Based on positive results from Phase I trials, a Phase II international multicenter double-blind randomized placebo-controlled trial was conducted.34 One hundred and seven adult patients with advanced-stage HCC who had previously progressed or had demonstrated intolerance to one prior systemic therapy (sorafenib or sunitinib) were randomized in a 2:1 ratio to receive tivantinib or placebo. The initial dose of tivantinib was 360 mg BID; however, this was later decreased to 240 mg BID due to a higher than expected incidence of grade 3 or higher neutropenia. In total, 38 patients received tivantinib 360 mg BID, 33 patients received tivantinib 240 mg BID and 36 patients received placebo. The median time to progression (TTP) was significantly longer in the tivantinib group (1.6 months [95% CI: 1.4–2.8]) compared to that in the placebo group (1.4 months [95% CI: 1.4–1.5]), with a hazard ratio (HR) of 0.64, 90% CI 0.43–0.94, p=0.04. The median PFS in the tivantinib group (1.5 months [95% CI: 1.4–2.7]) was longer than that in the placebo group (1.4 months [95% CI: 1.4–1.5]), with this trend approaching significance, HR 0.67, 95% CI: 0.44–1.04, p=0.06. There was no significant difference in overall survival between the two groups. According to the statistical analysis plan, the study participants were also subdivided based on their tumor MET status into high-expression (MET-high) and low-expression (MET-low) subgroups. There were 37 patients with MET-high tumors, 22 of whom received tivantinib (ten patients at 360 mg BID and 12 patients at 240 mg BID), and 40 patients with MET-low tumors, 27 of whom received tivantinib (13 patients at 360 mg BID and 14 patients at 240 mg BID). Patients who had MET-high tumors and received tivantinib had a longer median TTP (2.7 months vs. 1.4 months [HR 0.43, 95% CI: 0.19–0.97, p=0.03]), a longer median PFS (2.2 months vs. 1.4 months [HR 0.45, 95% CI: 0.21–0.95, p=0.02]) and a longer median overall survival (7.2 months vs. 3.8 months [HR 0.38, 95% CI: 0.18–0.81, p=0.01]) compared to placebo. There was no difference in those with MET-low tumors who received tivantinib and those who received placebo.

Based on the significant benefits seen in the MET-high group in the above-mentioned Phase II study, two Phase III trials have been initiated to further evaluate the benefit of tivantinib in patients with MET-high HCC tumors. The METIV-HCC trial (NCT01755767) is a large international randomized double-blind, placebo-controlled trial comparing tivantinib 120 mg BID to placebo in patients with MET-high HCC tumors who have failed or progressed with sorafenib.49 The primary end point is overall survival, and secondary end points are PFS and safety. This study has enrolled over 300 participants. A planned interim analysis was recently completed, and the study will continue to the final analysis as recommended by the data monitoring committee.50 The JET-HCC trial (NCT02029157) is a randomized, double-blind, placebo-controlled trial being conducted in Japan to evaluate the effect of tivantinib at 120 mg BID on MET-high HCC in patients previously treated with one prior course of sorafenib therapy. The primary end point of this study is PFS, and the secondary end point is overall survival. The study is currently recruiting patients, with a goal of 160 patients. The estimated study completion date is December 2016.


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DOSING AND TOXICITY

Tivantinib dosing for HCC has continued to evolve as more studies have been performed in this patient population. The two initial Phase I dosing trials did not include any patients with HCC, and both recommended a tivantinib dose of 360 mg BID.37,38 The three most common adverse events in both trials were fatigue, nausea and vomiting. Dose-limiting toxicities observed by Yap et al included one case of grade 3 fatigue at 200 mg BID, two cases of febrile neutropenia at 400 mg BID and one incidence of a combination of mucositis, palmar–plantar erythrodysesthesia and hypokalemia at 400 mg BID. Two cases of pancytopenia, vomiting and dehydration at 360 mg BID were seen in the Rosen et al trial. The hematologic toxicity associated with tivantinib is expected, as HGF promotes hematopoiesis by stimulating production of cytokines by the stromal cells in the bone marrow.51,52

