A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Reducing Unnecessary Biopsy of Breast Lesions: Preliminary Results with Combination of Strain and Shear-Wave Elastography

The aim of our study was to compare strain elastography (SE), acoustic radiation force impulse-inducing Virtual Touch Imaging ([VTI] Siemens Medical Solutions, Mountain View, CA, USA), Virtual Touch Imaging Quantification ([VTIQ] Siemens Medical Solutions) and combined methods in the evaluation of ultrasound (US) Breast Imaging-Reporting and Data System (BI-RADS) category 4 lesions to explore an applicable way to reduce unnecessary biopsy by reducing false positives of conventional US without yielding false-negative cases. A total of 267 patients with 278 BI-RADS category 4 lesions (151 benign and 127 malignant) were evaluated with conventional B-mode US, SE, VTI and VTIQ implemented on a Siemens Acuson S2000 US system. Diagnostic performance, including area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were evaluated. Overall, VTI alone exhibited the highest NPV (91.74%), although combined elastic methods exhibited higher NPV than single methods, with the highest NPV at 100% when the VTI, SE and VTIQ methods were combined. Compared with conventional US, PPV increased from 45.7% (127 of 278) to 63.18% (127 of 201) when adding combined elastography (VTI + SE +VTIQ). In addition, 52.5% (63/120) and 50.8% (61/120) of BI-RADS 4 A lesions were downgraded when using combined methods (VTI + SE and VTI + SE + VTIQ, respectively) without missing any cancer. However, 2 intraductal papillomas and 1 phyllodes tumor were not identified. In conclusion, the combination of different elastic methods have the potential to downgrade BI-RADS 4A lesions to reduce false-positive biopsies without increasing the risk of missing cancers.     

CT导向下~(125)I粒子植入治疗复发性盆腔恶性肿瘤

目的探讨CT导向下125I粒子植入治疗复发性盆腔恶性肿瘤的疗效。方法18例复发性盆腔恶性肿瘤患者采用CT导向下125I放射性粒子植入。粒子植入之前采用TPS模拟布源或遵循Halarism的125I经验公式:mCi=Da×5,Da为靶组织长、宽、高的平均值(L W H)/3,单位为cm,求出术中所需125I粒子的总活度及算出治疗粒子的数量。在螺旋CT导向下将125I放射性粒子植入盆腔肿瘤内。结果全组18例22个病灶治疗后2个月后采用PET-CT评价,完全缓解(CR)6例,部分缓解(PR)8例,稳定(NC)3例,进展(PD)1例。18例随访7~16个月,全部存活,近期平均生存期9.5个月。结论125I放射性粒子植入是治疗复发性盆腔恶性肿瘤的一种有效的方法。     

CT导向下经皮射频消融术治疗肾上腺恶性肿瘤

目的对29例肾上腺肿瘤患者行射频消融（RFA）治疗，研究其近期局部治疗效果、不良反应和副作用。方法肾上腺肿瘤患者共29例，病灶总数31个，其中直径≤2．0cm的病灶共5个，2．1-4．0cm者18个，4．1-6．0cm者5个，≥6．1cm者3个，经RFA治疗1个月后行螺旋CT双期增强扫描评价肿瘤治疗效果。结果上述病灶经消融治疗后达到完全坏死者分别为5个、18个、3个、2个。患者无严重并发症出现。结论RFA治疗安全可靠，副作用小，是治疗肾上腺恶性肿瘤的有效方法之一。     

Correlation of AIB1 overexpression with advanced clinical stage of human colorectal carcinoma

AIB1, a member of the steroid receptor coactivator 1 family, has been cloned on 20q12 and is a candidate oncogene in human breast cancer. It is commonly amplified and overexpressed in several types of human cancers. In this study, we examined the expression of AIB1, as related to clinicopathologic features, in 85 human colorectal cancers (CRCs). The status of the number of AIB1 copies, p53 expression, and DNA ploidy was also analyzed. The overexpression of AIB1 was detected in 35% of CRCs. Amplification of AIB1 was observed in 10% of CRCs. In addition, the overexpression of AIB1 was observed more frequently in CRCs in later clinical stages (T3 N1 M0/T3 N0 2M1), compared with that in T3 N0 M0 stage (P < .05). These results suggest that overexpression of AIB1 might provide a selective advantage for the developmental growth and/or progression of subsets of CRCs. In addition, a significant correlation (P < .05) of overexpression of AIB1 with p53 overexpression as well as with aneuploid DNA content was observed in these CRCs. The overexpression of p53 was also correlated significantly with CRC DNA ploidy (P < .05). Furthermore, there was a substantial population of CRCs showing overexpression of both AIB1 and p53 protein and all had aneuploid DNA content; most of these were in the later clinical stage. These findings suggest a possible convergence of AIB1 with a pathway involving p53, which might induce chromosomal instability and affect the clinical phenotype of a subset of CRCs.