Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Ahluwalia MS

PROVIDER: S-EPMC10491825 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Ahluwalia Manmeet S MS Rogers Lisa R LR Chaudhary Rekha R Newton Herbert H Ozair Ahmad A Khosla Atulya A AA Nixon Andrew B AB Adams Bonne J BJ Seon Ben K BK Peereboom David M DM Theuer Charles P CP

Communications medicine 20230908 1

<h4>Background</h4>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.<h4>Methods</h4>We conducted a pre-registered (NCT01564914), multic ...[more]

PMID: 37684373

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Project description:BackgroundBevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.MethodsThis multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.ResultsNinety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).ConclusionsBevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

Project description:BACKGROUND: Glioblastoma (GBM) remains an incurable malignancy with rapid progression and poor survival. GBM exhibits a hypoxic nature, and treatment with bevacizumab (BEV) may increase intratumoral hypoxia. TH-302 is an investigational prodrug that selectively releases the DNA cross-linker (Br-IPM) under hypoxic conditions. A phase I/II trial (NCT01403610) is evaluating the safety and efficacy of combined TH-302 and BEV treatment in patients with BEV-refractory GBM and investigating pharmacodynamics biomarkers. METHODS: Patients were randomized to TH-302 single dose (575 mg/m2) or placebo, administered one day before surgery, followed by TH-302 (240-670 mg/m2) + BEV treatment until disease progression. Before surgery, pimonidazole (Pimo) was administered to label hypoxia and the excised tumor tissue was processed for immunohistochemistry. Endogenous plasma metabolites and plasma carbonic anhydrase IX (CA-IX) were also assessed. RESULTS: Immunohistochemistry was conducted on 11 resected tumors. A strong correlation and co-localization was observed between Pimo (exogenous hypoxia marker) and CA-IX (endogenous hypoxia marker) expression (r = 0.9, p < 0.001). Plasma CA-IX levels correlated well with tissue CA-IX expression. The hypoxic fraction tended to be higher in patients with a stable disease or partial tumor responses. Patients treated with TH-302 prior to surgery tended to have higher levels of γH2AX positive cells, indicating increased DNA damage, and lower Ki67 (a proliferation marker) compared with patients who received placebo. Patients treated with a single dose of TH-302 prior to surgery with higher levels of γH2AX-positive cells tended to have better outcome. Metabolomic profiles in plasma and in tumor tissue differed with degree of hypoxia. CONCLUSION: The results suggest that CA-IX as a hypoxia marker might be a predictive biomarker for TH-302 and γH2AX a response biomarker for TH-302. Correlative studies show metabolomic profile varies with tumor hypoxia degree, indicating plasma metabolites for further study as potential prognostic or treatment response markers.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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