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Annals of Oncology : Official Journal... Nov 2013Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR).
RESULTS
Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms.
CONCLUSIONS
There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.
Topics: Aged; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Lactoferrin; Male; Middle Aged; Neoplasm Staging; Placebos; Treatment Outcome
PubMed: 24050956
DOI: 10.1093/annonc/mdt371 -
Expert Opinion on Biological Therapy Sep 2010Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in... (Review)
Review
IMPORTANCE OF THE FIELD
Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.
AREAS COVERED IN THIS REVIEW
Talactoferrin alpha is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.
WHAT THE READER WILL GAIN
Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alpha and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.
TAKE HOME MESSAGE
The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.
Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Evidence-Based Medicine; Humans; Lactoferrin; Lung Neoplasms; Treatment Outcome
PubMed: 20684737
DOI: 10.1517/14712598.2010.512914 -
Journal of Thoracic Oncology : Official... Oct 2011Non-small cell lung cancer (NSCLC) is often diagnosed in advanced stages and is associated with poor outcomes. Existing standards of care for NSCLC result in low overall... (Review)
Review
INTRODUCTION
Non-small cell lung cancer (NSCLC) is often diagnosed in advanced stages and is associated with poor outcomes. Existing standards of care for NSCLC result in low overall cure rates, suggesting that novel treatment approaches are needed. In this review, we provide an updated look at the clinical data on immunotherapeutic interventions, which potentiate the immune system's response to lung tumor cells.
METHODS
We searched articles on PubMed and abstracts from recent oncology meetings for publications on immunotherapies with clinical applicability to the treatment of NSCLC.
RESULTS
Results from phase 2 trials show vaccine therapies, which target either tumor cells themselves or aberrantly expressed tumor markers (mucin 1, melanoma-associated antigen 3, or epidermal growth factor), may be promising immunotherapeutics for NSCLC. Antigen-independent immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibodies, talactoferrin alfa, and toll-like receptor 9 agonists, act on a stimulated immune system regardless of the tumor antigen and may be feasible interventions for metastatic NSCLC. Several immunotherapies are undergoing phase 3 studies to assess optimal treatment settings and to determine clinical benefit compared with current standard treatments for NSCLC.
CONCLUSIONS
A growing body of evidence suggests that immune responses to lung tumors are present. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. Furthermore, treatments that enhance antitumor immune responses may prove to be synergistic with chemotherapy. Identification of biomarkers and further elucidation of immunotherapeutic mechanisms of action will be essential in determining which patients will experience the greatest benefit from immunotherapy.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Immunotherapy; Lung Neoplasms; Treatment Outcome
PubMed: 21876456
DOI: 10.1097/JTO.0b013e31822e28fc -
The Oncologist 2013Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials.
BACKGROUND
Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials.
METHODS
Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4+, CD8+, and regulatory T cells) and systemic cytokine levels were measured to assess immune response.
RESULTS
Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity).
CONCLUSIONS
The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.
Topics: CD4-Positive T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Disease-Free Survival; Female; Humans; Immune System; Interleukin-6; Killer Cells, Natural; Lactoferrin; Lung Neoplasms; Male; Neoplasm Staging; Pilot Projects; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha
PubMed: 23847257
DOI: 10.1634/theoncologist.2013-0199 -
Immunopharmacology and Immunotoxicology Apr 2014Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium...
CONTEXT
Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.
OBJECTIVE
Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.
METHODS
Talactoferrin was administered orally at 1.5 g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.
RESULTS
Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.
CONCLUSION
Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.
Topics: Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local
PubMed: 24494587
DOI: 10.3109/08923973.2013.864671 -
The Journal of Pediatrics Aug 2016To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection.
STUDY DESIGN
We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of 750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was 150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses.
RESULTS
Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes were not statistically significantly different between the 2 groups, and there were no between-group differences in growth or neurodevelopment over a 1-year posthospitalization period.
CONCLUSION
We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT00854633.
