undertaken. Results: Fifty-four pts were included between 06/09 and 12/09 from 10 centers. Median age was 60 yrs (range: 43-80), 59% were males, 46% PS 0, 63% PT in colon. Previous tts were 5FU 100%, I 100%, oxaliplatin 100%, bevacizumab 89%. The median number of cycles was 4 (1-8) and 13 pts (24%) completed at least 6 cycles. No toxic death was seen. Gr 3 toxicities were: hand-foot syndrome 15%, diarrhea 39%, neutropenia 19% and 16% showed Gr 4 neutropenia. In 46 pts (85%) S dose was reduced to 400 mg daily after two courses due to toxicity, then increased again to 800 mg in 55% of pts. The DCR was 64.9% [IC95%, 51-77] in intention to treat (52 evaluable pts). Median PFS and OS were 3.5 [IC95%, 2.0-3.7] and 7.7 months [IC95%, 4.8-9.7], respectively. Conclusions: NEXIRI regimen as second- or later-line tt for mCRC pts with KRAS mt shows promising activity in this heavily pre-treated KRAS mt population. These data justify conducting a randomized phase II/III trial to confirm the efficacy of this combination.

2011ASCO年会上公布了NEXIRI（多吉美+伊立替康）项目的二期临床结论。做为多靶点的多吉美联合伊立替康还是取得不错的疾病控制率（DCR64.9%）、无病生存期（PFS 3.5个月）和总生存期（OS 7.7个月），要知道这是在所有标准治疗都已失败之后取得的成绩。值得注意的是这里招的所有病人都是Kras突变型的，可能是因为Kras突变型病人的药物相对较少的缘故。当然，相信Kras野生型病人可以取得同样的成绩。

关于多吉美在肠癌方面的临床研究很多，有兴趣的病友可以看看下面这个链接。

http://clinicaltrials.gov/ct2/re ... p;lup_s=&lup_e=

肠的有没有人用过这个药呢？

那些英文全部认识——分成单个的字母  看不懂啊，版主老大

Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal cancer (LARC): A phase I/II trial (SAKK 41/08).

Background: 40% of patients (pts) with LARC present with K-ras mutation. Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing effects. These facts build a strong rationale to use Sor in combination with preoperative RT and Cape in pts with K-ras mutant tumors. Methods: Pts with K-ras mutated mrT3-4 and / or mrN+, M0 disease were recruited in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was defined as any G3 or higher non hematological toxicity (tox) or haematological tox during ≥ 7 days, which are possibly, probably or definitely related to trial treatment occurring during and up to 4 weeks after last administration. If ≤ 2 out of 7 pts experienced a DLT, then the next cohort was treated at a higher dose level. If > 2 out of 7 pts suffered from a DLT, this DL would be considered too toxic and a dose level below would be tested in the next cohort. The highest dose level with ≤ 2 out of 7 pts experienced a DLT would be recommended for the phase II part. In all dose levels RT was given in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total of 21 pts in 3 cohorts have been treated in the phase 1 study. After observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an amendment was implemented to reduce the Sor dose from 400mg BID to once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia (G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the recommended dose for phase II. Conclusions: After reducing the Sor dose to 400mg once daily, neoadjuvant treatment with Sor in combination with full dose Cape and RT was tolerable and the toxicities manageable.

. Dose level                                  Capecitabine (mg/m2)                     Sorafenib (mg)
(each with 7 pts)                          per day during 5 weeks                    per day during 5 weeks

DL 1 before amendment                         2 x 600                                        2 x 400
DL 1 after amendment                            2 x 600                                        1 x 400
DL 2 after amendment                            2 x 825                                        1 x 400

上述临床是针对Kras基因突变的病人设计的临床，结合了希罗达和放疗。这个一期临床的主要目的是将这种联合治疗的毒性控制在一定范畴。最终推荐的方案是希每日2 x 825，多每日1 x 400 。做为联合用药，这个剂量可做为起始用量参考。

我妈妈是胃肠道间质瘤现在服用多吉美，今天是第十六天，效果还没显现

主要是副作用厉害，用着难受。

这药肺腺的能用吗？

现在不是有治疗肠癌靶向药吗，还需要用多吉美+伊立替康，不如先试试肠癌靶向药的好。