PASADENA, Calif. (EGMN) – Two drugs – one old, one new – are showing promise in early clinical trials for the treatment of basal cell carcinomas.

 

If they prove to be useful, clinicians can thank scientists whose years of research successfully identified abnormalities in the hedgehog signaling pathway as the mechanism of disease for basal cell carcinoma (BCC), Dr. Jean Tang said at the annual meeting of the Pacific Dermatologic Association.

 

“Every major pharmaceutical company is now interested in the hedgehog pathway, so we may see a lot of treatments in the near future” for BCC and other cancers that have aberrations in this pathway, said Dr. Tang of Stanford (Calif.) University.

 

She and her associates are conducting a phase II trial of the experimental Genentech drug GDC-0449 in patients with many BCCs from basal cell nevus syndrome (Gorlin’s syndrome), and a separate proof-of-concept study of the antifungal drug itraconazole in patients with small numbers of BCCs who do not have basal cell nevus syndrome. Dr. Tang said she is pleased by the early results with both drugs so far.

 

For GDC-0449, a previous phase I study in 33 patients with locally advanced or metastatic BCC who took the drug for a median of 10 months found that 50%-60% had partial or complete responses and the drug was generally well tolerated (N. Engl. J. Med. 2009;361:1,164-72).

 

Of the 41 patients with basal cell nevus syndrome recruited thus far for the phase II trial – and randomized to 18 months of treatment with GDC-0449 or placebo – 23 patients (with 953 BCC tumors) have more than 1 month of data.

 

Although the study is still blinded, 15 patients in group A have developed a median of one new BCC during that month, compared with a median of 10 new BCCs in each of the 8 patients in group B, a significant difference that suggests group A may have received the drug and it may be working, Dr. Tang suggested.

 

In group A, patients started with a median of 252 BCCs and had 127 at the most recent follow-up, a 50% decline. In group B, patients started with 217 BCCs and had 267 at follow-up, a 23% increase in BCCs.

 

The difference between groups is significant, she said. The existing BCCs in group A also seem to have decreased in size.

 

“In the patients who have responded, it has changed their lives,” Dr. Tang said. “We are really excited about it.”

 

Patients in group A, however, were significantly more likely to develop dysgeusia (decreased taste sensation). The condition was seen in 14 of 15 patients, compared with none in group B. Seven patients in group A and none in group B reported some hair loss, though this difference was not statistically significant. Two patients in group A stopped treatment because of dysgeusia and hair loss, compared with no patient cessation in group B. Myalgia was also reported in group A but not group B.

 

These side effects may be acceptable to patients with basal cell nevus syndrome but probably not to patients with only one or two BCCs, Dr. Tang noted.

 

For the latter group, a proof-of-concept trial has randomized eight patients thus far to 1 month of treatment with 400 mg/day of oral itraconazole, a drug that has been on the market for approximately 2 decades and is considered relatively safe, she said. Patients are followed clinically for changes in their BCCs, and they undergo tumor biopsies before and after the 1-month therapy to measure the treatment’s effects on the hedgehog signaling pathway.

 

Preliminary data are “somewhat promising” in reducing BCC size, Dr. Tang said. The effect has not been as dramatic as with the GDC-0449 study, but neither have the side effects.

 

“This is very preliminary data but I wanted to share it with the other dermatologists in case some of them would like to put some patients on itraconazole, and, collectively, we can figure out whether or not it has a true effect” on BCC, she said.

 

In addition to the studies on itraconazole and GDC-0449, studies are underway by other investigators on experimental oral or topical agents by Novartis, Exelixis, and Infinity Pharmaceuticals that address aberrations in the hedgehog signaling pathway for the treatment of BCC.

加利福尼亚州帕萨迪纳(EGMN)——据一项早期临床试验显示，新型试验药GDC-0449和传统抗真菌药伊曲康唑有望用于治疗基底细胞癌(BCC)。

 

加利福尼亚州斯坦福大学的Jean Tang博士所在的研究团队主持进行了2项临床试验，1项是旨在验证基因泰克公司试验药GDC-0449治疗基底细胞痣综合征(又称Gorlin综合征，患者全身存在多处BCC病变)患者疗效的II期临床试验，另外1项则是旨在验证抗真菌药伊曲康唑治疗非基底细胞痣综合征患者(其全身仅存在少量BCC病变)疗效的概念验证试验。

 

既往就GDC-044910疗效所进行的一项I期临床试验(共纳入33例局部晚期或转移性BCC患者)表明，50%~60%的患者在服药10个月(患者的中位服药时间)后，病情出现部分或完全缓解，且患者对该药耐受性良好(N. Engl. J. Med. 2009;361:1,164-72)。

 

验证GDC-0449疗效的II期临床试验共纳入41例基底细胞痣综合征患者，患者被随机安排接受为期18个月的GDC-0449(A组)或安慰剂(B组)治疗，治疗时间＞1个月的患者数据被用于后续分析(共23例，BCC肿瘤数953处)。在这1个月的治疗时间内，A组(15例)和B组(8例)的患者新发BCC肿瘤的中位数分别为1个和10个，2者存在显著差异。A组患者在开始治疗前和最近一次随访时BCC肿瘤中位数分别为252个和127个，BCC肿瘤数降低50%。B组患者在上述2时间点的相应数值分别为217个和267个，BCC肿瘤数增高23%。此外，治疗后A组患者BCC肿瘤的体积也缩小了。

 

A组患者(14例/15例)出现味觉障碍的风险显著高于B组(0例)。A组(7例)和B组(0例)患者发生脱发的风险差异不存在统计学显著性。因味觉障碍和脱发而中止治疗的患者数目在A组和B组分别为2例和0例。此外，A组还有患者出现了肌痛症状，而B组未见。

 

以伊曲康唑为受试药物的概念验证试验则随机选取了8例患者进行伊曲康唑口服给药治疗(400 mg/d，为期1个月)，为了调查药物对患者BCC肿瘤的疗效并测量其对hedgehog信号通路的效应，研究者对患者进行了临床随访和肿瘤活检(治疗前后各1次)。初步数据表明，伊曲康唑可减小BCC肿瘤体积，尽管该药疗效不如GDC-0449显著，但不会引起明显副作用。

 

Tang博士在太平洋皮肤病协会年会上发言表示，经过多年的研究，科学家业已证明，BCC患者Hedgehog信号通路存在异常，诺华公司、Exelixis公司、Infinity Pharmaceuticals公司正加紧研发以hedgehog信号通路为治疗靶点的抗BCC药物，这些新药预计在不久后即会上市。

 

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