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Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

ABSTRACT: Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m² in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19-76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3-4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42-113) and Median time to death was 129 days (95% CI 86-199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9-6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.

SUBMITTER: Brenner AJ

PROVIDER: S-EPMC7841164 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

Brenner Andrew J AJ Floyd John J Fichtel Lisa L Michalek Joel J Kanakia Kunal P KP Huang Shiliang S Reardon David D Wen Patrick Y PY Lee Eudocia Quant EQ

Scientific reports 20210127 1

Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m<sup>2</sup> in combination wit ...[more]

PMID: 33504881

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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.

Project description:BackgroundGlioblastoma (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.MethodsWe 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).Results6 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.ConclusionsSingle-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.

Project description:PurposeThe presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.Patients and methodsFifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined.ResultsThe MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months.ConclusionsEvofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.

Dataset Information

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

Publications

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

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