Human Immunoglobulin G1 Monoclonal Antibody Research Articles

Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer

ABSTRACTIntroduction: Colorectal cancer is the third most common cancer worldwide. The prognosis of colorectal cancer patients still remains dismal and half of them will develop metastatic disease. Angiogenesis plays an essential role in colorectal tumorigenesis, and the VEGF pathway is one of the targets that has been validated up to now. The use of antiangiogenics along with chemotherapy has become an accepted standard for colorectal cancer.Areas covered: This review discusses the efficacy and safety profile of ramucirumab, a fully human immunoglobulin G1 monoclonal antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2), for the treatment of second-line metastatic colorectal cancer upon progression to first-line chemotherapy including anti-angiogenics.Expert opinion: Ramucirumab in combination with chemotherapy represents a valid option in second-line treatment of advanced colorectal cancer patients, who progressed on previous bevacizumab-based combinations. This agent demonstrates a similar benefit in terms of overall survival to other angiogenesis inhibitors (bevacizumab and ziv-aflibercept) used in this setting.

Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis.

BackgroundDaclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.ObjectiveTo characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsTwenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.ResultsDAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration–time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%–40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.ConclusionThe PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.

Incidence and risk of hypertension associated with ramucirumab in cancer patients: A systematic review and meta-analysis

Ramucirumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has been approved for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma. Hypertension has been described as a common adverse event with ramucirumab, but the incidence and risk have not been well determined. We conduct this meta-analysis to investigate the overall incidence and risk of developing hypertension associated with use of ramucirumab. Databases from PubMed, Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) meeting up to May 31, 2014, were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating ramucirumab in cancer patients with adequate data on hypertension. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% confidence intervals (CIs) by using either random--effect or fixed--effect models according to the heterogeneity of included studies. A total of 2,649 patients with a variety of solid tumors from eight prospective clinical trials were included in our analysis. The incidence of all--grade and high-grade hypertension associated with ramucirumab was 16.4% (95%CI: 11.9-22.3%) and 9.8% (95%CI: 7.2-13.0%), respectively. Patients treated with ramucirumab had a significantly increased risk of developing all-grade (RR: 2.28, 95%CI: 1.61-3.24, P < 0.001) and high-grade (RR: 3.59, 95%CI: 2.32-5.53, P < 0.001) hypertension compared with patients treated with control medication. No evidence of publication bias was observed. The use of ramucirumab is associated with a significantly increased risk of developing hypertension when compared with controls. Close monitoring and appropriate managements are recommended during the therapy.

Pertuzumab in gastrointestinal cancer

ABSTRACTIntroduction: Human epidermal growth factor receptor 2 (HER2) and HER3 are altered in multiple tumor types, including gastrointestinal cancer. The HER2/HER3 dimer is crucial for HER2-mediated signaling in HER2-positive tumors. HER2-targeting agents, including trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab, have been approved for the treatment of HER2-positive breast cancer, with trastuzumab also approved for the treatment of HER2-positive gastric cancer. Pertuzumab, a recombinant humanized immunoglobulin (Ig) G1 monoclonal antibody targeting HER-2, binds to the dimerization domain (extracellular domain II) of HER2, which leads to blocking of ligand-induced HER2 heterodimerization. It is under investigation in gastrointestinal cancers, including HER2-positive gastric cancer.Area covered: In this review, the authors summarize the biology of HER2/HER3 and its alterations in gastrointestinal cancers. The authors focus specifically on the current status of development of pertuzumab in gastrointestinal cancers.Expert opinion: The HER2/HER3 alteration in gastrointestinal cancers is quite interesting. In HER2-positive gastric cancer, the dual blockade of HER2 and HER3 using trastuzumab and pertuzumab is being tested in an international phase III trial, the JACOB study. This strategy may benefit HER2-positive gastric cancer patients more as in the case of HER2-positive breast cancer. In other gastrointestinal cancers, including biliary tract cancer, esophageal cancer, pancreatic cancer, and colorectal cancer, there is huge room for the development of pertuzumab.

Mogamulizumab treatment of refractory peripheral T-cell lymphoma following autologous stem cell transplantation: A case report.

Peripheral T-cell lymphoma (PTCL) represents a small heterogeneous group of non-Hodgkin lymphoma (NHL) that accounts for ~10% of NHLs in western countries and ~25% of NHLs in Japan. The disease remains extremely difficult to treat. Therefore, novel treatment modalities are required. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody that targets CC chemokine receptor 4. To the best of our knowledge, the efficacy of mogamulizumab in patients who are refractory to conventional chemotherapy following autologous stem cell transplantation has not been investigated previously. The present study reports a patient with PTCL who relapsed following autologous stem cell transplantation and became resistant to salvage chemotherapy, in whom mogamulizumab showed evident efficacy without severe adverse event.

