Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review.

BAY 81-8973 (Kovaltry®) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate® FS/KOGENATE®, Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens. BAY 81-8973 was extensively studied in the LEOPOLD clinical development program, which enrolled participants of all age groups (children, adolescents, and adults) with severe hemophilia A. The pharmacokinetic profile of BAY 81-8973 was shown to be noninferior to, and for some variables more favorable than, rFVIII-FS and another commercial full-length rFVIII product. BAY 81-8973 was shown to be efficacious when used for prophylaxis, on-demand treatment, and perioperative hemostasis. The efficacious prophylaxis dose of BAY 81-8973 was approximately 20-40 IU/kg given two or three times per week, which achieved low annualized bleeding rates. Either the one-stage or the chromogenic assay provides accurate measurements for postinfusion monitoring of BAY 81-8973 levels, with no product-specific calibration standard needed. The incidence of treatment-related adverse events was ⩽7% across all LEOPOLD studies, and no previously treated patient developed anti-BAY 81-8973 inhibitors in the completed primary studies.

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

PURPOSE: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. PATIENTS AND METHODS: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. RESULTS: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. CONCLUSION: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Contribution of mast cell-derived interleukin-1ß to uric acid crystal-induced acute arthritis in mice.

OBJECTIVE: Gouty arthritis is caused by the precipitation of monosodium urate monohydrate (MSU) crystals in the joints. While it has been reported that mast cells (MCs) infiltrate gouty tophi, little is known about the actual roles of MCs during acute attacks of gout. This study was undertaken to assess the role of MCs in a mouse model of MSU crystal-induced acute arthritis. METHODS: We assessed the effects of intraarticular (IA) injection of MSU crystals in various strains of mice with constitutive or inducible MC deficiency or in mice lacking interleukin-1ß (IL-1ß) or other elements of innate immunity. We also assessed the response to IA injection of MSU crystals in genetically MC-deficient mice after IA engraftment of wild-type or IL-1ß(-/-) bone marrow-derived cultured MCs. RESULTS: MCs were found to augment acute tissue swelling following IA injection of MSU crystals in mice. IL-1ß production by MCs contributed importantly to MSU crystal-induced tissue swelling, particularly during its early stages. Selective depletion of synovial MCs was able to diminish MSU crystal-induced acute inflammation in the joints. CONCLUSION: Our findings identify a previously unrecognized role of MCs and MC-derived IL-1ß in the early stages of MSU crystal-induced acute arthritis in mice.

Current strategies in the management of hypereosinophilic syndrome, including mepolizumab.

BACKGROUND: Patients with hypereosinophilic syndrome (HES) vary considerably in their clinical presentation with regard to the severity and pattern of end-organ involvement. Clinical manifestations range from nonspecific symptoms to life-threatening, multisystem damage caused by eosinophil infiltration and local release of proinflammatory mediators and toxic granule products from these invading cells. The primary objective of treatment is to reduce blood and tissue eosinophilia and prevent eosinophil-mediated tissue damage as safely as possible. Systemic corticosteroids, such as prednisone, are first-line therapy for the management of patients with symptomatic HES who lack the Fip1-like 1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) gene fusion mutation. The tyrosine kinase inhibitor, imatinib, is first-line treatment for FIP1L1-PDGFRA-positive patients). Because of the toxicity and serious side-effects that can occur with oral corticosteroids, alternative therapies may need to be introduced to reduce the cumulative corticosteroid exposure while maintaining disease control. SCOPE: Among corticosteroid-sparing agents are cytotoxic drugs and interferon-alpha; anti-interleukin-5 (IL-5) monoclonal antibodies are also currently under investigation for the treatment of HES. This manuscript reviews the available treatments for HES and the range of side-effects associated with long-term corticosteroid use, and then focuses on the anti-IL-5 monoclonal antibodies, mepolizumab and reslizumab. Of these, only mepolizumab has been studied in a randomized, placebo-controlled trial. Literature search methodology utilized www.pubmed.gov and www.clinicaltrials.gov with search terms including hypereosinophilic syndrome and corticosteroid side-effects coupled with search terms including eosinophils, mepolizumab and reslizumab through March 2010. FINDINGS: Three case studies are presented that demonstrate the limitations of corticosteroid therapy in terms of tolerability and quality of life, and the subsequent use of mepolizumab as a corticosteroid-sparing agent in these individuals. CONCLUSION: Targeted eosinophil-directed therapy with an anti-IL-5 neutralizing monoclonal antibody reduced the need for corticosteroids in these three HES patients without disease exacerbations.

Phase II study of sorafenib in patients with metastatic or recurrent sarcomas.

PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.

Alternative medicine utilization by African Americans and improving life expectancy: is there a correlation?

