SHANGHAI – U.S.-China biotech CASI Pharmaceuticals Inc. initiated dosing in Chinese patients with ENMD-2076, a selective angiogenic kinase inhibitor, in a phase II study for triple-negative breast cancer (TNBC). That marks CASI's first foray with ENMD-2076 in China.

The company made a strategic decision a few years ago to pivot strongly to China while maintaining strong ties to the U.S. The China trial is an expansion of the ongoing U.S. trials approved under China's Multi Regional Clinical Trial (MRCT) guidelines. (See BioWorld Today, Feb. 27, 2015.)

The MRCT approval pathway is used by companies to register imported drugs in China that are undergoing trials elsewhere and is most often used by multinational corporations (MNCs). In the past year, authorities have been interpreting those guidelines with a new level of scrutiny, giving some MNCs headaches as they see their early stage trials pushed back for further regulatory reviews. (See BioWorld Today, Dec. 3, 2014.)

But CASI, a small biotech that deftly straddles both the U.S. and China, found it encountered few problems applying for clinical trials in China. The firm applied for three indications and was approved to commence trials for all three: TNBC, metastatic soft-tissue sarcoma and advanced ovarian clear cell carcinoma (OCCC).

"In our approach, we give China the same weight as the trial being conducted overseas," said CASI CEO Ken K. Ren. "Our Chinese investigator will be co-PI for this international trial, so that really gives the Chinese investigator data more weight . . . as part of a global program."

The China trial will be a two-stage study, first recruiting 25 Chinese patients to determine the proper, well-tolerated dose of the candidate. Although ENMD-2076 has been dosed in 200 patients in the U.S., the company is looking to identify any potential differences in the Chinese population. The second stage will recruit a further 30 patients.

The goal of the trial is to have supplemental information to support the global trial data package for registration in the U.S. and China, to see the effects in Chinese patients and to work toward identifying a correlative biomarker, according to Ren and the firm's chief medical officer, Rong Chen, who spoke with BioWorld Today.

"Currently, the U.S. trials are coming along well. We expect to have data for the biomarker analysis, together with efficacy, to be reported by the end of this year," Ren said. "These data will provide further guidance to our trial so we can move forward."

Part of the challenge is that TNBC is little understood, having proved resistant to antibodies or targeted therapies. There is no first-line therapy for the aggressive disease, while chemotherapy is often used with a high rate of relapse.

China is similar to many countries in that breast cancer is the most common cancer in women, but in other respects the situation differs. China accounts for just 9.6 percent of the global number of deaths from breast cancer, according to a paper in June 2014 issue of The Lancet, and the incidence of breast cancer has been linked to China's unique reproductive patterns and the country's rapidly changing socioeconomic conditions.

While the overall rate of breast cancer is relatively low in China, it has increased more than twice as fast as global rates since 1990 and, by the year 2021, will have an estimated 2.5 million cases overall.

There is little data on the number of women with TNBC, but it s believed to be somewhere between 15 percent and 20 percent of the number of breast cancer patients overall.

While working with U.S. academic scientists, CASI found that ENMD-2076 showed an increased sensitivity in TNBC in animal models that correlated with the overexpression and mutation of the p53 gene. Thus, one of the objectives is to validate that finding as a biomarker related to the sensitivity of the drug.

The China trial is being conducted by at the Cancer Hospital of Chinese Academy of Medical Sciences in Beijing. CASI said there is currently no timeline for the China trial.

"We will expand and take some time; the focus is to see the biomarker correlation," Chen explained. "Once we see clearly the biomarker correlation we can design a more advanced [phase] IIb protocol and move to that stage very quickly."

OVARIAN CLEAR CELL CARCINOMA

Just two days after initiating dosing for TNBC, the company said it received CFDA approval to start testing ENMD-2076 for OCCC.

The company will follow a phase II protocol to evaluate the safety and efficacy in ENMD-2076 in advanced OCCC patients who will be given 250 mg of ENMD-2076 orally per day. The number of patients recruited in China, said Chen, "will depend on the progress of the trials being conducted in Canada and the U.S. as well as the overall outcome of the study."

The primary endpoint includes the rate of progression-free survival at six months and the rate of the overall response rate with a complete or partial response.

CASI is also taking a biomarker approach. "One of the objectives of the trial is to see if any correlative biomarkers may be identified related to the sensitivity of Chinese patients to our drug," Ren said. Thus, the secondary endpoints include length of response and levels of certain biomarker expression.

The TNBC and OCCC studies are being conducted independently, but CASI leaves open the option to explore and compare data in correlative genomic profiling and biomarker studies to see if a correlation between the two exists.

OCCC accounts for 10 percent to 13 percent of all ovarian cancers but presents a considerable clinical challenge with a poor prognosis; patients are often resistant to platinum-based chemotherapy. Based on information provided by CASI, the annual incidence rate for ovarian cancer in China was 34,351 cases in 2012 (or about 3,435 cases of OCCC annually).

The China trials for ENMD-2067 allow CASI to implement its new approach, which Ren said is "to leverage clinical trials both overseas and in China to support filing in China, U.S. and worldwide for our own proprietary drugs so we can develop drugs more cost effectively."