Topics: Administration, Oral; Bacteremia; Cross Infection; Double-Blind Method; Enterocolitis, Necrotizing; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Meningitis; Pneumonia; Protective Agents; Sepsis; Treatment Outcome; Urinary Tract Infections
PubMed: 27260839
DOI: 10.1016/j.jpeds.2016.04.084 -
Annals of Oncology : Official Journal... Sep 2012Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Most... (Review)
Review
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Most patients with NSCLC are diagnosed at an advanced stage and have a poor prognosis, with a 5-year survival rate of <5%. Despite the introduction of new chemotherapeutic agents and molecularly targeted drugs, outcomes remain poor, emphasising the need for new treatment approaches. Inducing or potentiating immune responses via immunotherapeutic manipulation is a viable treatment approach for lung cancer. Antigen-specific, tumour-cell, and dendritic cell-based vaccines have all been evaluated in lung cancer, and some have shown promising clinical activity in phase II trials. These include liposomal BLP25 vaccine (L-BLP25), which targets mucin 1, and melanoma-associated antigen 3 (MAGE-A3) antigen-specific cancer immunotherapeutic (ASCI), which targets MAGE-A3, a peptide expressed almost exclusively on tumour cells. MAGE-A3 ASCI is being evaluated in the adjuvant setting in a phase III trial of patients with early-stage NSCLC, while a phase III trial of L-BLP25 is enrolling patients with unresectable stage III NSCLC. T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4]) are also being investigated. For example, in patients with NSCLC treated with paclitaxel and carboplatin, the phased administration of ipilimumab (an antibody against CTLA-4) resulted in substantial improvements in immune-related progression-free survival compared with chemotherapy alone (5.7 versus 4.6 months; P = 0.05). Immunotherapy in lung cancer is starting to deliver promising results in clinical trials. However, further research will be required to establish the optimal timing of therapy (i.e. in the adjuvant or metastatic settings). In addition, it will be important to determine if immunotherapies are most effective when used alone or in combination with other agents.
Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CTLA-4 Antigen; Cancer Vaccines; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Humans; Immunotherapy; Ipilimumab; Lactoferrin; Lung Neoplasms; Membrane Glycoproteins; Neoplasm Proteins; Nivolumab; Paclitaxel
PubMed: 22918925
DOI: 10.1093/annonc/mds260 -
Cancer Jul 2008Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its...
BACKGROUND
Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).
METHODS
Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.
RESULTS
TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.
CONCLUSIONS
TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Kidney Neoplasms; Lactoferrin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Analysis
PubMed: 18484647
DOI: 10.1002/cncr.23519 -
Journal of Clinical Medicine Research Feb 2011Talactoferrin alfa (also known as recombinant human lactoferrin, rhLF) is a novel immunomodulatory protein that has previously demonstrated anti-tumor properties in...
UNLABELLED
Talactoferrin alfa (also known as recombinant human lactoferrin, rhLF) is a novel immunomodulatory protein that has previously demonstrated anti-tumor properties in animal models. Following a successful phase I trial, it was administered orally to patients with metastatic renal cell carcinoma (RCC) in a phase II trial conducted at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, among other sites. We report a case series of 4 patients treated at our institution with very encouraging progression-free survivals, all exceeding 30 months, in order to suggest that this agent merits further study. These four patients with radiographically progressive metastatic RCC received single-agent oral talactoferrin in daily doses of 9 grams, given in cycles of 2 weeks on/2 weeks off, until evidence of toxicity or disease progression. Given the small sample size and the heterogenous tumor biology of RCC, tumor growth rate was used as a primary endpoint so that each patient could serve as their own control. The agent's effectiveness was then determined through radiographic tracking of the tumors before, during, and after treatment, with use of the Response Evaluation Criteria in Solid Tumors (RECIST) protocol to follow target lesions. The results showed that the drug was well tolerated, with no occurrence of talactoferrin-related grade 3 or 4 adverse events or laboratory anomalies by NCI-CTEP criteria. The four patients described in the case series demonstrated very encouraging progression-free survivals, all exceeding 30 months. We conclude that decreased tumor growth rate may correlate with increased progression-free survival. Talactoferrin is a promising, well-tolerated agent whose clinical benefits should be evaluated in a randomized phase III study with a placebo control arm.
KEYWORDS
Talactoferrin; Immunotherapy; Renal cell carcinoma; Metastatic.
PubMed: 22043271
DOI: 10.4021/jocmr499w -
Journal of Thoracic Oncology : Official... Jun 2011The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer.
INTRODUCTION
The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer.
METHODS
Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety.
RESULTS
The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29-47%; p = 0.05) and 15% (27-42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group.
CONCLUSION
TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.
Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Double-Blind Method; Female; Humans; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Prospective Studies; Survival Analysis; Treatment Outcome
PubMed: 21532506
DOI: 10.1097/JTO.0b013e3182156250