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Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

ABSTRACT: BACKGROUND:Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1? (HIF-1?), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1? in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1? following bevacizumab treatment, resulting in synergistic antitumor effects. PATIENTS AND METHODS:Patients with refractory solid tumors were enrolled. Objectives were to evaluate the modulation of HIF-1? protein and target genes in tumor biopsies following administration of the combination of EZN-2208 administered weekly?×?3 (days 1, 8, 15) and bevacizumab administered every 2 weeks, in 28-day cycles, and to establish the safety and tolerability of the combination. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were obtained following bevacizumab alone (before EZN-2208) and after administration of both study drugs. RESULTS:Twelve patients were enrolled; ten were evaluable for response. Prolonged stable disease was observed in 2 patients, one with HCC (16 cycles) and another with desmoplastic round cell tumor (7 cycles). Reduction in HIF-1? protein levels in tumor biopsies compared to baseline was observed in 5 of 7 patients. Quantitative analysis of DCE-MRI from 2 patients revealed changes in K(trans) and k(ep). The study closed prematurely as further clinical development of EZN-2208 was suspended by the pharmaceutical sponsor. CONCLUSION:Preliminary proof-of-concept for modulation of HIF-1? protein in tumor biopsies following administration of EZN-2208 was observed. Two of 10 patients had prolonged disease stabilization following treatment with the EZN-2208 and bevacizumab combination.

SUBMITTER: Jeong W

PROVIDER: S-EPMC7670584 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

Jeong Woondong W Park Sook Ryun SR Rapisarda Annamaria A Fer Nicole N Kinders Robert J RJ Chen Alice A Melillo Giovanni G Turkbey Baris B Steinberg Seth M SM Choyke Peter P Doroshow James H JH Kummar Shivaani S

Investigational new drugs 20131116 2

<h4>Background</h4>Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1α following bevacizumab treatment, resulting in synergistic antitumor effects.<h4>Patients and meth ...[more]

PMID: 24242862

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Project description:BackgroundRecent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations. However, timely and efficient identification of neoantigens is still one of the major obstacles to using personalized neoantigen-based cancer immunotherapy.MethodsTwo different pipelines of neoantigens identification were established in this study: (1) Clinical grade targeted sequencing was performed in patients with refractory solid tumor, and mutant peptides with high variant allele frequency and predicted high HLA-binding affinity were de novo synthesized. (2) An inventory-shared neoantigen peptide library of common solid tumors was constructed, and patients' hotspot mutations were matched to the neoantigen peptide library. The candidate neoepitopes were identified by recalling memory T-cell responses in vitro. Subsequently, neoantigen-loaded dendritic cell vaccines and neoantigen-reactive T cells were generated for personalized immunotherapy in six patients.ResultsImmunogenic neo-epitopes were recognized by autologous T cells in 3 of 4 patients who utilized the de novo synthesis mode and in 6 of 13 patients who performed shared neoantigen peptide library, respectively. A metastatic thymoma patient achieved a complete and durable response beyond 29 months after treatment. Immune-related partial response was observed in another patient with metastatic pancreatic cancer. The remaining four patients achieved the prolonged stabilization of disease with a median PFS of 8.6 months.ConclusionsThe current study provided feasible pipelines for neoantigen identification. Implementing these strategies to individually tailor neoantigens could facilitate the neoantigen-based translational immunotherapy research.TRIAL REGSITRATION. ChiCTR.org ChiCTR-OIC-16010092, ChiCTR-OIC-17011275, ChiCTR-OIC-17011913; ClinicalTrials.gov NCT03171220.FundingThis work was funded by grants from the National Key Research and Development Program of China (Grant No. 2017YFC1308900), the National Major Projects for "Major New Drugs Innovation and Development" (Grant No.2018ZX09301048-003), the National Natural Science Foundation of China (Grant No. 81672367, 81572329, 81572601), and the Key Research and Development Program of Jiangsu Province (No. BE2017607).

Dataset Information

Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

Publications

Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

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