This phase 1-2 trial assessed the efficacy and tolerability of an oral angiogenesis inhibitor—PTK787/ZK222584 (PTK)—in combination with intravenous doxorubicin for the treatment of advanced hepatocellular carcinoma (HCC) patients.
This phase 1-2 trial assessed the efficacy and tolerability of an oral angiogenesis inhibitor—PTK787/ZK222584 (PTK)—in combination with intravenous doxorubicin for the treatment of advanced hepatocellular carcinoma (HCC) patients.
In phase 1, advanced HCC patients received PTK at escalating doses together with doxorubicin 60 mg/m2 given as an intravenous bolus every 3 weeks to establish the maximum tolerated dose (MTD). Subsequently, in phase 2, all patients received the same regimen with oral PTK at the MTD dose every 3 weeks for a maximum of 6 cycles.
Nine patients were recruited in phase 1, with the MTD established as 750 mg daily. Overall, 27 patients received the regimen with PTK at 750 mg daily. The median age was 52 years (range, 23-73 years), and 63 percent of patients were chronic hepatitis B carriers. Notably, the majority of patients had Child-Pugh B cirrhosis. The overall response rate was 26.0%, with all the responding patients having partial response. Another 20% of patients achieved stable disease for at least 12 weeks. The median progression-free survival was 5.4 months (range, 0.27-23.6 months), and overall survival was 7.3 months (range, 0.8-23.6 months). The commonest grade 3 or 4 nonhematological toxicities were mucositis (11%) and alopecia (7%), respectively. Grade 3 or 4 neutropenia was observed in 7 (26%) patients; 2 had neutropenic sepsis.
The combination of PTK with intravenous doxorubicin shows encouraging activity in treating advanced HCC patients. Cancer 2010. © 2010 American Cancer Society.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide.1 Surgical resection and liver transplantation of HCC are the main curative treatments, but these operations are only applicable to patients with localized HCC.2, 3 Whereas the long-term survival of patients with early HCC amenable to surgical treatment has improved in recent years, the prognosis of patients with advanced HCC remains poor. Systemic chemotherapy has not been shown to improve patient survival thus far.4 Doxorubicin is among the most commonly used chemotherapies for HCC,5 with a single-agent tumor response rate of 0% to 15% in most reports.6, 7
HCC is a highly vascular tumor with a high propensity for vascular invasion and is closely associated with active neovascularization.8, 9 Thus, tumor angiogenesis plays an important role in the development and progression of HCC. Vascular endothelial growth factor (VEGF) is essential for tumor growth throughout the process of hepatocarcinogenesis.10 Its overexpression varies from 37% to 100% in HCC cells, and aberrant VEGF expression is a prominent feature in HCC.11 PTK787/ZK222584 (PTK) is an oral angiogenesis inhibitor and exerts its effect via antiangiogenic pathways.12 It is a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases. Moreover, it also has an inhibitory effect on platelet-derived growth factor (PDGF) receptor kinase and c-kit protein tyrosine kinase.13
In the present study, we aimed to assess the efficacy and tolerability of PTK in combination with intravenous doxorubicin for the treatment of advanced HCC patients. However, in view of the finding that most HCC patients have underlying cirrhosis with suboptimal liver function, the tolerance of this combination in this patient population is unknown. Thus, we started with a phase 1 trial and then progressed to a phase 2 trial after obtaining the maximum tolerated dose (MTD).
This was a single-center, prospective, single-arm, phase 1-2 study of PTK combined with intravenous doxorubicin in subjects with advanced HCC not suitable for either surgical or locoregional therapy. The protocol was approved by the local ethic committee and written consent was obtained from the patients before enrollment.
Advanced HCC patients who were not suitable for surgery or various locoregional therapies at the Queen Mary Hospital, Hong Kong were enrolled. HCC was diagnosed either by cytohistological confirmation or by noninvasive criteria according to European Association for the Study of the Liver criteria: cirrhotic patients either with focal lesion >2 cm with arterial hypervascularization demonstrated by 2 coincident imaging techniques or with focal lesion >2 cm with arterial hypervascularization demonstrated by 1 imaging technique and associated with alpha fetoprotein (AFP) level >400 ng/mL.14 Staging was by both American Joint Committee on Cancer (AJCC) and Cancer of the Liver Italian Program score. The eligibility criteria included adult patients aged 18 to 75 years, patients with Child-Pugh class A or B cirrhosis, Karnofsky performance status ≥70%, expected life expectancy of ≥12 weeks and with adequate organ function, and complete blood picture (absolute neutrophil count >1.5 × 109/L, platelet count >100 × 109/L) and biochemistry (total bilirubin of ≤2 × upper limit of normal, serum creatinine ≤2 × upper limit of normal, serum aspartate aminotransferase and alanine aminotransferase ≤5 × upper limit of normal). Moreover, the disease must be measurable with at least 1 lesion, which was at least 1 cm in 1 dimension either on computed tomography (CT) or magnetic resonance imaging (MRI) scan.
