Adding Novel Antibody to Pazopanib Shows Promise in Soft Tissue Sarcoma

Combining the investigational anti-endoglin antibody TRC105 with the VEGF inhibitor pazopanib (Votrient) showed promising antitumor activity in patients with soft tissue sarcoma (STS), according to phase Ib data from a phase Ib/II study presented at the 2015 Connective Tissue Oncology Society (CTOS) Annual Meeting.

“Targeting VEGF and endoglin concurrently improves angiogenesis inhibition over targeting either pathway alone. Endoglin appears particularly relevant in sarcoma,” said Steven Attia, DO, of the department of Hematology/Oncology at Mayo Clinic in Jacksonville, Florida, who presented the results.

The phase Ib study accrued 18 patients with various sarcoma subtypes, including leiomyosarcoma (n = 9), angiosarcoma (n = 2), synovial sarcoma (n = 2), myxofibrosarcoma (n =2), epithelioid sarcoma (n = 1), epithelioid hemangioendothelioma (n = 1), and myxoid spindle cell sarcoma (n = 1).

The median patients age was 55, and patients were required to have an ECOG performance status of 0 or 1. Enrolled patients had progressed following chemotherapy. The median number of prior lines of systemic therapies was 2. Five patients had received prior treatment with pazopanib.

Following a 2- to 4-week lead-in period of pazopanib alone (800 mg orally once daily), TRC105 was administered starting in cycle 2. Dose escalation proceeded from an 8 mg/kg weekly infusion of TRC105 (n = 3) to 10 mg/kg weekly (n = 15). There were no dose-limiting toxicities. Primary outcome measures were recommended phase II dose and safety.

Six of 18 (33%) patients experienced ≥10% tumor reduction according to RECIST 1.1 criteria, including one ongoing completed response that lasted >30 weeks (as of June 2015). This patient had cutaneous angiosarcoma that had previously progressed on pazopanib/docetaxel therapy. The duration of therapy ranged from 8 weeks to >60 weeks.

“Half of the patients had some degree of tumor reduction including 4 patients who had progression on prior pazopanib,” said Attia. Median progression-free survival (PFS) was 5.5 months. Four patients received treatment for over a year.

Adverse events (AEs) of grade ≤2 that are characteristic of each drug did not increase in frequency or severity during concurrent dosing, according to Attia. The most common AE with TRC105 was grade ≤2 telangiectasia (including associated epistaxis and gingival bleeding). The most common AEs reported with pazopanib included grade ≤2 fatigue and diarrhea.

“Of note, there were no grade 4 drug-related toxicities, and infrequent grade 3 drug-related toxicities,” Attia said. “Dose escalation increased from 8 mg/kg to 10 mg/kg without dose-limiting toxicity. Importantly, the addition of TRC105 did not potentiate the toxicities of pazopanib.”

The endoglin pathway is upregulated following VEGF inhibition and is expressed on sarcoma tissue, according to Attia. Immunohistochemistry (IHC) has shown that endoglin is densely expressed on tumor vessels and on certain STS tumor tissue, particularly angiosarcoma.

Attia noted that tumor endoglin expression by IHC may serve as a biomarker to predict highly responsive STS subtypes. Efficacy endpoints of the phase Ib study will be correlated with endoglin IHC expression.

The phase II part of the phase Ib/II study is ongoing. It is a multicenter open-label, nonrandomized study in metastatic STS, in which patients are allowed to have received up to 4 lines of prior therapy. TRC105 is being administered at the recommended 10-mg/kg weekly dose established in phase Ib, along with pazopanib at 800 mg/day. Prior pazopanib is not permitted. The primary endpoint is PFS and the study is stratified by tumor-mitigated endoglin expression using IHC.

Tracon Pharmaceuticals, the company developing TRC105, hopes to enroll 94 patients with STS in the ongoing phase II research, including the 18 patients from phase Ib, 63 patients in phase II, and a 13-patient phase II cohort that includes only patients with angiosarcoma.

“Angiosarcoma is a tumor type that expresses high levels of endoglin, and we are very encouraged with the data that we have seen to date for TRC105 in combination with Votrient,” Charles Theuer, MD, PhD, president and CEO of Tracon, said in a statement. “We expect to report PFS data in soft tissue sarcoma stratified by tumor endoglin expression from the ongoing phase Ib/II trial in the first half of 2016. Planning for the phase III trial of TRC105 in combination with Votrient in angiosarcoma is currently underway, and we expect to initiate the trial in 2016.”

Attia S, Riedel RF, Robinson SI, et al. A phase IB dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS). Presented at: 2015 CTOS Annual Meeting; November 4-7; Salt Lake City Utah. Paper 002.