Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma

Jonasch, Eric; Stadler, Walter M.; Bukowski, Ronald M.; Hayes, Teresa G.; Varadhachary, Atul; Malik, Rajesh; Figlin, Robert A.; Srinivas, Sandy

doi:10.1002/cncr.23519

Cited by 40 publications

(36 citation statements)

References 34 publications

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“…Indications of anticancer activity were observed in both cancer types. Based on these results, follow-up phase II studies have been conducted with indications of anti-cancer activity in patients with both NSCLC [14][15][16] and RCC [17]. Talactoferrin is now in phase III clinical development for the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors

Hayes

Varadhachary

2009

Invest New Drugs

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Purpose: We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors. Methods: Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following doseescalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin. Results: Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses. Conclusions: Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.

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Section: Discussionmentioning

confidence: 99%

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors

Hayes

Varadhachary

2009

Invest New Drugs

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“…9) This multitude of biological activities has created great interest in the use of LF in drug discovery. 10) Recently, we have developed PEGylated LF with high biological activities and enhanced pharmacokinetics properties. 11) PEGylation refers to the modification of biological molecules by the linking of one or more polyethylene glycol (PEG) groups.…”

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confidence: 99%

The pH-Dependent Formation of PEGylated Bovine Lactoferrin by Branched Polyethylene Glycol (PEG)-N-Hydroxysuccinimide (NHS) Active Esters

Nojima

Iguchi

Suzuki

et al. 2009

Biological & Pharmaceutical Bulletin

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Lactoferrin (LF) is an 80-kDa member of the transferrin family of iron-binding glycoproteins and is found in various biological fluids, especially milk.2) The multifunctional LF protein exhibits a wide variety of activities including immunomodulation, 3) iron binding, 4) anti-microbial, 5) anti-inflammatory, 6,7) cell proliferation 8) and anti-oxidation. 9) This multitude of biological activities has created great interest in the use of LF in drug discovery.10) Recently, we have developed PEGylated LF with high biological activities and enhanced pharmacokinetics properties.11) PEGylation refers to the modification of biological molecules by the linking of one or more polyethylene glycol (PEG) groups. This approach is utilized in many pharmaceutical and biotechnical applications. 12,13) N-Hydroxysuccinimide (NHS) active esters of PEG (PEG-NHS) are frequently used for the amino group modification of target proteins. NHS activated esters produce stable amide linkages between PEG and primary amines such as N-terminal a-amine and lysine e-amine residues. PEG-NHS typically couples to the free amino group of the targeted protein at physiological pH, ranging from pH 7 to 9. NHS active esters are known to possess highly hydrolytic activities under basic conditions. Although bioconjugation by NHS active esters is generally considered to be the mechanism of PEGylation, detailed reports of actual PEGylated reactions by NHS active esters are rare. Thus, the aim of this study was to investigate the kinetics of the conjugation reaction between branched PEG-NHS and bovine lactoferrin (bLF), focusing on pH dependency. The present investigation demonstrates the importance of the pH values in the PEGylated reactions. MATERIALS AND METHODSpH-Dependent PEGylation of Bovine Lactoferrin (bLF) PEGylated reaction mixtures contained bLF (MG nutritionals, Melbourne, Australia) and branched 40-kDa PEG-NHS reagent (SUNBRIGHT GL2-400GS2, NOF Corporation, Tokyo, Japan) at a 1 : 10 molar ratio. Reaction mixtures were dissolved in the following buffers at the indicated pH: 50 mM acetate buffer (pH 4.0, 5.0); 50 mM phosphate buffer (pH 6.0, 7.0, 8.0); or 50 mM borate buffer (pH 9.0). The final bLF concentration was 0.5 mg/ml. Reactions were carried out for 1 h at 25°C and stopped by the addition of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer. The reaction mixtures were then subjected to 7.5% SDS-PAGE under non-reducing conditions and visualized by Coomassie Brilliant Blue (CBB) staining. Conjugation Reaction Kinetics in Buffers of Different pH ValuesTwo kinds of branched PEG-NHS with average molecular weights of 20 kDa (SUNBRIGHT GL2-200GS2, NOF Corporation, Tokyo, Japan) or 40 kDa (see above) were used. Conjugation reactions were carried out as described above except that the incubation time was 24 h, and the buffers used were phosphate-buffered saline (PBS, pH 7.4), 50 mM borate (pH 9.0) and Good's buffers (BICINE, CHES and TAPS, pH 9.0). Reaction samples (corresponding to 2 mg bLF) were taken at indicat...

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“…NSCLC patients (n=12) experienced 87% relative reduction in TGR and renal cell carcinoma (RCC) patients (n = 7) experienced a 98% relative reduction in TGR [84]. In a phase 2 clinical trial of TLf in RCC, Jonasch et al [85] reported that TLf given at a dose of 1.5 g twice daily (12 weeks on, 2 weeks off) resulted in no toxicities to 44 patients with RCC, 6.4 months mPFS, 21.1 months median overall survival, and a 77% 1-year survival rate. The effect of orally administered bLF was also evaluated clinically in patients with ≤5 mm colorectal polyps.…”

Section: Lactoferrin and Lactoferricinmentioning

confidence: 97%

The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells

Mejía

Dia

2010

Cancer Metastasis Rev

153

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The process of carcinogenesis is complex and not easy to eliminate. It includes the initial occurrence of genetic alterations which can lead to the inactivation of tumor-suppressor genes and further accumulation of genetic alterations during tumor progression. Looking for food and food components with biological properties, collectively called nutraceuticals, that can hinder such alterations and prevent the inactivation of tumor-suppressor genes is a very promising area for cancer prevention. Proteins and peptides are one group of nutraceuticals that show potential results in preventing the different stages of cancer including initiation, promotion, and progression. In this review, we summarized current knowledge on the use of nutraceutical proteins and peptides in cancer prevention and treatment. We focused on the role of plant protease inhibitors, lactoferrin and lactoferricin, shark cartilage, plant lectins, and lunasin in the apoptosis, angiogenesis, and metastasis of cancer cells. Also included are studies on bioavailability and clinical trials conducted on these promising proteins and peptides.

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Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma

Cited by 40 publications

References 34 publications

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors

The pH-Dependent Formation of PEGylated Bovine Lactoferrin by Branched Polyethylene Glycol (PEG)-N-Hydroxysuccinimide (NHS) Active Esters

The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells

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