In the phase 1 part, 3 dose levels were tested, with 3 patients enrolled in each dose level as follows: level 1, PTK 750 mg daily + doxorubicin 60 mg/m2; level 2, PTK 1000 mg daily + doxorubicin 60 mg/m2; Level 3, PTK 1250 mg daily + doxorubicin 60 mg/m2. All patients received oral PTK together with doxorubicin 60 mg/m2 every 3 weeks for a maximum of 6 cycles. The dose-limiting toxicity (DLT) was defined as any grade 4 toxicities, grade 3 neutropenia, the occurrence of neutropenic sepsis, grade 3 thrombocytopenia, or any grade 3 toxicities that did not return back to grade 1-2 within 3 weeks except alopecia. If none of the first 3 patients developed DLT, the dose would be escalated to the next level. If 1 or more of the 3 patients developed DLT, another 3 patients would be added to that dose level. If 2 or more of the 6 patients experienced DLT, that dose level was considered intolerable, and the maximum tolerated dose was fixed at the next lower dose level. Dose modifications were required for drug-related toxicities. The dose of doxorubicin was modified based on the nadirs according to the guideline shown in Table 1. Subsequently, in phase 2, all patients received oral PTK at MTD together with doxorubicin 60 mg/m2 given as an intravenous bolus every 3 weeks for a maximum of 6 cycles.
|1||ANC||≥1 × 109/L||100% dose|
|≥ 0.75 × 109/L and <1 × 109/L||50% dose|
|<0.75 × 109/L||Omit dose|
|2||Platelet||≥75 × 109/L||100% dose|
|≥50 × 109/L and <75 × 109/L||50% dose|
|<50 × 109/L||Omit dose|
|3||Bilirubin||≤20 μmol/L||100% dose|
|≤40 μmol/L and >20 μmol/L||50% dose|
|≤60 μmol/L and >40 μmol/L||25% dose|
|>60 μmol/L||Omit dose|
|(Patients with a baseline bilirubin ≤40 μmol/L and >20 μmol/L should receive 50% dose)|
|4||≥Grade 3 toxicity in serum creatinine||Omit dose|
A full history and complete physical examination including performance status were performed at every clinical visit. Disease assessment was performed mainly by CT scan around every 3 cycles, that is, every 9 weeks. MRI and positron emission tomography with 11C-acetate as radioisotope were performed in case of uncertainty of response. Response was determined by independent radiologists and classified according to Response Evaluation Criteria in Solid Tumors criteria.15
Safety assessments consisted of monitoring and recording all the adverse events and serious adverse events throughout the study period. Apart from monitoring of vital signs, regular collection of urine, hematology, and blood chemistry of the enrolled subjects were performed. All patients who received at least 1 cycle of treatment were considered evaluable for safety. Toxicity was evaluated according to National Cancer Institute criteria.16
The primary endpoint of the phase 1 study was the MTD of PTK when combined with intravenous doxorubicin in treating advanced HCC patients. In phase 2, the primary endpoint was progression-free survival (PFS). The secondary endpoints included the objective tumor response rate (RR) and overall survival (OS). Moreover, disease control rate was defined as the percentage of patients who had either radiological response or stable disease (SD).
Survival analysis was computed by the Kaplan-Meier method. PFS was calculated from the date of commencement of study drugs to the date of documented progression or death. OS was calculated from the date of commencement of study drugs to the date of death or last follow-up. The analysis was performed on an intent-to-treat basis.
The main purpose of the phase 1 study was to find MTD with dose escalation. A minimum of 3 patients and a maximum of 6 patients at each dose level (3 dose levels) were recruited depending on the occurrence of DLT. In the phase 2 part, Simon's 2-stage optimal design was used for sample size estimation. In the first stage, 14 patients were enrolled. If ≤2 of the 14 patients responded to the treatment, accrual would be stopped, and the regimen was considered probably not worthwhile for further development in this patient population. If ≥3 patients responded, then additional patients would be enrolled to provide a sufficient number of patients to evaluate safety and efficacy of the regimen. All statistical analysis was performed by Statistical Package for Social Science version 13.0 for Windows (SPSS Inc., Chicago, Ill).
Between October 2005 and June 2006, 9 patients were enrolled into the phase 1 part. At a PTK dose level of 750 mg daily, initially 3 patients were recruited, but 1 patient developed DLT (neutropenic fever). Thus, an additional 3 patients were recruited, and no DLT was observed at the dose level of 750 mg daily. The dose was escalated to 1000 mg with 3 patients recruited. DLT occurred in all 3 recruited patients. Two patients developed grade 4 neutropenia as DLT, whereas 1 patient had grade 4 mucositis as DLT. Therefore, the MTD was defined as 750 mg daily. An additional 21 patients were recruited in phase 2 using this MTD of PTK. The results of the 27 patients who received PTK at the dose of 750 mg daily together with intravenous doxorubicin are analyzed below.
Twenty-seven patients had received PTK 750 mg daily together with doxorubicin 60 mg/m2 for the treatment of advanced HCC. Table 2 shows the demographic data of these patients. The median age was 52 years (range, 23-73 years), and the majority were men. All the enrolled patients had good performance status. Seventeen (63%) patients were chronic hepatitis B carriers, and 2 (9.1%) patients were chronic hepatitis C carriers. Notably, only 2 (7.4%) patients had underlying Child-Pugh A cirrhosis, and of the remaining patients, 25 (92.6%) had Child-Pugh B cirrhosis. Twenty-one Child-Pugh B patients had a score of 7; only 4 patients had a score of 8. Nineteen (70.4%) patients had stage 4 disease according to the AJCC staging system, whereas 3 (11.1%) and 5 (18.5%) patients had stage IIIC and stage IIIA disease, respectively. The commonest site of metastases was lung (63%), and portal vein tumor thrombosis was presented in 4 (14.8%) patients. More than half of the patients had received liver resection for HCC, and about one-third of the patients had undergone transcatheter arterial chemoembolization for advanced HCC. Moreover, 6 patients had radiofrequency ablation, and only 1 patient had received alcohol injection for HCC. Notably, none of the enrolled patients had received any prior systemic therapy or radiotherapy for the treatment of advanced HCC.
|Karnofsky performance score|
|HBsAg positive||17 (63)|
|Anti-HCV antibody positive||2 (9.1)|
|AJCC stage at the time of study entry|
|Invasion of major vessels|
|Portal vein invasion||4 (14.8)|
|Hepatic vein invasion||0|
|Inferior vena cava invasion||2 (7.4)|
|Liver resection||15 (56)|
|Local ablative procedures|
|Alcohol injection||1 (3.7)|
Overall, the median number of cycles of PTK at 750 mg with intravenous doxorubicin was 5 (range, 1-6). Disease assessments could not be done in 4 patients, as they discontinued the study early for the following reasons: 2 patients died of a hemorrhagic complication after 1 course of treatment, and the other 2 patients discontinued early because of treatment-related toxicities. The overall RR with the remaining 23 evaluable patients was 26.0%. There was no complete response observed, and 6 (26.0%) patients had achieved partial response (PR). Another 5 (21.7%) patients achieved SD for at least 12 weeks. Overall, the disease control rate was 47.7%. Among the 14 patients with elevation of AFP at baseline, 5 patients had an AFP decline of >50%. Figure 1 shows the typical CT scan images of a patient with PR to the treatment regimen. The median PFS was 5.4 months (range, 0.27-23.6 months) (Fig. 2), and OS was 7.3 months (range, 0.8-23.6 months) (Fig. 3).
All patients were assessed for toxicities. Table 3 shows the details of treatment-related toxicities in the enrolled patients. Regarding nonhematological toxicities, nausea (67%) was the most commonly encountered toxicity, followed by alopecia (59.3%) and diarrhea (40.7%). The most common grade 3 or 4 nonhematological toxicities were mucositis (11%) and alopecia (7%). Hypertension occurred in 6 (22.2%) patients, although the majority of the patients had only grade 1 or 2 toxicity. Of note, 2 patients had developed hemorrhagic complications after receiving only 1 course of the combination treatment; 1 patient died of uncontrolled gastrointestinal bleeding, and the other died of cerebellar hemorrhage. Ten patients had developed neutropenia; 70% of these patients had grade 3 or 4 toxicity. Overall, neutropenic sepsis was reported in 2 patients. Ten (37%) patients required dose reduction of doxorubicin according to the schedule depicted in Table 1. Seven patients required dose reduction because of grade 3 or 4 neutropenia, and the other 3 patients because of grade 3 mucositis.
|Toxicity||Any Grade||Grade 1 or 2 (%)||Grade 3 (%)||Grade 4 (%)|
|Diarrhea||11 (40.7%)||10 (37%)||0 (0%)||1 (3.8%)|
|Malaise||6 (22.2%)||6 (22.2%)||0 (0%)||0 (0%)|
|HFSR||7 (25.9%)||7 (25.9%)||0 (0%)||0 (0%)|
|Alopecia||16 (59.3%)||14 (51.9%)||2 (74.1%)||0 (0%)|
|Rash||3 (11.1%)||3 (11.1%)||0 (0%)||0 (0%)|
|Abdominal pain||3 (11.1%)||3 (11.1%)||0 (0%)||0 (0%)|
|Hypertension||6 (22.2%)||5 (18.5%)||1 (3.8%)||0 (0%)|
|Nausea||17 (63.0)||16 (59.3%)||1 (3.8%)||0 (0%)|
|Mucositis||12 (44.5%)||9 (33.3%)||3 (11.1%)||0 (0%)|
|Hemorrhage||2 (7.4%)||0 (0%)||0 (0%)||2 (7.4%)|
|Thrombocytopenia||13 (48.1%)||12 (44.5%)||0 (0%)||1 (3.8%)|
|Neutropenia||10 (37.0%)||3 (11.1%)||1 (3.8%)||6 (22.2%)|
|Anemia||8 (29.6%)||7 (25.9%)||1 (3.8%)||0 (0%)|
Advanced HCC is a relatively chemoresistant tumor and is highly refractory to cytotoxic chemotherapy. Single-agent doxorubicin alone has been shown to produce an RR of about 0% to 15%, but with no proven survival benefit.17 More recently, a randomized phase 2 study showed encouraging survival results in combining sorafenib with doxorubicin for the treatment of advanced HCC patients.18 In patients had doxorubicin alone, the median PFS and OS were 2.8 and 6.5 months, respectively. In contrast, the median PFS (6.9 months) and OS (13.7 months) were doubled in patients receiving the combination of sorafenib and doxorubicin. Despite these promising survival results, doxorubicin either as a single agent or in combination of sorafenib had a low overall response rate (2%-4%). This pivotal combination study shows the promise in combining a targeted agent together with chemotherapy in the treatment of advanced HCC patients. Similar to the sorafenib and doxorubicin combination study, we report the results of our phase 1-2 trial in assessing the efficacy and tolerability of another targeted therapy—PTK in combination with intravenous doxorubicin for the treatment of advanced HCC. The overall disease control rate was 47.7%, with 26.0% of patients achieving PR for at least 12 weeks. Moreover, the median PFS and OS were 5.4 months and 7.3 months, respectively. Thus, the current results demonstrate encouraging preliminary activity in using PTK and intravenous doxorubicin combination in the management of advanced HCC. Interestingly, when PTK was combined with chemotherapy in the treatment of metastatic colorectal cancer (MCRC), there was no survival benefit when compared with chemotherapy alone.19, 20 This may be attributed to the finding that angiogenesis plays a more important role in the pathogenesis of HCC than MCRC.
Angiogenesis is a complex, multistep process initiated by the release of angiogenic factors from tumor cells. Angiogenic factors, such as VEGF,9 PDGF,21 basic fibroblast growth factor,22 angiopoietins,23 and heparanase,10 released from both the tumor cells and the surrounding stromal cells, participate in the neovascularization of HCC. In analogue to PTK, bevacizumab is another main antiangiogenic agent. Bevacizumab binds VEGF with high affinity,24 thereby inhibiting tumor growth, peregrine/anticrime growth factor release, and metastasis.25 Moreover, it may enhance chemotherapeutic agent delivery to the tumor by normalizing tumor vasculature,26 decreasing the elevated interstitial pressure in the tumor, and increasing vascular permeability.25 Bevacizumab as a single agent or in combination with other agents has shown initial encouraging activity in treating advanced HCC. In the study conducted by Siegel et al., among 46 enrolled patients with locally advanced HCC, single-agent bevacizumab achieved a 13% RR, 65% of patients were progression-free at 6 months,27 and the median time to tumor progression was 6.9 months. Moreover, a phase 2 study conducted by Thomas et al.28 showed promising activity of bevacizumab in combination with erlotinib for the treatment of advanced HCC. In this nonrandomized phase 2 study, the combination showed 25% PR and 37.5% SD. The PFS and OS were 9 months and 15.7 months, respectively. All of the above studies support the notion that the antiangiogenic approach is promising in the management of advanced HCC.
Recently, 2 phase 3 randomized placebo-controlled trials in the West29 and Asia-Pacific region30 have clearly shown the survival benefit in using single-agent sorafenib in patients with advanced HCC. In fact, sorafenib is an antiangiogenic multitargeted tyrosine kinase inhibitor. It exerts its antiangiogenic effect by inhibiting VEGF and PDGF receptors, and targets cancer cell proliferation via Raff kinase inhibition. It is currently the only approved treatment for advanced HCC. In the Western trial, the patients randomized to the sorafenib arm had median time to progression (TTP) of 5.5 months and OS of 10.7 months. Conversely, in the Asian trial, the TTP and OS were 2.8 months and 6.5 months, respectively. Of note, the overwhelming majority of the patients enrolled in these 2 pivotal sorafenib trials had Child-Pugh A cirrhosis, with good clinical parameters and preserved liver function. In contrast, most of the recruited patients in this study had Child-Pugh B cirrhosis. This was because during the phase 2 recruitment period, most of patients with Child-Pugh A cirrhosis were offered sorafenib. However, sorafenib was not yet the standard treatment for advanced HCC patients with underlying Child-Pugh B cirrhosis; thus, most of these patients were recruited into clinical trials. Despite these adverse prognostic factors in patients recruited in our present study, the survival results demonstrated in the current study were at least comparable to the 2 pivotal sorafenib studies. Moreover, 26% of patients had partial response in our study, which was in distinct contrast to the 3% to 6% RR obtained in the SHARP29 and Asian studies.30
Doxorubicin is usually associated with significant hematological and nonhematological treatment-related toxicities. In particular, grade 3 or 4 neutropenia is frequently encountered in patients treated with doxorubicin.7 In the sorafenib and doxorubicin combination study,18 > one-third of the recruited patients experienced significant grade 3 or 4 neutropenia regardless of whether they received single-agent doxorubicin or the sorafenib and doxorubicin combination. Similarly, in the present study, > one-third of the patients developed neutropenia, with neutropenic sepsis occurring in 2 patients. The commonest nonhematological toxicities encountered in our current study were mucositis and alopecia, which were caused by the administration of doxorubicin. Overall, > one-third of the patients required dose reduction for doxorubicin during their treatment courses. This implies that doxorubicin treatment may pose significant treatment-related toxicities in advanced HCC patients. Thus, doxorubicin may not be an ideal choice of chemotherapy partner in future clinical trials for advanced HCC. Conversely, mild hypertension occurred in around one-fifth of the recruited patients, and it was likely related to PTK administration.31 Bleeding complication is usually among the commonest causes of mortality in patients receiving antiangiogenic-based therapy. In the phase 2 study of bevacizumab in HCC conducted by Siegel et al.,27 11% of the enrolled patients had grade 3 or higher hemorrhage, including 1 patient who died of variceal bleeding. Similarly, in our current study, 2 patients died of uncontrolled bleeding after the administration of PTK and doxorubicin. However, it is worthwhile to note that the patients recruited in this study had more advanced cirrhosis and hence were more prone to bleeding complications. Thus, these phenomena suggest that zealous patient selection is needed before offering antiangiogenic therapy to patients with advanced HCC patients.
This is the first study on combination of PTK with intravenous doxorubicin for HCC patients. Several major limitations of the study needed to be addressed. First, the current combination is an empirical combination without preclinical data supporting potential synergistic action between doxorubicin and PTK. Also, the relative contribution of either agent in the treatment of advanced HCC is still unknown, although in a phase 1 study conducted by Koch et al., a 750-mg daily dosage of PTK showed preliminary efficacy in advanced HCC patients.32 Second, the study does not include any detailed pharmacokinetic or pharmacodynamic parameters for analysis. Third, disease assessment was only performed every 9 weeks instead of the current standard of 6 to 8 weeks in most systemic trials of advanced HCC patients. Thus, the calculation of PFS, which largely depends on the schedule of radiological assessment, may be overestimated. Last but not least, doxorubicin may not be an ideal chemotherapy partner because of its significant treatment-related toxicities and unproven efficacy in advanced HCC. Nevertheless, this study is an important proof-of-concept study that demonstrates the encouraging activity in using an antiangiogenic agent—PTK—to augment the efficacy of intravenous doxorubicin in treating advanced HCC patients. On the basis of our current results, the idea of combining antiangiogenic agents together with chemotherapy may warrant further evaluation in future clinical trials.
Supported by a research grant from Novartis and the University of Hong Kong.