Understanding the Dose Regimen for Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma (MM) after Prior Proteasome Inhibitors (PIs) and Immunomodulatory Drugs (IMiDs): A Quantitative Pharmacologic Perspective

Introduction: Daratumumab is a first-in-class human anti-CD38 immunoglobulin G1 (IgG1) monoclonal antibody in clinical development for multiple myeloma (MM). Nonlinear concentration- and time-dependent pharmacokinetics was observed due to target-mediated drug disposition. Identification of an optimal dose regimen was complicated by the interactions between daratumumab pharmacokinetics and pharmacodynamics of the target (CD38) and a clinical dosing schedule with decreasing dose frequency over time. The objective of this analysis was to understand and justify the recommended dose and dosing schedule for daratumumab in MM patients from a quantitative pharmacologic perspective.Methods: Analyzed data were from a phase 1/2, 2-part study beginning with dose-escalation followed by a single-arm multiple cohort phase (GEN501, NCT00574288) and a phase 2 study that evaluated the efficacy and safety of daratumumab monotherapy (MMY2002, NCT01985126). Doses ranged from 0.01 to 24 mg/kg and dose schedules varied by cohort in these studies. We explored the exposure-response relationship for the efficacy and safety endpoints. Simulations were conducted based on a previously developed population pharmacokinetic model to understand the association between target saturation and daratumumab exposure.Results:There was a maximum effect (Emax) relationship between daratumumab exposure (ie, maximal trough concentration) and overall response rate (ORR), and between daratumumab and target saturation. The concentration associated with 90% maximal effect on ORR (ECORR90) was 274 µg/mL which is similar to the concentration providing 99% model-predicted target saturation (ECTAR99, 236 µg/mL). The 16 mg/kg dose was the lowest tested dose at which the majority (approximately 80%) of subjects achieved serum concentrations above ECORR90 and ECTAR99 thresholds after weekly administration (weekly for 8 weeks). Since the total clearance of daratumumab decreased over time, the intensive weekly dosing at the beginning of treatment was intended to overcome the high initial clearance and rapidly establish the efficacious concentration. Thereafter, every 2-week followed by every 4-week 16 mg/kg dosing intervals appeared to be adequate to saturate the target and maintain the total clearance close to the non-specific linear clearance. Although the concentration of daratumumab tended to decrease following every 2-week and every 4-week dosing intervals until reaching steady state, the reduction in concentration over time observed in the studies was not associated with either shorter duration of response or higher risk of disease progression. This result corroborates the clinical analysis which indicated the rate of subjects experiencing disease progression was consistent in the every 2-week and every 4-week dosing periods.The exposure-safety analysis demonstrated no apparent relationship between the drug exposure and infusion-related reactions, thrombocytopenia, anemia, neutropenia, or lymphopenia. Although the overall event rate of infection increased numerically with drug exposure, this trend was not observed for infections of Grade 3 or higher. The clinical data suggested that the safety profile of the 16 mg/kg dose was consistent with the total population, and there was no increasing trend noted in the overall incidence of treatment-emergent adverse events across increasing dose groups. Treatment with 16 mg/kg daratumumab weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter until progression resulted in high ORRs of 29% in Study MMY2002 and 36% in Study GEN501.Conclusion: Our analysis demonstrated that the recommended dose regimen is appropriate in the relapsed or refractory MM patient population. Lowering the dose would likely result in reduced efficacy, whereas increasing the dose may not improve the benefit-risk profile. In addition, the dosing schedule rapidly establishes efficacious concentrations during the initial, intense, weekly dosing period and maintains target saturation thereafter; thus reducing the risk of disease progression at the later, less frequent, dosing periods (i.e., every 2 weeks and every 4 weeks). DisclosuresXu:Janssen: Employment. Yan:Janssen: Employment. Puchalski:Janssen: Employment. Lonial:Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Lokhorst:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding. Voorhees:Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liu:Janssen: Employment. Khan:Janssen: Employment. Jansson:Janssen: Employment. Ahmadi:Janssen: Employment. Perez Ruixo:Janssen: Employment. Zhou:Janssen: Employment. Clemens:Janssen: Employment.

Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors

Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. NCT00786383.

New active drugs for the treatment of advanced colorectal cancer.

