A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study

Introduction To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin. Methods Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during cycles 1 and 2. Results Thirty-five patients were enrolled. The MTD was reached at the first DL, (pazopanib 400 mg daily + cisplatin 75 mg/m2 every 21 days). Main DLTs were pulmonary embolism, neutropenia, thrombocytopenia, and elevation of liver enzymes. Overall, most common adverse events were anemia (83%), fatigue (80%), thrombocytopenia (80%), neutropenia (73%), hypertension (59%), neurotoxicity (56%), and anorexia (53%). Sixteen patients (46%) discontinued the study due to toxicity. One patient (sarcoma) had a complete response, and three patients (one with breast cancer and two with ovarian cancers) had a partial response. Pharmacokinetic (PK) analyses showed interactions with aprepitant, resulting in increased exposure to pazopanib, which might explain partly the poor tolerance of the combination. Conclusion Cisplatin and pazopanib could not be administered at their single agent full doses, partly due to a PK interaction between pazopanib and aprepitant. Funding This work was funded by GlaxoSmithKline and by the charity Ligue Nationale de Lutte Contre le Cancer. Trial registered ClinicalTrials.gov identifier, NCT01165385.


INTRODUCTION
Therapeutic options are limited in advanced or refractory malignancies. The addition of angiogenesis inhibitors to cytotoxic drugs could enhance antitumor activity. Moreover, anti-angiogenic agents may normalize ''leaky'' tumor vasculature and increase the delivery of chemotherapy agents to the tumor site and enhance their efficacy [1]. The combination of chemotherapy and angiogenesis inhibition is already approved in some tumor types, using the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab.
Preclinical data suggested that anti-angiogenic agents targeting multiple tyrosine kinases might have better anti-tumor activity [7].
Pazopanib is an orally active multi-targeted tyrosine kinase inhibitor of VEGFR-1, 2, and 3, platelet derived growth factor receptor a and b, fibroblast growth factor receptor 1 and 3, and c-Kit. It has been approved for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcomas at a dose of 800 mg daily. Tested as a single agent in several phase II studies, pazopanib has also demonstrated efficacy in various types of solid tumors, such as metastatic differentiated thyroid cancers [8], medullary thyroid carcinoma [9], gastroenteropancreatic neuroendocrine tumors [10], and recurrent/metastatic breast cancer treated with up to two prior lines of chemotherapy [11].
Several combinations of pazopanib and chemotherapy have been investigated in clinical trials, using gemcitabine [12], pemetrexed [13,14], paclitaxel [15,16], paclitaxel and carboplatin [17], paclitaxel and lapatinib [18], docetaxel [19] or ixabepilone [20]. For triple negative breast cancer, where no targeted treatment is approved, recent data favor an activity of platinum salts and a positive impact of anti-angiogenic treatment [5]. Platinum salts are major cytotoxic agents, used in various types of advanced tumors. The feasibility of combining cisplatin with pazopanib was investigated in a phase I, open-label, dose-escalation, and pharmacokinetic (PK) study, to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) in patients with recurrent or refractory solid malignancies. Blood samples were collected for PK evaluation, and a population PK analysis was performed as previously described [21]. Imaging (CT scan or MRI) for efficacy assessment was to be performed every two cycles or sooner if clinically indicated. were not considered at the study initiation. DL1RS was considered safe with 1 DLT over 9 evaluable patients. In total, among 29 evaluable patients, 5 experienced at least one DLT: 1 in DL1, 3 in DL2, and 1 in DL1RS (Table 3).

DISCUSSION
In this study, we assessed the feasibility and the MTD of pazopanib plus cisplatin, a combination that has the potential for providing therapeutic benefits in patients with recurrent/refractory tumors, due to the addition of anti-angiogenic effects to chemotherapy.
Main toxicities were myelosuppression, fatigue, and hypertension, consistent with the known toxicity profile of both drugs. It has been shown that the addition of tyrosine kinase inhibitors (TKI) significantly increases toxicity compared to chemotherapy alone, especially myelosuppression, fatigue, skin toxicity, hypertension, and diarrhea [22]. Since no previous study assessed the combination of cisplatin and pazopanib, the starting doses were chosen below those used in monotherapy. In addition, DLT were evaluated over cycles 1 and 2 to observe cumulative toxicities as suggested for targeted agents [23].
The first dose-finding study in patients with cancer that yielded the recommendation of the 800-mg daily dose showed limited toxicity, the most frequent being hypertension [24]. In renal cell carcinoma, pazopanib compared to sunitinib appeared to be better tolerated with a few G3 or 4 adverse events [25]. In medullary thyroid carcinoma, G3 or 4 toxicities were infrequent, consisting mostly of fatigue (14%) or diarrhea (9%) [9]. In breast cancer, 14% of patients had G3 or 4 hepatic enzymes increases, 14% had G3 or 4 neutropenia, and 14% had G3 hypertension [11].
Several studies have investigated pazopanib and cytotoxic drugs combination. In the phase I dose-escalation study of pazopanib combined with gemcitabine, the MTD could not be determined, since no DLTs were observed at the highest DL, pazopanib 800 mg and gemcitabine 1250 mg/day, i.e., doses used as single agent for each drug [12]. Most frequent adverse events were fatigue, nausea, anorexia, and decreased leucocytes. One-third of patients experienced G4 neutropenia or thrombocytopenia.
The combination with pemetrexed was explored in a phase I study in 25 patients with advanced solid tumors after failure of standard therapy [13]. The MTD was pazopanib 800 mg daily and pemetrexed 500 mg/m 2 q3W; 44% of patients experienced G4 neutropenia at some point during the study. Two patients out of 20, both with NSCLC, had partial response. These promising results led to perform a phase II trial of pazopanib ? pemetrexed compared to cisplatin ? pemetrexed in NSCLC [14]. This trial was discontinued prematurely due to unacceptable toxicity in the pazopanib ? pemetrexed arm (3 toxic deaths among 61 patients).
Interestingly, pazopanib was safe in combination with continuous infusion of ifosfamide, since doses up to 1000 mg could be administered without major toxicity [26].
However, the same combination with administration of ifosfamide in bolus was poorly tolerated and pazopanib had to be decreased to 200 mg.
A phase I trial showed that pazopanib 800 mg daily and paclitaxel 80 mg/m 2 at day