辉瑞CDK抑制剂palbociclib获得美国FDA“突破性疗法”称号

http://yypharm.cn/xinyaojieshao/kzhll/2013-04-14/434.html
时间：2013-04-14  作者：朱贵东  来源：美中药源  点击数： 68
【新闻事件】：制药巨头辉瑞本周三宣布，其细胞周期蛋白依赖性激酶（CDK）抑制剂palbociclib（PD-0332991）获得美国FDA“突破性药物”称号，这也是美国FDA自2012年7月进一步拓展“创新与安全法案”以来授予的第四个“突破性疗法”，且是唯一一个未上市的实验药获得该项殊荣。FDA的这项决议是根据palbociclib和来曲唑（letrozole）联合用药的一个二期临床实验结果，用于治疗雌激素受体（ER）阳性、HER2阴性，局部晚期或转移性乳腺癌。根据现有实验结果，palbociclib联合用药和来曲唑单独用药相比，中位无进展生存期从单独用药的7.5个月延长至26.1个月，具有统计学显著。主要副作用包括疲乏和嗜中性白血球减少。

【药源解析】：CDK是一个很老而又具有争议的抗肿瘤靶点，自上世纪九十年代开始就进行过多项临床实验，因为药效不明显且显示较高毒性而一直未能进入晚期临床研究。鉴于CDK对正常细胞的调控功能，大部分专家相信尤其是广谱的CDK抑制剂作为抗肿瘤药的治疗窗口会很小。制药巨头赛诺菲、施贵宝、罗氏等制药公司早些年就停止了其CDK抑制剂的开发。

笔者认为，CDK抑制剂的研发过程从很大程度上反映了新药研发领域的两种开发策略。上世纪九十年代，CDK是抗肿瘤研发领域的热点之一，多路诸侯一拥而上，结果发现CDK抑制剂研发的难度要远比预期难得多，CDK对所有细胞的增殖与死亡都起着关键的调控作用，广谱的CDK抑制剂，尤其是针对未经过基因筛选的患者很难展现较高的治疗窗口。剂量大了毒性太高，而小了又没有药效。所以，当时报道的CDK抑制剂基本没有明显的治疗窗。其次，因为大部分CDK亚型的化学结构很接近，化学上也很难得到高选择的抑制剂。理想状态下，只有那些选择性超过一千倍以上的化合物才真正具有临床意义，而这个要求对于CDK的多种亚型来说在化学上几乎是一个不可完成的目标。第三，研究CDK抑制剂还缺乏相关的生物标记物，从而很难根据基因特征来筛选患者。所以在开发策略上是“捏软柿子”，“打不过就跑”，还是分析事物的本质，在原有基础之上找到突破是研发理念的选择，各有各的缺陷和优势。


策略上赛诺菲、施贵宝、罗氏等制药公司选择退出无可非议，因为任何公司的研发资源都有限，在当时情况下的确当然应该选择哪些更有希望的研究课题。再加上肿瘤信号通路的复杂性和互换性，比如CDK2从一定程度上可以起CDK4和CDK6的功能，甚至也可以被其它信号通路取代，使CDK甚至整个蛋白酯酶研发领域更扑簌迷离。辉瑞的初步成功表明，选择性地抑制精心挑选的一组激酶能取得更好的疗效。Palbocyclib同时抑制细胞周期蛋白依赖性激酶亚型4（CDK4）和亚型6（CDK6）。CDK4、CDK6和细胞周期蛋白D结合，调节细胞周期G1期的时相转变。抑制CDK4、CDK6能阻止视网膜母细胞抑癌基因蛋白（Rb）的钝化，干扰肿瘤的生长。而且临床结果的分析比较指出，palbocyclib的应答率和雌激素阳性直接相关，表明ER是较好的生物标记，也是这个早期临床实验成功的关键因素之一。辉瑞已经开始Palbocyclib的一个随机、多中心、双盲的三期临床实验，评价作为一线药物，治疗ER阳性、HER2阴性，局部晚期或转移性绝经后妇女的乳腺癌。ISI分析师Mark Schoenebaum预测palbociclib要到2017年以后才能上市，销售额峰值将高达二十到六十亿美元。

