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Three Phase I trials have evaluated tivantinib monotherapy in samples without HCC and found tivantinib to be well tolerated with mild clinical benefit.37–39 The first of these was conducted as an open-label, sequential 3 + 3 dose escalation design with an initial dose of 100 mg BID at a single center in the United Kingdom.37 Fifty-one patients with advanced solid organ tumors including prostate, melanoma, gastric, colorectal, sarcoma and breast were included in the trial. No patients with HCC were enrolled. The primary objective was to evaluate safety and tolerability and determine the maximum tolerated dose (MTD), establish a recommended Phase II dose (RP2D) and define dose-limited toxicities. Tivantinib was deemed safe and well tolerated, with an MTD/RP2D of 360 mg BID. Stable disease was observed in 14 patients, as defined by Response Evaluation Criteria in Solid Tumors.40

Similarly, a multicenter open-label single-arm dose escalation trial with an initial dose of 10 mg BID was conducted in the United States.38 Seventy-nine patients with advanced solid organ tumors, including colorectal, renal, ovarian, pancreatic, sarcoma and thyroid among others, were enrolled. No HCC patients were included in the sample. Tivantinib was well tolerated, with an MTD/RP2D of 360 mg BID. The PFS for all 79 patients was 77% at 6 weeks, 52% at 12 weeks and 34% at 21 weeks.

The same concept was evaluated in Japan in a multicenter dose-escalating open-label trial with a 3 + 3 design at an initial dose of 70 mg BID.39 Forty-seven Japanese patients with solid organ tumors were enrolled, although no HCC patients were included in the cohort. It is of interest that these patients were enrolled based on their CYP2C19 polymorphism status. The CYP2C19 enzyme plays a key role in the metabolism of tivantinib. It has been shown that 30–80% of Asians have a genetic polymorphism of CYP2C19, making them very poor metabolizers of tivantinib. This same polymorphism, in contrast, is found in only 12–19% of Whites or Blacks.41 Tivantinib was well tolerated by both normal and poor metabolizers of CYP2C19, although a dose adjustment down to 240 mg BID was recommended for poor metabolizers.

The first study of tivantinib monotherapy in patients with HCC was a Phase IB study conducted by Santoro et al.42 Three hundred and sixty milligrams of tivantinib was administered twice per day to 21 adult patients with Child-Pugh A and B cirrhosis and HCC in 28-day treatment cycles. All 21 patients eventually discontinued the treatment, 17 due to disease progression and four due to adverse events. Only 16 patients were able to be evaluated for tumor response, and while none of them demonstrated any objective response to therapy, nine did show stable disease (Table 2). The overall median time to disease progression was 3.3 months (range 1.47–5.3 months) among those who were able to be evaluated and 1.8 months (range 1.6–5.3 months) in the intention-to-treat analysis. Pharmacokinetic analysis found significant tivantinib accumulation in the plasma of HCC patients compared to the accumulation in other solid tumors, but no correlation was found between tivantinib exposure and adverse events. Several years later, a Phase I trial using tivantinib monotherapy was performed in a Japanese sample with advanced HCC.43 Only 28 patients were included in the trial, and though the authors found no complete or partial responses, they did see stable disease in 20 of the 28 patients.

Multiple Phase I studies have been performed using tivantinib as part of a combination therapy with sorafenib, sunitinib, erlotinib and gemcitabine.44–47 A preclinical study showed that tivantinib and sorafenib had an additive effect in three HCC cell lines (JHH-4, PLC/PRF/5 and SK-Hep-1) but did not find any degree of synergy between tivantinib and sunitinib in any of the 87 cancer cell lines tested.48 One of the clinical trials, a Phase I trial, assessed the combination of tivantinib and sorafenib in 87 adults with advanced solid organ tumors.44 Twenty patients had HCC with Child-Pugh A (n=14) and B (n=6) cirrhosis. An overall response rate of 11.5% and a 10% response in the HCC population were observed. Among the HCC patients, there was one complete response, one partial response and 12 cases of stable disease. Interestingly, both the complete response and the partial response were noted in patients who had a high concentration of tumor MET, and overall three of four patients with high concentrations of tumor MET achieved disease control. The median PFS was 3.5 months (95% confidence interval [95% CI]: 3–11.1), and the disease control rate was 70%. Patients with HCC who had received prior treatment with vascular endothelial growth factor (VEGF) therapy, sorafenib and/or sunitinib had a longer PFS than those who did not receive prior VEGF therapy (15.9 months [95% CI: 1.7–15.9] vs. 3.5 months [95% CI: 3–7.4]).

A pooled analysis was conducted by Chai et al46 on all Phase I studies with tivantinib in HCC and biliary tract cancer patients. Overall, 53 patients were treated with tivantinib: 42 were diagnosed with HCC, ten with cholangiocarcinoma and one with gallbladder adenoma. Twenty-three patients received tivantinib monotherapy, and 30 received a combination of tivantinib and either sorafenib (n=20), gemcitabine (n=8) or erlotinib (n=2). The overall response rate was 6%, but the disease control rate was 62%, with one complete response, two partial responses and 30 cases of stable disease.