A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma

Abstract

Purpose: A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination. Patients and methods: Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as 5% viable cells. Results: 25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3þ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3þ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension. Conclusion: Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.

Elderberry interaction with pazopanib in a patient with soft‑tissue sarcoma: A case report and literature review

“…Intending to preserve the limb, surgery with perioperative (pre- or post-operative RT) is the treatment of choice in patients with localized sarcoma ( 22 ). In the present case, neoadjuvant pazopanib was added to radiation to improve the local control rates based on the results of the PASAART-1 and -2 trials ( 8 ). The GI toxicity experienced by the patient soon after starting pazopanib and the resolution of symptoms after stopping elderberry hint towards a possible drug-drug interaction.…”

“…Pazopanib is approved by the US Food and Drug Administration (USFDA) for patients with metastatic renal cell carcinoma and those with metastatic or locally advanced unresectable soft-tissue sarcoma (STS) who experienced progression after chemotherapy (7). Several trials in patients with localized high-risk extremity STS have also explored the utility of administering neoadjuvant pazopanib with preoperative radiation therapy (RT) with mixed results (8,9). The patient presented in the current study was consuming elderberry supplements when she started pazopanib.…”

Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma

“…This pharmacokinetic study was embedded in an international, multicenter phase II trial (NCT02575066) [ 5 ]. Written informed consent was obtained, the study protocol was approved by the local ethics commissions and the study was conducted in accordance with the declaration of Helsinki.…”

“…Haas et al showed that the neoadjuvant use of pazopanib 800 mg once daily in combination with 50 Gy preoperative radiotherapy (RT) seems tolerable and shows promising results in terms of efficacy also in patients with non-metastatic, intermediate or high-grade STS of the extremities, in the phase I PASART-1 study (NCT01985295) [ 4 ]. The combined treatment regimen was subsequently assessed in the phase II PASART-2 trial (NCT02575066) [ 5 ]. The main efficacy endpoint of this single arm trial was the rate of pathological complete response (pCR), defined as ≤5% viable tumor cells in the resection specimen at central pathology review.…”

Biology and Management of High-Grade Myxofibrosarcoma: State of the Art and Future Perspectives

“…In the Indian retrospective study, Kataria et al reported that, out of four MFS patients, two (50%) had SD and two (50%) had PD [95]. More recently, a prospective multicenter phase 2 trial (NCT02575066, acronym PASART-2) was performed to investigate the efficacy of neo-adjuvant pazopanib and concurrent external beam radiotherapy for high-risk, localized STS [96]. In the NCT02575066 trial, of the 25 patients, 8 (32%) had MFS.…”