Newer active drugs have been recently added to the pharmacological armamentarium for the treatment of metastatic colorectal cancer. Aflibercept, a recombinant fusion protein composed of the extracellular domains of human vascular endothelial growth factor receptors (VEGFR) 1 and 2 and the Fc portion of human immunoglobulin G1 (IgG1), is an attractive second-line option in combination with folfiri for patients who have failed folfox +/- bevacizumab. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGFR-2, provided similar results in the same setting. Tas-102, an oral fluoropyrimidine, and regorafenib, a multi-tyrosine kinase inhibitor, are both able to control the disease in a considerable proportion of patients when all other available treatments have failed. These new therapeutic options along with the emerging concept that previous therapies may also be reitroduced or rechallenged after regorafenib and Tas-102 failure are bringing new hope for thousands of patients and their families.

Abstract A55: Tumor-associated fibroblasts: A new target for cancer treatment

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a 50% rate of local failure with current standard of care. We recently reported that patient-derived tumor associated fibroblasts (TAF) facilitate HNSCC proliferation and metastasis to the cervical lymph node and lung of mice. Although the paracrine molecular interactions between HNSCC and TAFs have not been fully described, we demonstrated that TAFs (and not HNSCC) secrete hepatocyte growth factor (HGF), a ligand for the c-Met receptor on HNSCC cells. Further, activation of the HGF-c-Met pathway increased HNSCC growth and invasion. In addition, we demonstrated that HNSCC cells induce the expression of HGF from TAFs. We hypothesized that inhibition of TAF-secreted HGF would reduce HNSCC proliferation, invasion and migration. We tested the efficacy of ficlatuzumab (AV-299) a humanized HGF inhibitory immunoglobulin G1 (IgG1) monoclonal antibody in mitigating TAF-induced HNSCC progression. . Ficlatuzumab exhibits antitumor effects in xenograft models as a single agent and has been tested in patients with non-small cell lung cancer in a phase I setting. The antitumor efficacy of HGF neutralization has not been tested in the context of TAFs in HNSCC. Our data demonstrate that ficlatuzumab is effective in mitigating TAF-induced HNSCC proliferation, migration and invasion through inhibition of the c-met pathway in HNSCC. Citation Format: Chase Hamilton, Shary Shelton, Kiran Kakarala, Sufi Mary Thomas. Tumor-associated fibroblasts: A new target for cancer treatment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A55. doi:10.1158/1538-7445.CHTME14-A55

Ramucirumab: first global approval.

Ramucirumab (Cyramza™ [US]), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) for the treatment of cancer. Ramucirumab has received its first global approval in the US for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who experience disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is the first treatment to be approved by the US FDA for this setting. This article summarizes the milestones in the development of ramucirumab leading to this first approval for the treatment of gastric cancer and gastro-oesophageal junction adenocarcinoma.

Profile of ustekinumab and its potential in patients with moderate-to-severe Crohn's disease.

The advent of anti-tumor necrosis factor (TNF)-α therapy has been a major advance in the medical management of Crohn’s disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNFα therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to play a key role in the pathogenesis of CD, and serve as a potential target for additional biologic therapies. Monoclonal antibodies targeting IL-12/23 have shown efficacy in animal models of colitis, and are currently being studied in Phase III clinical trials of CD. This review focuses on ustekinumab, a fully human immunoglobulin G1 monoclonal antibody, which blocks activity of IL-12 and IL-23 through binding the p40 subunit, and describes the current efficacy and safety data for ustekinumab in patients with CD.

Loss of CCR4 antigen expression after mogamulizumab therapy in a case of adult T‐cell leukaemia‐lymphoma

Loss of <scp>CCR</scp>4 antigen expression after mogamulizumab therapy in a case of adult <scp>T</scp>‐cell leukaemia‐lymphoma

An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours

BackgroundCixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. MethodsIn this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10mg/kg) for 1h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12weeks. In each tier of disease histology, Simon’s optimum 2-stage design was applied (PFR at 12weeks P0=20%, P1=40%, α=0.10, β=0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12weeks to proceed to stage 2. ResultsA total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n=17), 14% for leiomyosarcoma (n=22), 32% for adipocytic sarcoma (n=37), 18% for synovial sarcoma (n=17) and 11% for Ewing family of tumours (n=18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). ConclusionsPatients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.

