A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors

Weng, David E.; Masci, Paul; Radka, Susan F.; Jackson, T. Elise; Weiss, Patricia; Ganapathi, Ram; Elson, Paul; Capra, William B.; Parker, Vann P.; Lockridge, Jennifer A.; Cowens, J. Wayne; Usman, Nassim; Borden, Ernest C.

doi:10.1158/1535-7163.mct-04-0210

Cited by 73 publications

(34 citation statements)

References 15 publications

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“…In a mouse nasopharyngeal carcinoma model developed in National Cancer Centre Singapore, addition of antiangiogenic agents potentiated the effects of photodynamic therapy in addition to having antitumor effects in themselves (21). Finally, a small phase I study of a VEGFR-1 inhibitor in solid tumors showed few minor responses in nasopharyngeal carcinoma patients (22).…”

Section: Introductionmentioning

confidence: 99%

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Lim

Ivy

et al. 2011

Clinical Cancer Research

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Purpose: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma.Experimental Design: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamiccontrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done.Results: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume.Conclusion: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile.

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Section: Introductionmentioning

confidence: 99%

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Lim

Ivy

et al. 2011

Clinical Cancer Research

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“…In situ hybridization revealed that during the progression from a low-grade glioma to glioblastoma, the expression of VEGFR1 mRNA precedes that of VEGFR2 mRNA (20). Moreover, recent studies have reported that the significant inhibition of tumor growth could be achieved using a number of VEGFR1-targeting approaches (34)(35)(36)(37)(38)(39)(40). Thus, VEGFR1 is another attractive target for cancer vaccines against tumor angiogenesis.…”

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confidence: 99%

Inhibition of Tumor Growth with Antiangiogenic Cancer Vaccine Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 1

Ishizaki¹,

Tsunoda²,

Wada³

et al. 2006

Clinical Cancer Research

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Purpose: Antiangiogenic therapy is now considered to be one of promising approaches to treat various types of cancer. In this study, we examined the possibility of developing antiangiogenic cancer vaccine targeting vascular endothelial growth factor receptor 1 (VEGFR1) overexpressed on endothelial cells of newly formed vessels in the tumor. Experimental Design: Epitope-candidate peptides were predicted from the amino acid sequence of VEGFR1 based on their theoretical binding affinities to the corresponding HLAs. The A2/Kb transgenic mice, which express the a1and a2 domains of human HLA-A*0201, were immunized with the epitope candidates to examine their effects. We also examined whether these peptides could induce human CTLs specific to the target cells in vitro.Results: The CTL responses in A2/Kb transgenic mice were induced with vaccination using identified epitope peptides restricted to HLA-A*0201. Peptide-specific CTL clones were also induced in vitro with these identified epitope peptides from peripheral blood mononuclear cells donated by healthy volunteers with HLA-A*0201. We established CTL clones in vitro from human peripheral blood mononuclear cells with HLA-A*2402 as well. These CTL clones were shown to have potent cytotoxicities in a HLA class I^restricted manner not only against peptide-pulsed target cells but also against target cells endogenously expressing VEGFR1. Furthermore, immunization of A2/Kb transgenic mice with identified epitope peptides restricted to HLA-A*0201 was associated with significant suppression of tumor-induced angiogenesis and tumor growth without showing apparent adverse effects. Conclusions:These results strongly suggest thatVEGFR1is a promising target for antiangiogenic cancer vaccine and warrants further clinical development of this strategy.

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“…16 However, at the time of the conception of this trial, a phase 1 study by Weng and colleagues had demonstrated evidence suggesting that RPI.4610 monotherapy was clinically effective, leading to the choice of this regimen. 11 Although Weng et al had used doses up to 300 mg/m 2 /d, the 2 responses noted in the phase 1 trial had occurred in patients who received lower doses (10 mg/m 2 / d and 100 mg/m 2 /d), supporting the use of this dose for the current trial.…”

Section: Discussionmentioning

confidence: 67%

“…[8][9][10] Phase 1 clinical studies have demonstrated that RPI.4610, when administered as monotherapy or in combination with carboplatin, was well tolerated and had activity in advanced solid tumors. 7,11 Dose and schedule of RPI.4610 were determined by previous experience in preclinical and phase 1 studies. Initially, animal studies established the safety of daily subcutaneous dosing of RPI.4610, at doses up to 300 mg/m 2 /d, in mouse and monkey models.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, although previous pharmacokinetic studies have shown that RPI.4610 demonstrated acceptable bioavailability (mean, >50%), higher levels may be required to ensure target inhibition. 11 Thus, the question of whether adequate inhibition of VEGF signaling occurred remains a viable issue. This may suggest that synthetic anti-RNA molecules do not effectively or efficiently cross the cell membrane or that the biology is more complex than simply blocking selective RNA.…”

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confidence: 99%

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An open‐label, phase 2 trial of RPI.4610 (angiozyme) in the treatment of metastatic breast cancer

Morrow

Murthy

Ensor

et al. 2012

Cancer

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BACKGROUND:Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR‐1 and VEGFR‐2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR‐1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well‐tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC.METHODS:This phase 2, multicenter, single‐arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m2 for 12 weeks.RESULTS:Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow‐up was 2.76 months (range, 0.89‐36.6 months). No partial responses nor complete responses were found. Median progression‐free survival was 1.41 months (95% confidence interval [CI], 1.35‐1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11‐23.66). Treatment‐related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever.CONCLUSIONS:Although RPI.4610 demonstrated a well‐tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012.© 2012 American Cancer Society.

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A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors

Cited by 73 publications

References 15 publications

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Inhibition of Tumor Growth with Antiangiogenic Cancer Vaccine Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 1

An open‐label, phase 2 trial of RPI.4610 (angiozyme) in the treatment of metastatic breast cancer

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