Unacceptable Toxicity in Phase I Trial Adding Pazopanib to Chemotherapy for Sarcoma: A Precautionary Tale

Research Article

Sarcoma Res Int. 2017; 4(1): 1037.

Verschraegen C*, Rehman H, Kalof A, Lemos D, Anker CJ, Leavitt B and Lisle J

Verschraegen C*, Rehman H, Kalof A, Lemos D, Anker CJ, Leavitt B and Lisle J

University of Vermont Cancer Center, Burlington, USA

*Corresponding author: Claire Verschraegen, University of Vermont Cancer Center, Burlington, VT, USA

Received: January 03, 2017; Accepted: January 25, 2017; Published: January 27, 2017

Abstract

Purpose: To determine the optimal dose (Phase II Recommended Dose (P2RD)) of pazopanib in combination with a biweekly gemcitabine and docetaxel regimen in patients with high risk Soft Tissue Sarcomas (STS) treated in the neoadjuvant setting.

Methods: Chemotherapy naïve patients with high risk STS, greater than 5cm and amenable to definitive resection were treated with gemcitabine 1500mg/ m² and docetaxel 50mg/m² every 2 weeks for up to 8 doses. Pazopanib at an initial dose of 400mg daily was added on Days 4 to 13 of each 2 week-dosing period. Patients received definitive therapy with surgery and radiation therapy, as indicated. Primary endpoint and secondary endpoints were P2RD and safety, pathologic response, and progression-free survival, respectively.

Results: The trial was stopped for treatment intolerance after accruing 6 patients in the initial cohort. Only one patient received all 8 planned doses without reductions or delays. In the first cycle, 2 patients had a DLT of diarrhea with neutropenic fever and diverticulitis from C. Difficile infection, each. Elevated aminotransferase led to pazopanib discontinuation in 2 cases. Grade 2 and 3 adverse events and leading to a dose modification were infection in 4 patients, diarrhea in 3, liver anomalies in 3, neutropenia in 2, and pulmonary embolism in 1. There were 1 complete and 1 partial pathologic responses. Five patients recurred with a median PFS of 10.4 months (range, 6.2 to 26 months), 2 patients died. Only 1 patient remains alive and free of disease.

Conclusion: Pazopanib should not be combined with chemotherapy. There is no evidence of added benefits and the observed toxicity is not warranted in the neoadjuvant setting. They should rather be used sequentially in patients with progressive STS.

Keywords: Soft tissue sarcomas; Phase I trial; Gemcitabine; Docetaxel; Pazopanib

Introduction

Soft Tissue Sarcomas (STS) represent a very heterogeneous family of tumors derived from mesenchymal cells. Despite a variety of cells of origin, most STS are treated with the same chemotherapy regimens, although there are some exceptions. For example alveolar, soft part sarcoma is now treated with tyrosine kinase inhibitor in first line. Treatment of sarcomas is multidisciplinary, but the approach to the management of high risk primary STS remains controversial. While the combination of surgery and radiotherapy prevents local recurrence, the role of adjuvant or neoadjuvant chemotherapy to reduce the risk of metastatic disease or to reduce tumor size to facilitate an R0 resection is not established. Over 50% of patients with very high risk STS will eventually develop metastatic disease. Additional curative options must be identified in appropriate patients. The definition of high risk STS is also somewhat controversial. For the purpose of this clinical trial, we considered any high grade STS greater than 5cm in the greatest dimension, for which chemotherapy could be indicated in the first line setting. Although doxorubicinbased regimens are favored in first line for metastatic disease, the new combination of docetaxel and gemcitabine might have greater activity in some STS subtypes [1] with less long term toxicity [2], especially when administered on an every two-week schedule [3].

Vascular Endothelial Growth Factor (VEGF) is a potent tumorproduced angiogenic factor whose overexpression is usually associated with an adverse outcome in most STS [4]. Median pretreatment serum VEGF levels are significantly raised in patients with grade 2 and grade 3 sarcomas compared with concentrations in patients with benign lesions. Serum VEGF expression correlates with grade in soft tissue sarcoma and reflects response to treatment [5]. The tyrosine kinase inhibitor, pazopanib, is now approved for recurrent or metastatic STS, with good clinical benefit [6]. Health-related quality of life does not improve with pazopanib, but the improvement in progressionfree survival without impairment of quality of life was considered meaningful. When administered as a single agent, side effects are manageable and include hypertension, diarrhea, nausea, liver inflammation, mild myelosuppression, and hair de-pigmentation [7]. In combination with chemotherapy, however, there is a synergistic effect on the toxicity profile and combination with multi-agent chemotherapy is not tolerable (Table 1) [8-14]. This study proposes to combine the least toxic chemotherapy regimen [3] with intermittent pazopanib administration to avoid pharmacokinetics synergy, to be tested in the neoadjuvant setting for patients with high risk STS.