Bone-Targeted Agents and Skeletal-Related Events in Breast Cancer Patients with Bone Metastases: The State of the Art

Most women with advanced breast cancer will develop bone metastases, which are associated with the development of skeletal-related events (sres) such as pathologic fractures and spinal cord compression. This article reviews the evolving definition and incidence of sres, the pathophysiology of bone metastases, and the key evidence for the safety and efficacy of the currently available systemic treatment options for preventing and delaying sres in the setting of breast cancer with bone metastases.The bisphosphonates are structural analogues of endogenous pyrophosphate; three of them (clodronate, pamidronate, and zoledronate) are currently approved for use in Canada in the setting of breast cancer with bone metastases. Denosumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human rankl (receptor activator of nuclear factor κB ligand), thereby preventing osteoclast formation, function, and survival, and reducing cancer-induced destruction of bone. Denosumab has recently been approved in Canada for reducing the risk of sres from the bone metastases associated with a variety of malignancies, including breast cancer. How to predict the patients that will benefit most from prophylactic treatment, the agents to select and the timing of switches between agents, the dosing schedules and durations of treatment to choose, the potential utility of the agents in the adjuvant setting, and the utility of additional endpoints such as markers of bone resorption are among the outstanding questions with respect to the optimal use of antiresorptive agents for patients with breast cancer and bone metastases.

Enterocolitis in a Patient Being Treated With Ipilimumab for Metastatic Melanoma

Question: A 69-year-old man with a suprasternally localized 3-cm skin mass and multiple lung metastases was referred for treatment. The tumor was completely excised, and histology revealed a nodular malignant melanoma (Clarke level V, tumor thickness 12 mm). Subsequently, chemotherapy with dacarbazine (DTIC) was started. After tumor progression, second-line treatment with ipilimumab was initiated. In the further course, the patient developed fevers and a watery diarrhea without hematochezia. Imaging studies did not show any signs of infection. A slightly elevated C-reactive protein, leukocytosis, and lymphopenia were noted. Routine microbiological testing of blood and stool samples were negative for pathogenic bacteria, Clostridium difficile toxin, parasites, rotavirus, cytomegalovirus, Epstein–Barr virus, and tuberculosis. The patient refused a colonoscopy at that time. An empiric antibiotic therapy with piperacillin and tazobactam and oral methylprednisolone 40 mg/d was started. At the time of discharge, symptoms had improved, although the patient complained about up to 4 soft bowel movements per day. A few days later, he was readmitted again with watery diarrhea. Colonoscopy showed discontinuous, multiple, deep ulcerations (maximum size, 3 cm) throughout the colon (Figure A). The rectum was spared and no fistulas were noted. Microbiological examination of biopsies did not reveal any pathogenic germs. Histologic examinations confirmed ulcerative epithelial defects with lymphocytic infiltrates and capillary-rich granulation tissue (Figure B; provided with kind permission of Professor Hans-Michael Kvasnicka, MD, Senckenbergisches Institut für Pathologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany). What is the diagnosis? Look on page 504 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The patient developed an immune-related enterocolitis after treatment with ipilimumab. Ipilimumab is a fully human immunoglobulin (Ig)G1 monoclonal antibody against cytotoxic T-lymphocyte–associated antigen 4, which can induce anti-tumor immunity. In a pivotal clinical trial, patients with previously treated unresectable stage III or IV melanoma were treated with a gp100 vaccine with or without ipilimumab.1Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11247) Google Scholar In this study, ipilimumab (3 mg/kg) improved the overall survival, regardless of a concomitant gp100 vaccination (ipilimumab group, 10.1 months; gp100 group, 6.4 months; hazard ratio [HR], 0.66; P = .003). Thus, ipilimumab was recently approved as monotherapy for adult patients with advanced malignant melanoma who have received prior therapy. In this study, the incidence of a grad 3/4 immune-mediated enterocolitis was 5%. Moreover, ipilimumab (10 mg/kg) plus DTIC improved overall survival in patients with previously untreated metastatic melanoma (ipilimumab plus DTIC, 11.2 months; placebo plus DTIC, 9.1 months; HR, 0.72; P < .001).2Robert C. Thomas L. Bondarenko I. et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526Crossref PubMed Scopus (3579) Google Scholar Immune-related gastrointestinal events were the most frequent side effects after ipilimumab treatment, with grade 3/4 toxicity in 7.6% of patients. Noteworthy, in this study no bowel perforations or drug-related deaths occurred. Immune-related enterocolitis and diarrhea after ipilimumab usually respond to steroid treatment and should be managed according to published algorithms to avoid severe complications such as bleeding and perforation.3Kaehler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286Crossref PubMed Scopus (96) Google Scholar After the diagnosis of an immune-related enterocolitis, our patient was treated with a pulse therapy with IV prednisolone (250 mg/d). Additionally, he received parenteral nutrition and IV hydration. He responded to the treatment promptly and was started again on enteral nutrition and oral methylprednisolone with a slow taper over 8 weeks. Follow-up sigmoidoscopy after 4 weeks showed single, healing ulcerations. At this time, the diarrhea had completely resolved and tumor stabilization was documented. In summary, instructions about relevant symptoms and an early diagnosis and initiation of adequate treatment are essential for prevention of severe complications of an immune-related enterocolitis in patients being treated with ipilimumab.

