我父亲肺鳞癌的治疗贴(2014年3月1日驾鹤西去）

老马 发表于 2012-11-3 23:05

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Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overco ...

英语水平实在有限，大概了解一点。谢谢噢！

A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.
; w. b6 s& d" c: d& NBackground: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.

: ]  k3 G! r4 yhttp://www.asco.org/ASCOv2/Meeti ... mp;abstractID=96289

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英文名                BEZ235 Tosylate
: M; v- Z7 G7 j( F7 m- H别名                4-[2,3-Dihydro-3-methyl-2-oxo-8-(3-quinolinyl)-1H-imidazo[4,5-c]quinolin-1-yl]-alpha,alpha-dimethylbenzeneacetonitrile 4-methylbenzenesulfonate
产品名称                BEZ235 对甲苯磺酸盐
0 B2 c3 B, k0 v4 L, J* q: ~1 QFormula:
3 k% }4 O" c. ?- EC30H23N5O
Molecular Weight:
469.54
2 L5 w5 s, G% e% c) s, x
3 i& O% U/ X1 l; n2-甲基-2-[4-[3-甲基-2-氧代-8-(喹啉-3-基)-2,3-二氢咪唑并[4,5-c]喹啉-1-基]苯基]丙腈


# s, }7 D$ X( S+ |8 r% D+ sFirst-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors.
0 h4 b1 E; }8 L1 K$ tBackground: The PI3K pathway plays a major role in cancer cell growth and survival, and is frequently aberrantly hyperactivated in tumors. BEZ235 is a potent and highly selective reversible PI3K pathway inhibitor with antiproliferative and apoptotic activity in cancer cells. BEZ235 strongly inhibited activation of downstream effectors (e.g. Akt) and displayed antitumor activity in xenograft models harboring PI3K pathway alterations. In preclinical toxicology studies, BEZ235 treatment was well tolerated. Methods: This phase I, multicenter, open-label, single-agent, dose-escalation, study was conducted in pts with histologically confirmed, advanced, unresectable solid tumors. BEZ235 was administered once daily as a gelatin capsule either fasted or fed (10-1,100 mg) until unacceptable toxicity or disease progression. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Anti-tumor activity of BEZ235 was assessed by CT and PET. Early efficacy data are based on central review. Results: A total of 59 pts have entered the trial (13 breast [22%], 10 CRC [17%]). There were no DLTs with BEZ235 treatment. Frequently reported AEs included nausea, vomiting, diarrhea, fatigue/asthenia, anemia, and anorexia; they were mild or moderate, manageable, and reversible upon treatment discontinuation. AUC and Cmax increased non-proportionally with dose and were variable within and among pts. BEZ235 exhibited dose- and day-dependent PI3K inhibition as measured by elevation of plasma C-peptide levels. 2 PR (1 Cowden syndrome pt, 1 breast pt) and 16 MR were observed. 14 of 51 evaluable pts had stable disease ≥4 months; tumors from 6 of these 14 pts carried dysregulations of the PI3K pathway. 4 of the 14 (29%) patients with SD ≥4 months had breast cancer. 18 of 35 evaluable pts had detectable decreases of 18FDG- uptake. Conclusions: BEZ235 was well tolerated with a favorable safety profile. Available PD and efficacy data show that BEZ235 is active in pts (especially in those with PI3K pathway dysregulated tumors). Based on PK data, future studies will use a new formulation of BEZ235 with improved bioavailability and PK properties.