这个药抗癌谱很广，肺癌都有实验。希望有YL。

palbociclib（PD-0332991）有两个II期临床实验，一个是联合来曲唑 。125mg每天PD-0332991是吃3周停1周，联合每天2.5mg来曲唑
http://cancerres.aacrjournals.or ... MeetingAbstracts/S1


另外一个是单药实验

http://meetinglibrary.asco.org/content/113257-132
Abstract:


Background: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Initial efficacy of PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4/6 was shown in a variety of solid tumors and in combination with letrozole in a randomized phase II trial.

Methods: We performed a phase II, single arm trial of PD0332991 in women with advanced BC. The primary objectives were safety and efficacy. Eligible patients had histologically-confirmed, stage IV BC with primary or metastatic tumor positive for retinoblastoma (Rb) protein expression, measureable disease by RECIST and adequate organ function/performance status. PD0332991 was given at 125 mg orally, days 1 – 21 of a 28-day cycle. Tumor was assessed every 2 cycles. A two-stage statistical design was employed. Secondary objectives included predictive biomarker assessment.

Results: 36 patients were enrolled; 28 who completed cycle 1 are reported: 18 (64%) HR+/Her2-, 2 (7%) HR+/Her2+ and 8 (29%) HR-/Her2-. 90% had prior chemotherapy for metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%). One episode of neutropenic sepsis occurred in cycle 1 in patient with 6 prior chemo regimens. All other toxicities were grade 1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) pts for cytopenias. For response data see table. Responses occurred at dose levels as low as 50 mg. Median PFS (months, 95% CI) was 4.1 (2.3,7.7)for ER+/Her2-, 18.8 (5.1,∞) for ER+/Her+ and 1.8 (0.9,∞) for ER-/Her2-. 27/28 patients discontinued study for progressive disease (PD); 1 due to patient preference.

Conclusions: Therapy with PD0332991 alone is well-tolerated and demonstrates response or prolonged stable disease (SD) in patients with BC despite prior hormonal and chemotherapy. Expansion within subtypes and molecular predictors of response are being investigated. Clinical trial information: NCT01037790.

这个实验里HR+/HER2+的病人也有长达18.8个月的PFS，但病例太少，需要更大规模验证。这提示我们三阳型乳腺癌病人也可以试用PD-0332991。

4393 The Combination Of Palbociclib Plus Bortezomib Is Safe and Active In Patients With Previously Treated Mantle Cell Lymphoma: Final Results Of a Phase I Trial
Program: Oral and Poster Abstracts
Session: 624. Lymphoma: Therapy with Biologic Agents, excluding Pre-Clinical Models: Poster III
Monday, December 9, 2013, 6:00 PM-8:00 PM
Hall G (Ernest N. Morial Convention Center)
Peter Martin, MD1, Maurizio DiLiberto, PhD2*, Christopher E Mason, PhD3*, Scott A Ely, M.D.4, Jia Ruan, MD, PhD5, Richard R. Furman, MD2, David Chiron, PhD6*, Xiangao Huang, PhD6, David C Madoff, M.D.7*, Jonathan Navi7*, Jessica Lewis, PA-C8*, Alison Bender, PA-C8*, Amelyn Rodriguez, RN8*, June Greenberg, RN9*, Morton Coleman, MD1*, Selina Chen-Kiang, PhD6 and John P. Leonard, M.D.10

1Hematology and Oncology, Weill Cornell Medical College, New York, NY
2Weill Cornell Medical College, New York, NY
3Department of Physiology and Biophysics and Institute for Computation Biomedicine, Weill Cornell Medical College, New York, NY
4Department of Pathology and Laboratory Medicine, Weill-Cornell Medical College, New York, NY
5Division of Hematology/Medical Oncology, Weill Cornell Medical College, New York, NY
6Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
7Weill Cornell Medical College, New York
8Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
9Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY
10Weill Medical College of Cornell University, New York, NY