Bone Targeted Therapy in the Treatment of Skeletal Related Events (SREs) in Breast Cancer

This article has been retracted. Most women with advanced breast cancer will develop bone metastases, which are associated with the development of skeletal-related events (SREs) such as pathologic fractures and spinal cord compression. This article reviews the evolving definition and incidence of SREs, the pathophysiology of bone metastases, and the key evidence for the safety and efficacy of the currently available systemic treatment options for preventing and delaying SREs in the setting of breast cancer with bone metastases. The bisphosphonates are structural analogues of endogenous pyrophosphate; three of them (clodronate, pamidronate, and zoledronate) are currently approved for use in Canada in the setting of breast cancer with bone metastases. Denosumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human RANKL (receptor activator of nuclear factor κ B ligand), thereby preventing osteoclast formation, function, and survival, and reducing cancer-induced destruction of bone. Denosumab has recently been approved in Canada for reducing the risk of SREs from the bone metastases associated with a variety of malignancies, including breast cancer. How to predict the patients that will benefit most from prophylactic treatment, the agents to select and the timing of switches between agents, the dosing schedules and durations of treatment to choose, the potential utility of the agents in the adjuvant setting, and the utility of additional endpoints such as markers of bone resorption are among the outstanding questions with respect to the optimal use of antiresorptive agents for patients with breast cancer and bone metastases. doi: http://dx.doi.org/10.4021/wjon589w

An Observational Study of the First Experience with Bevacizumab for the Treatment of Patients with Recurrent High-Grade Glioma in Two Belgian University Hospitals

Background. Bevacizumab (BEV), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF has demonstrated activity against recurrent high-grade gliomas (HGG) in phase II clinical trials. Patients and Methods. Data were collected from patients with recurrent HGG who initiated treatment with BEV outside a clinical trial protocol at two Belgian university hospitals. Results. 19 patients (11 M/8 F) were administered a total of 138 cycles of BEV (median 4, range 1–31). Tumor response assessment by MRI was available for 15 patients; 2 complete responses and 3 partial responses for an objective response rate of 26% for the intent to treat population were observed on gadolinium-enhanced T1-weighted images; significant regressions on T2/FLAIR were documented in 10 out of 15 patients (67%). A reduced uptake on PET was documented in 3 out of 4 evaluable patients. The six-month progression-free survival was 21% (95% CI 2.7–39.5). Two patients had an ongoing tumor response and remained free from progression after 12 months of BEV treatment. Conclusions. The activity and tolerability of BEV were comparable to results from previous prospective phase II trials. Reduced uptake on PET suggests a metabolic response in addition to an antiangiogenic effect in some cases with favorable clinical outcome.

Blockade of Insulin-Like Growth Factor Type-1 Receptor with Cixutumumab (IMC-A12): A Novel Approach to Treatment for Multiple Cancers

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.

Concomitant occurrence of acneiform eruption, alopecia areata, and urticaria during adalimumab treatment in a patient with pustulosis palmoplantaris: Case report and literature review

Abstract Adalimumab is a fully human immunoglobulin G1 monoclonal antibody against tumor necrosis factor (TNF)-α that is increasingly used for the treatment of many autoimmune diseases. However, it has also been reported that adalimumab can induce many adverse cutaneous reactions, including paradoxical psoriasiform eruptions. We describe a patient with pustulosis palmoplantaris who developed four cutaneous adverse reactions, including eczematous lesions, acneiform eruption, alopecia areata, and urticaria during adalimumab treatment. A common histopathological finding in these acneiform and urticarial lesions was the presence of eosinophilic infiltrates. Some authors assume that cross-regulation between TNF-α and interferon-α may contribute to development of a clinical spectrum of cutaneous reactions in predisposed individuals undergoing anti-TNF therapy. The use of different biologics, including adalimumab, etanercept, and ustekinumab, did not seem to improve pustulosis palmoplantaris disease activity in our patient.

Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer

Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.