A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors.
Background: BEZ235 is a potent and highly specific oral dual mTOR/PI3K inhibitor. BEZ235 hard-gelatin capsule (Burris, ASCO 2010) and SDS capsule (Rodon, SABCS 2010) were reported previously. Here we present the dose escalation with the new BEZ235 formulation (BEZ235 SDS sachet). Methods: Phase I dose-escalation study of BEZ235 given orally once daily to adult patients with advanced solid tumors. A Bayesian logistic regression model with overdose control was used to guide dose escalation. Results: At the time of abstract submission, 25 patients have been treated with BEZ235 SDS sachet once daily at 4 dose levels: 800 mg (6); 1,000 mg (4), 1,400 mg (8), 1,600 mg (7). Tumor types enrolled included: colorectal (8), breast (4), NSCLC (3), renal (3) and sarcoma (3). 4/25 patients have been treated for >3 cycles, 10/25 patients progressed within the first three cycles of treatment and 8/25 are on treatment at time of abstract preparation. Maximum tolerated dose (MTD) for BEZ235 SDS sachet is 1,600 mg/d. Dose limiting toxicities (DLT) included: 2 cases of grade 3 fatigue/asthenia (at 1,400 mg) and 1 grade 3 thrombocytopenia (at 1,600 mg). Most common adverse events (AE) which are considered possibly treatment related included: nausea, diarrhea, vomiting and fatigue (G1-G3). At 1,600 mg, PK was evaluated in 7 patients. The absorption was slow with a tmax within 4 to 6 hours post-dose. The elimination half-life is ranging from 3.5 to 13.5 hours. At steady state, the median Cmax was 1,800 ng/mL (CV% = 38) and exposure was 22,375.5 ng.h/mL (CV% = 44). The accumulation ratio based on exposures between day 1 and steady state was estimated to be approximately 6 fold. Conclusions: BEZ235 SDS sachet was well tolerated with a favorable safety profile. Following the Bayesian model recommendation, the MTD for BEZ235 SDS sachet was determined as 1600 mg/d. Based on safety and pharmacology, this formulation is the chosen one for phase II clinical trials and it is being investigated in monotherapy in solid tumor patients with PI3K pathway alterations and in combination with trastuzumab for breast cancer.

这个BEZ235看来没有很强的免疫抑制作用。

老马 发表于 2012-11-7 18:57

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! k: d4 i/ @0 G# }- b今天是本次服药周期吃2992的第7天，胃口不错，第4天时腹泻一次。

老马，我爸刚做了CEA检察，升300多？ CEA618,!!!  但是我爸自己感觉基本情况都还好，早上还起来慢跑半个小时， 吃饭也还行，转移处有点痛，吃一粒路盖克就行了， 原来刚做完6期化疗CEA26时，痛得更厉害，要吃3粒路盖克才能入睡，不知道咋回事?  CEA618这太高了， 我想要不要做一，二期化疗打压一下？能推荐一下好的化疗方案吗？（我爸2011年7月份查出左肺中分化肺腺癌IV期骨转移，到12月底做了6期培美+顺铂化疗，第五期和六期好象没起作用，第六期后左肩疼痛，后吃易就基本不痛了， 现在正在吃易，估计易开始耐药了！）

泰素帝单药化疗

爸爸2012年“十一”过后，做64位增强CT发现左下组织团块影，疑是肺癌。
   10月19日住院，10月24日手术 切除左下肺1/3,清除淋巴结5袋。 11月2日出院。
   术后病理显示左下肺低分化鳞癌（IIIA期），残余支气管端无癌细胞，但是第7、9组淋巴结转移。
   现在一直瞒着爸爸，医生也告诉他是良性的。后面打算做化疗，再试试特或易。想请教一下老马：
  J# v) U$ R6 h   1）基因检测是不是必须得做？我想即使检测没有突变，后期也要吃特或易。
   2）爸爸现在每天晚上都要咳嗽，一两个小时起来咳一次，问过心胸外科医生，说白天多咳，晚上就咳得少了。请问还有什么好办法？
% k( v$ ?5 l3 t+ c3 i8 ~0 ^$ A8 N   3)第一次化疗是不是用紫衫醇+顺铂比较好，放疗尽量不要做，容易引起放射性肺炎？
9 y3 X# S$ V1 C7 S   谢谢！

第一次化疗用紫衫醇+顺铂或者吉西他滨+顺铂都可以。
如果考虑接放疗加强，就用紫衫醇+顺铂方案，吉西他滨会大大增强放疗的副作用。
4 ~( z! B# @  [' Z; F基因检测顺便做一下吧，因为有现成的手术病理。

非常感谢老马 谢谢！让我们一起加油！