Introduction
Mantle cell lymphoma (MCL) is characterized by cell cycle dysregulation due to cyclin D1 and CDK4 overexpression. Palbociclib (PD 0332991) is an orally bioavailable, specific, reversible inhibitor of CDK4/6 that induces prolonged early G1 arrest (pG1) in MCL cells and durable remissions in patients with MCL. Moreover, we have evidence that palbociclib-induced pG1 sensitizes MCL cells to killing by bortezomib and that sensitization is amplified upon withdrawal of palbociclib, when MCL cells synchronously enter S phase (pG1-S). Targeting CDK4 in combination with bortezomib, therefore, is a rational and novel therapeutic combination. We report the final results of a phase I trial of palbociclib plus bortezomib in patients with previously treated MCL.

Methods

Adults with previously treated MCL and adequate bone marrow and organ function were received palbociclib orally at doses of 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) for 12 days. Bortezomib was administered by IV or SC injection at 1 mg/m2 (dose levels 1-3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15, and 18 of each 21-day cycle. Subjects underwent core needle biopsies of tumor tissue pre-treatment, on day 8 (in pG1) and on day 21 (in pG1-S phase) of cycle 1. Subjects were restaged following cycles 2, 5, and 8 and then every 4 cycles. Subjects could remain on the study regimen until progression, unacceptable toxicity, or withdrawal. Dose levels were escalated according to the standard 3+3 schema. Dose limiting toxicity (DLT) was defined as treatment-related grade 3-4 toxicity occurring during cycle 1 or a delay in cycle 2 of > 1 week due to treatment-related grade 4 neutropenia or thrombocytopenia. The primary objective was to estimate the maximum tolerated dose of the combination. Secondary objectives included response rate, duration of response, and evaluation of the pharmacokinetic and pharmacodynamic profiles at multiple time points and across all dose levels.

Results

Nineteen subjects were enrolled: 6 in dose level 1, 3 in dose level 2, 7 in dose level 3, and 3 in dose level 4. The median age was 64 years (range 42-81). The median number of prior therapies was 3 (range 1-7). The number of subjects with low, intermediate, and high-risk MIPI scores was 6, 11, and 2, respectively. Two subjects experienced DLT: thrombocytopenia (level 1), neutropenia (level 3). Grade 3-4 hematologic toxicity included neutropenia (63%), thrombocytopenia (53%), lymphopenia (32%), and anemia (11%). Treatment-related grade 3-4 non-hematologic toxicity included zoster (1). Grade 1-2 toxicities occurring in >2 pt included: fatigue (47%), pain (42%), bleeding/bruising (37%), increased creatinine (26%), constipation (26%), rash (21%), nausea/vomiting (21%), sensory neuropathy (21%), dyspnea (21%), hypoalbuminemia (16%), cough (16%), edema (16%), infection (16%), increased AST (16%), hypocalcemia (16%), increased alk phos (16%). Reasons for ultimately stopping treatment include: progression (9), toxicity (6), and non-compliance (1). All 3 patients at dose level 4 required dose delays/reductions during cycle 2 due to toxicity. There appeared to be an association with dose of palbociclib and response, with one responder at each of dose levels 1 and 2, and 4 patients remaining free from progression for 1 year at dose level 3, including one complete response. Only one responding patient progressed on therapy. All patients with serial biopsies achieved pG1 on day 8, with reduction in CDK4/CDK6-specific Rb phosphorylation and Ki67 by immunohistochemistry.  The primary MCL tumor cells express cell cycle genes scheduled for early G1 such as cyclin D1 and CDK4, but not genes programmed for other phases of the cell cycle such MKi67, E3F3, CDK1, CCNA2, as determined by RNA-seq.