The Santoro et al42 trial was the first to evaluate tivantinib dosing exclusively in HCC patients. Based on the results of prior studies, a starting dose of 360 mg BID was selected. Overall, 20 of the 21 patients developed a drug-related event, with the most frequent events being neutropenia (52%), anemia (48%), asthenia (48%) and leukopenia (38%). Eleven patients (52%) developed adverse reactions that were grade 3 or grade 4 in severity, the most common of which were neutropenia (73%), anemia (45%) and leukopenia (36%). In general, neutropenia was the main cause of dose reduction, treatment interruption and treatment discontinuation. Four patients developed a serious adverse reaction that required treatment discontinuation. These reactions included one case of grade 3 anemia, one case of grade 3 anemia and grade 4 neutropenia, one case of grade 4 leukopenia and grade 4 neutropenia, and one case of grade 4 neutropenia with grade 5 septic shock leading to death. Due to interpatient variability, the authors did not find any correlations among adverse events with tivantinib dose, exposure or Child-Pugh status; however, they did recommend that tivantinib dosing in HCC patients be reduced to 240 mg BID due to the high amount of hematologic toxicity.

A pooled analysis from all Phase I/IB and Phase II studies assessed the exposure response of tivantinib in 289 patients, 73 of whom had HCC.53 The pharmacokinetic analysis demonstrated that the clearance of tivantinib in HCC patients was reduced by 67%, which resulted in a threefold increase in exposure compared to other types of cancer. A significant relationship was also found between tivantinib exposure and incidence of grade ≥2/3 neutropenia. The authors suggested that a starting dose of 240 mg BID of tivantinib rather than 360 mg BID would result in a decrease in the incidence of grade ≥3 neutropenia from 28% to 16% in HCC patients.

Similar results were seen in a later Phase II trial by Santoro et al,34 in which the treatment dose was reduced from 360 mg BID to 240 mg BID due to a high incidence of grade ≥3 neutropenia. Overall, hematologic toxicities (neutropenia, anemia and leukopenia) occurred more frequently in the tivantinib group than in the placebo group, and the incidence of grade ≥3 neutropenia was higher in the tivantinib 360 mg BID group than either the tivantinib 240 mg BID or the placebo group. There was even a trend toward longer overall survival in the tivantinib 240 mg BID group (7.5 months, 95% CI 4.4–not available) compared to the 360 mg BID group (6.4 months, 95% CI 4–9). Both the currently active Phase III trials, METIV-HCC and JET-HCC, are evaluating tivantinib at 120 mg BID. The METIV-HCC trial initially started patients on 240 mg BID; however, the dose was decreased to 120 mg BID in response to a higher than expected incidence of neutropenia.54 However, it should be noted that the METIV-HCC trial used a different formulation of tivantinib than the Santoro et al Phase II trial.23 Once the dose was decreased to 120 mg BID, a safety analysis showed that a dose of 120 mg BID of the new formulation resulted in an incidence of neutropenia similar to that seen at a dose of 240 mg in the Phase II trial.55 In addition, a pharmacokinetic analysis showed that the plasma exposure of the new formulation at 120 mg BID was comparable to that of the capsule formulation used in the Santoro et al trial.55 The JET-HCC trial set its dosing at 120 mg BID based on dosing studies in Japanese samples.43

Patients with a CYP2C19 polymorphism may require even lower doses of tivantinib. Yamamoto et al39 were the first to examine the effect of the CYP2C19 polymorphism in patients taking tivantinib. Forty-seven patients were included in the study, 14 of whom were considered poor metabolizers. The study was unable to demonstrate a relationship between dose level and plasma exposure; however, it was found that the mean exposure of tivantinib in poor metabolizers at 240 mg BID was equivalent to that of normal metabolizers at a dose of 360 mg BID. Based on this finding, the authors recommended that those with the CYP2C19 polymorphism receive doses of 240 mg BID, while those with normal CYP2C19 enzymes receive 360 mg BID. This study did not include any patients with HCC. A second trial was conducted by Okusaka et al43 to specifically look at tivantinib dosing in those with the CYP2C19 polymorphism and HCC. Twenty-eight patients were included in the study, seven of whom had the CYP2C19 polymorphism. All patients tolerated tivantinib at a dose of 120 mg BID, but once the dose was increased to 240 mg BID, five of nine normal metabolizers developed dose-limiting toxicities, either neutropenia or febrile neutropenia, which resolved with drug interruption and treatment with granulocyte colony-stimulating factor medications. Because normal metabolizers were unable to tolerate a dose of 240 mg BID, those with the CYP2C19 polymorphism were never escalated to a dose higher than 120 mg BID. The authors concluded that Japanese patients with HCC were unable to tolerate a dose of tivantinib >120 mg BID, irrespective of CYP2C19 polymorphism status. This study served as the basis for the dosing regimen in the JET-HCC trial.