Tiziana Life Sci PLC - Phase 2a Clinical Data
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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
This Phase 2a multi-center, single-arm, repeated-dose (100 mg once daily; 4 days on/3 days off for 4 weeks; defining each cycle) and 6-month duration study was conducted to evaluate the safety, tolerability and anti-tumor activity of Milciclib in Sorafenib-resistant patients with unresectable or metastatic advanced HCC. The trial enrolled 31 patients in
As previously announced on
MAJOR HIGHLIGHTS OF THE CLINICAL DATA
As per the study protocol, data collection was limited to 6-months. Thus, clinical data were not collected from patients under compassionate use treatment. The clinical activity assessment in evaluable patients was based on the investigators' review using the modified Response Evaluation Criteria in Solid Tumors (mRECIST).
· 14 out of 28 (50%) evaluable patients completed 6-month duration of the trial.
· 9 out of 14 patients (64.2%) were approved by their respective ethical committees to continue the treatment.
· 5 of the 9 patients on compassionate use had received Milciclib for a total of 9, 9, 11, 13 and 16 months.
· As of
· Both median TTP and PFS were 5.9 months (95% Confidence Interval ("CI") 1.5-6.7 months) out of the 6-months duration of the trial.
· 17 of 28 (60.7%) evaluable patients showed 'Stable Disease' (SD; met at least once in an 8-week interval).
· One patient (3.6%) showed 'Partial Response' (PR).
· 18 of 28 (64.3%) evaluable patients showed 'Clinical Benefit Rate' defined as CBR=CR+PR+SD (with CR representing Complete Remission).
Sorafenib® (Bayer) was approved, based on the clinical data from the pivotal Phase 3 (SHARP) clinical trial1, as the first line therapy for naive HCC patients. The clinical data from that study showed median TTP of 5.5 months (95% CI 4.1-6.9 months), CBR of 43% and 71% SD by RECIST criteria1. Conversely, the clinical data from a phase 2 trial with Sorafenib in patients with advanced HCC, showed SD (33.6%), TTP of 4.2 months and median OS of 9.2 months2.
Regorafenib was approved, based on the clinical data from the pivotal Phase 3 (RESORCE) clinical trial3, as the second line therapy for sorafenib-resistant HCC patients. In this study, Regorafenib showed median PFS of 3.1 months (95% CI 2.8-4.2 months), median TTP of 3.2 months (95% CI 2.9-4.2 months) and disease control rate (DCR, similar to CBR) of 65% by mRECIST. On the other hand, the clinical data from a Phase 2 study in patients with intermediate and advanced HCC, Regorafenib showed median TTP of 4.3 months (95% CI 2.9-13.1 months), SD (69%) and PR was 3%4.
"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
"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" said Dr.
1. Llovet, J., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J-F., de Oliveira, A., Santoro, A., Raoul, J-L, Forner, A., Schwartz, M., Porta, C., Zeuzem, S., Bolondi, L., Greten, T., Galle, P., Seitz, J-F., Borbatch, I., Haussinger, D., Giannaris, T., Shan, M., Moscovici, M., Voliotiz, D., and J. Bruix. (2008) Sorafenib in Advance Hepatocellular Carcinoma. N Engl. J Med. 359:378.
2. Abou-Alfa, G., Schwartz, L., Ricci., S., Amadori, D., Santoro, A., Figer,
3. Bruix, J, Qin, S., Merle, P., Granito, A., Huang, Y-H, Bodoky, G., Pracht, M., Yokosuka, O., Rosmorduc, O., Breder, V., Gerolami, R., Masi, G., Ross, P., Song, T., Bronowicki, J-P., Ollivier-Hourmand, I., Kudo, M., Cheng, A-L., Llovet, J.M., Finn, R., LeBerre, M-A., Baumhauer, A., Meinhardt, G. and Han, G. (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial.
4. Bruix, J., Tak, W-Y., Gasbarrini, A., Santoro, A.,
5. Jindal, A., Palejwala, V. and Shailubhai, K. (2018). Oral treatment with milciclib either alone or in combination with sorafenib inhibited tumor growth in an orthotopic model of hepatocellular carcinoma. Hepatology 68 Number 1 (Suppl): 879A (Abstract 1543)
The person who arranged for the release of this announcement on behalf of the Company was Dr
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HCC is the fifth most common cancer and the third highest cause of cancer mortality worldwide. The primary risk factor for HCC is hepatic cirrhosis. Between 2003 to 2012, rates of new liver cancer cases went up 38% according to the
Regorafenib (Stivarga®) and Nivolumab (Opdivo®) are both approved by the FDA for second line treatment of advanced HCC. The complex multi-factorial etiology of HCC warrants a need for systemic therapies that target different signaling cascades to provide improved efficacy and safety for both naive patients presenting with unresectable, advanced stage and those who suffer recurrence after curative treatments (resection, ablation and transplantation).
Milciclib (PHA-848125AC) is a small molecule inhibitor of several cyclin dependent kinases such as CDK1, CDK2, CDK4, CDK5 and CDK7. CDKs are serine threonine kinases that play crucial roles in progression of the cell cycle from G1 to S phase. Overexpression of CDKs and other downstream signaling pathways that regulate cell cycles have been frequently associated with development of resistance towards chemotherapies. In a Phase 1 study, oral treatment with Milciclib was well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in NSCLC, pancreatic and colon cancer, thymic carcinoma and thymoma. Additionally, milciclib met its primary endpoint in two separate Phase 2 multi-center clinical trials (CDKO-125A-006: 72 patients and CDKO-125A-007: 30 patients) in thymic carcinoma and thymoma patients.
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