Endoglin inhibitor TRC105 with or without bevacizumab for bevacizumab-refractory glioblastoma (ENDOT): a multicenter phase II trial.

BACKGROUND: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM. METHODS: We conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS). RESULTS: 6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed. CONCLUSIONS: Single-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.

Glioblastoma is an aggressive and lethal brain tumor, with patients typically expected to survive for 14 to 16 months after diagnosis. Nearly all patients experience tumor recurrence once conventional treatment strategies fail, after which a drug called bevacizumab is used. However, subsequent treatment options are extremely limited. We performed a clinical trial in which we investigated how safe and effective a new drug called TRC105 (carotuximab) is in patients who no longer respond to chemotherapy, radiotherapy or bevacizumab. We tested TRC105 both with and without bevacizumab, since TRC105 might enhance the activity of bevacizumab. We found that patients survived for an average of 5.7 months when given TRC105 and bevacizumab in combination. These findings suggest that further clinical trials are needed to confirm whether or not this combination therapy is a useful approach in patients with glioblastoma recurrence.

An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC). SUBJECTS, MATERIALS, AND METHODS: Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. RESULTS: Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-ß receptor 3 correlated with overall response rate. CONCLUSION: TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064). IMPLICATIONS FOR PRACTICE: TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer.

PURPOSE: Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab. EXPERIMENTAL DESIGN: Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. RESULTS: TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single-agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and 6 remained without progression for longer periods than during their prior VEGF inhibitor therapy. CONCLUSIONS: TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor-refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.

A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors.

INTRODUCTION: TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed. PURPOSE: Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression. METHODS: Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months. CONCLUSIONS: When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER.

A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.

PURPOSE: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. PATIENTS AND METHODS: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. RESULTS: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. CONCLUSION: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer.

Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis. RESULTS: Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during >or= 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions. CONCLUSION: Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.