An ongoing phase IIa clinical trial has demonstrated the safety and efficacy of milciclib maleate at 6 months in patients with unresectable or metastatic hepatocellular carcinoma who were resistant or intolerant to sorafenib.
Kunwar Shailubhai, PhD
An ongoing phase IIa clinical trial has demonstrated the safety and efficacy of milciclib maleate at 6 months in patients with unresectable or metastatic hepatocellular carcinoma (HCC) who were resistant or intolerant to sorafenib (Nexavar) (NCT03109886). Tiziana Life Sciences, the company developing milciclib, noted in a press release that the primary endpoint of the study was met.
At the 6-month duration of the trial, the clinical benefit rate was 64.3% among 28 evaluable patients. Additionally, the monotherapy was considered to be well tolerated with manageable toxicities.
"The positive clinical activity and tolerability data of milciclib in Sorafenib-resistant and advanced HCC patients are very encouraging and provides affirmation for continued development of milciclib, either as monotherapy or combination therapy," Kunwar Shailubhai, PhD, the CEO and chief scientific officer of Tiziana, said in the press release.
Milciclib is a small molecule inhibitor of cyclin dependent kinases (CDKs). The overexpression of CDKs has been associated with resistance to chemotherapy agents.
The multi-center, single-arm trial enrolled 31 patients with recurrent or metastatic HCC in Italy, Greece, and Israel. All of the patients had failed prior sorafenib or were intolerant to or refusing treatment with sorafenib. Additionally, patients were required to have a Child-Pugh score of 6 or less and an ECOG performance status of 0 or 1. Prior local or locoregional therapy was allowed as long as it was completed at least 4 weeks prior to enrollment. Those with fibrolamellar HCC or mixed hepato-cholangiocarcinoma, clinical ascites, or grade 3 esophageal varices were not eligible for enrollment in the trial.
Patients received 100 mg once daily for 4 days on followed by 3 days off in 4-week cycles. At the end of the third cycle, treatment was stopped for tumor assessment on day 90. Those who were considered to be benefiting from treatment after 3 cycles were able to resume treatment until day 180.
The primary endpoint of the trial was safety and secondary endpoints included objective response rate, progression-free survival, time to progression, and duration of response.
Twenty-eight patients were evaluable for response, of which 14 had completed the 6-month duration. The median time to progression and the median progression-free survival were both 5.9 months (95% CI, 1.5-6.7). Seventeen patients (60.7%) achieved stable disease and 1 patient (3.6%) had a partial response.
The toxicity profile for milciclib was considered manageable and no drug-related deaths were reported in the trial to date.
“The current therapies for HCC are often associated with severe toxicities, resulting in poor patient compliance. Hence, there is an immediate need for efficacious therapies that will not compromise patients’ quality of life. We believe that the overall safety profile of milciclib is an important competitive advantage over existing therapies currently used for treating HCC,” said Gabriele Cerrone, chairman and founder of Tiziana Life Sciences, in a statement.
Milciclib has also demonstrated synergistic activity in combination with tyrosine kinase inhibitors against HCC and is therefore being considered for further trials as part of combination regimens to treat patients with HCC.
Tiziana Life Sciences Reports Positive Phase 2a Clinical Data Exhibiting Positive Clinical Activity with Milciclib Monotherapy in Advanced Sorafenib-refractory or -intolerant Patients with Unresectable or Metastatic Hepatocellular Carcinoma [press release]. New York/London: Tiziana Life Sciences plc; September 4, 2019. https://bit.ly/2lUa8il. Accessed September 4, 2019.