Conclusion

Daily palbociclib 125 mg for 12 days can be safely combined with bortezomib 1 mg/m2 twice weekly, while higher doses were limited by myelosuppression.  The combination induced durable responses in some patients. Palbociclib induced pG1, even at the lowest dose. However, the initial cell cycle control by palbociclib did not predict clinical response. Rather, pG1 appears to induce an imbalance in gene expression that is associated with response to the combination of palbociclib plus bortezomib. Strategies to control the cell cycle and dissect the underpinning mechanisms appear promising in MCL and warrant further evaluation.

Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan: Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Leonard: Millennium: Consultancy.

既然PD-0332991是针对乳腺而且治癌广普,我想先吃吃,希望能有机会.

seacat 发表于 2014-1-6 14:56
palbociclib（PD-0332991）有两个II期临床实验，一个是联合来曲唑 。125mg每天PD-0332991是吃3周停1周，联 ...

请问PD-0332991如果治疗大细胞肺腺癌效果会怎样呢？

决不放弃11 发表于 2014-3-16 15:14
请问PD-0332991如果治疗大细胞肺腺癌效果会怎样呢？

没有相关研究。

请问这个药能入脑吗？

试不起的不要试，有作用的药物也有伤害的

这次的2014年ASCO报告

A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated CDKN2A

Subcategory:
Lung Cancer - Non-Small Cell Metastatic
Category:
Lung Cancer - Non-Small Cell Metastatic
Meeting:
2014 ASCO Annual Meeting
Session Type and Session Title:
General Poster Session, Lung Cancer - Non-Small Cell Metastatic
Abstract Number:
8077

Citation:
J Clin Oncol 32:5s, 2014 (suppl; abstr 8077)

Author(s):
Priya Kadambi Gopalan, Mary Colleen Pinder, Alberto Chiappori, Alison Marguerite Ivey, Andres Gordillo Villegas, Frederic J. Kaye; University of Florida, Gainesville, FL; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL


Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

2014 ASCO Annual Meeting Proceedings Errata
Abstract:

Background: The Retinoblastoma pathway is targeted for mutational or epigenetic inactivation in more than 70% of NSCLC. The most common event is loss of CDKN2A expression (p16 protein), usually by hypermethylation, resulting in deregulated CDK4/6 activity and cell cycle progression. Palbociclib is a highly specific CDK4/6 inhibitor and has been shown to inhibit cell cycle progression and promote cellular senescence. Methods: We conducted a phase II, single arm trial of palbociclib in 19 previously-treated patients with recurrent or metastatic NSCLC. Only patients whose tumors were negative for p16 expression by immunohistochemistry were eligible. The primary endpoint was response rate. A Simon’s 2-stage design was employed, with 2 or more responses required to proceed to the second stage. Palbociclib at 125 mg daily was given orally on days 1-21 of a 28-day cycle. Tumors were assessed by RECIST every 2 cycles. Secondary endpoints included overall survival, progression-free survival, toxicity and biomarker analysis. Results: Of the 16 evaluable patients who received at least one month of therapy, there were no responses, and the trial was closed to accrual. However, 8 patients with previously progressive NSCLC had stable disease (SD) lasting 16, 17, 20, 24, 35, 38, 41 and 42 weeks. The remaining 8 patients had progressive disease within 8 weeks. The median PFS was 12.5 weeks. There was no correlation between SD and histology or EGFR mutation status. One patient experienced grade 3 and 4 toxicities as a result of transaminitis and rhabdomyolysis (generalized muscle weakness and increased CPK) thought to be due to concomitant use of high-dose (80 mg) simvastatin. Three patients developed grade 3 or 4 neutropenia, and one patient developed grade 3 thrombocytopenia. All other toxicities were grade 1 or 2. Conclusions: Palbociclib therapy alone was well-tolerated, and stable disease (SD) was achieved in 50% of evaluable patients, suggesting the induction of cellular senescence. PFS was comparable to other second-line chemotherapeutic agents. Molecular predictors of clinical benefit (SD) are currently under investigation. Clinical trial information: NCT01291017.