The life expectancy of African Americans and Caucasians has been increasing in the United States and in many other countries around the world since the late 1800s. However, as long as statistics have been accrued on race and ethnicity, the life expectancy of African Americans and Blacks in general has been significantly lower than that of Caucasians. Basic public health and medical preventive education is needed because higher cardiovascular disease (CVD) rates is one of the primary reasons for the differences between life expectancy between African Americans and Caucasians. It is also of an apparent separate but perhaps related interest that several recent preliminary studies suggest that African Americans, more than any other race, may have some of the lowest uses of alternative medicine due to skepticism, as well as educational efforts and trust in their health care professional. Despite a common belief that African Americans harbor profound distrust of specific areas of the medical profession, it is of interest that this finding has not held validity in the area of alternative medicine. Therefore, since lifestyle changes are considered alternatives in most of these studies, this would suggest that a greater educational emphasis on behavioral modification could establish a foundation or a model of preventive medical education that can be utilized for underserved populations around the world.

Update on colorectal cancer imaging.

Colorectal cancer remains a leading cancer killer worldwide. The disease is both curable and preventable, and yet the importance of widespread screening is only now starting to be appreciated. This article reviews the variety of diagnostic tests, imaging procedures and endoscopic examinations available to detect colorectal cancer and polyps in their early stage and also presents details on various screening options. The critical role of the radiologist is elaborated on including accurate assessment of the tumor extent within the bowel wall and beyond and the detection of lymph node and distant metastases. Staging with CT, MR imaging, endorectal ultrasound, and positron emission tomography are of paramount importance in determining the most appropriate therapy and the risk of tumor recurrence and overall prognosis.

Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.

PURPOSE: This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients. METHODS: Patients with inoperable HCC, no prior systemic treatment, and Child-Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients. RESULTS: Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy. CONCLUSION: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

Liver regeneration in humans is characterized by significant changes in cellular phosphorus metabolism: assessment using proton-decoupled 31P-magnetic resonance spectroscopic imaging.

In the present study we applied proton-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) to noninvasively assess liver metabolism in patients who had undergone a partial hepatectomy (PH). Proton-decoupled 31P chemical shift imaging was performed in 47 patients 2-28 days following major hepatectomy, and the results were compared with those from eight control subjects. All studies were performed on a 1.5T MR imager (General Electric, Milwaukee, WI) equipped with a stand-alone proton decoupler. A 31P-1H resonator pair was used for data acquisition, and 31P data were obtained in 34 min. Liver regeneration was characterized by increases in phosphoethanolamine (PE), and decreases in nucleoside triphosphates (NTP), glycerophosphoethanolamine (GPE), and glycerophosphocholine (GPC). These alterations were most marked 48-72 hr after hepatectomy and returned to baseline within 3 weeks. The level of PE measured by MRSI was also found to depend on the percentage of liver that was removed, while changes in levels of cellular high energy phosphates were independent of the size of liver resection. Implementation of proton-decoupling was critical for assessing individual phosphomonoester and phosphodiester components. This study demonstrates that 31P MRSI can be used to assess metabolic changes in humans during liver regeneration, and may be useful for assessing derangement of the regenerative process or guiding adjuvant chemotherapies.

Extent of hepatic resection does not correlate with toxicity following adjuvant chemotherapy.

BACKGROUND: In patients with liver metastases from colorectal cancer, survival can be increased by hepatic resection. Treatment with hepatic arterial infusion (HAI) and systemic chemotherapy following resection may further increase survival and decrease recurrence, but may also result in hepatic and systemic toxicity. This article will address the question of whether large hepatic resections resulting in a greater loss of healthy liver predisposes patients to developing toxicity from the subsequent chemotherapeutic regimens. DESIGN: Retrospective analysis of 88 patients who underwent liver resection of colorectal metastases followed by adjuvant HAI and systemic chemotherapy and whose computerized tomography (CT) scans were done at Memorial Sloan-Kettering Cancer Center (MSKCC). Liver volumes were calculated from CT scans and used to determine the percentage change in healthy liver volume between the pre- and post-operative CT scans. Hepatic and systemic toxicities were defined according to the Common Toxicity Criteria of the National Cancer Institute. RESULTS: Patients experienced a mean percentage decrease in healthy liver tissue of 17% (range: 57% decrease to 32% increase) at an estimated 1 month after resection and at the initiation of chemotherapy. In a logistic regression model using percentage change in the healthy liver volume as a continuous variable, no significant association was revealed between percentage of healthy liver resected and diarrhea (P = 0.47), leukopenia (P = 0.37), neutropenia (P = 0.31), high bilirubin (P = 0.27), or alkaline phosphatase (P = 0.79). CONCLUSIONS: A greater loss of healthy liver following resection of hepatic metastases from colorectal cancer does not seem to predispose to the development of toxicity from adjuvant HAI and systemic chemotherapy.

High-dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma.

BACKGROUND: Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression. METHODS: Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded. RESULTS: Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed. CONCLUSIONS: Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned.