A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1.

Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.

Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States.

BACKGROUND: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials. METHODS: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression. RESULTS: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0). CONCLUSIONS: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.

Epidemiology of Chemotherapy-Induced Anemia in Patients with Non-Hodgkin Lymphoma.

INTRODUCTION: Anemia is a common adverse effect of myelosuppressive chemotherapy, and the development of chemotherapy-induced anemia (CIA) is more common in patients with hematologic malignant tumors. OBJECTIVE: To assess the incidence and treatment pattern of CIA in patients diagnosed with non-Hodgkin lymphoma (NHL) from a large managed care organization in California. METHODS: Patients diagnosed with NHL between 2010 and 2012 were studied to provide an updated picture of CIA in current hematology-oncology practice. Trends in anemia treatment patterns were examined from 2000 to 2013. All data were collected from Kaiser Permanente Southern California electronic health records. RESULTS: Of 699 chemotherapy-treated patients with NHL diagnosed between 2010 and 2012, 36.9% and 11.6% developed moderate (hemoglobin < 10 g/dL) and severe (hemoglobin < 8 g/dL) CIA during chemotherapy, respectively. Proportions of moderate CIA events treated with erythropoiesis-stimulating agents (ESAs) decreased from 2000 to 2013: 34% in phase 1 (January 1, 2000, to December 31, 2006), 22% in phase 2 (January 1, 2007, to March 24, 2010), and 6% in phase 3 (March 25, 2010, to June 30, 2013). An increasing trend of red blood cell transfusion was observed: 12% in phase 1, 22% in phase 2, and 27% in phase 3. Similar calendar trends were observed for management of severe CIA events. DISCUSSION: In contrast to previous European reports, we note a higher incidence of CIA in patients with NHL in this US community practice setting. CONCLUSION: Moderate to severe CIA is common in patients with NHL receiving chemotherapy. Multiple ESA-related policy changes occurred from 2000 to 2013. A large proportion of CIA episodes were currently not treated with ESA, and transfusions have become more common. Further studies are needed to determine associations between CIA symptom burden and CIA treatment as they relate to patient outcomes and quality of life.

First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1.

PURPOSE: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1-expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors. PATIENTS AND METHODS: Adults with previously treated, advanced, NY-ESO-1-positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses). RESULTS: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti-NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti-NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis. CONCLUSIONS: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.

Systemic Anti-Cancer Therapy in Synovial Sarcoma: A Systematic Review.

Synovial sarcoma (SS) is an aggressive malignancy which accounts for approximately 5⁻10% of all soft-tissue sarcomas. SS has pathologic and genomic characteristics that define it as a distinct subtype of soft tissue sarcoma (STS). STS subtypes continue to be recognized as distinct entities with specific characteristics, including differential chemo-sensitivity. The objective of this study was to conduct a descriptive review of current data on survival outcomes of systemic anti-cancer therapy specific to SS. A systematic literature review was conducted, using a custom search strategy to search EMBASE, Medline and CENTRAL for clinical trials and observational studies reporting overall survival (OS), progression-free survival (PFS) and/or response for cohorts of at least 50 SS patients. We identified 28 studies meeting these criteria, 25 of which were retrospective studies. Only three prospective studies were identified. Survival reports varied widely between studies based on the population, in particular on the disease stage, and reporting was heterogeneous in terms of the time points reported on. For patients with localized disease, reports of five-year PFS ranged from 26% to 80.7% and five-year OS from 40% to 90.7%, whereas five-year OS for patients with metastatic disease was very low at around 10%; and in one case, 0% was reported. Only four of the included publications reported outcomes by type of systemic anti-cancer therapy received. Our study draws attention to the fact that additional prospective studies to better define the most appropriate treatment for SS in all stages and lines of therapy are still needed.

Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review.

Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC) without RAS gene mutations. However, treatment with anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Because these dermatologic toxicities can result in treatment discontinuation and affect patient quality of life, their management is an important focus when administering anti-EGFR monoclonal antibodies. The present systematic review describes the current data reporting the nature and incidence of, and management and treatment options for, dermatologic toxicities occurring during anti-EGFR treatment of mCRC. A search of the National Library of Medicine PubMed database from January 1, 2009, to August 18, 2016, identified relevant reports discussing dermatologic toxicity management among patients with mCRC receiving anti-EGFR therapy. The studies were grouped by type and rated by level of evidence using the GRADE approach developed by the Agency for Healthcare Research and Quality. Overall, 269 reports were reviewed (nonrandomized trials, n = 120; randomized trials, n = 31; retrospective studies, n = 15; reviews, n = 39). Dermatologic toxicity of any grade occurs in most patients who receive anti-EGFR therapy; approximately 10% to 20% of patients experienced grade 3/4 toxicity. The most common dermatologic toxicities include papulopustular/acneiform rash, xerosis, and pruritus; however, nail changes, hair abnormalities, and ocular conditions also occur. Guidance for managing these toxicities includes the use of inexpensive emollient ointments and moisturizers, avoidance of sun exposure, avoidance of irritants, and the use of short showers. Several studies also found that preemptive treatment was more effective than reactive treatment at limiting the incidence and severity of skin toxicity. With appropriate treatment, the dermatologic toxicities associated with anti-EGFR monoclonal antibody therapy can be managed, minimizing patient discomfort and the need for therapy interruption and/or discontinuation. Additionally, preemptive treatment can reduce dermatologic toxicity severity, ultimately yielding better quality of life.

Transfusion practice patterns in patients with anemia receiving myelosuppressive chemotherapy for nonmyeloid cancer: results from a prospective observational study.

PURPOSE: The decision to prescribe packed red blood cell (PRBC) transfusions in patients with chemotherapy-induced anemia (CIA) includes assessment of clinical features such as the patient's cancer type and treatment regimen, severity of anemia symptoms, and presence of comorbidities. We examined contemporary transfusion practices in patients with nonmyeloid cancer and CIA. METHODS: Key inclusion criteria were age ≥ 18 years with nonmyeloid cancer, receiving first/second-line myelosuppressive chemotherapy, baseline hemoglobin (Hb) ≤ 10.0 g/dL, and planned to receive ≥ 1 PRBC transfusions. Exclusion criteria were receipt of erythropoiesis-stimulating agents within 8 weeks of screening and/or chronic renal insufficiency. Data were collected from patients' medical records, laboratory values, and physician/provider questionnaires. Proportion of patients for each clinical consideration leading to a decision to prescribe a PRBC transfusion and 95% exact binomial confidence intervals were determined. RESULTS: The study enrolled 154 patients at 18 sites in USA; 147 (95.5%) received a PRBC transfusion. Fatigue was the most common symptom affecting the decision to prescribe a PRBC transfusion (101 [69.2%] patients). Of the three reasons selected as primary considerations for prescribing a PRBC transfusion, anemia symptoms (106 [72.1%] patients) was the most frequently reported, followed by Hb value (37 [25.2%] patients) and medical history (4 [2.7%] patients). CONCLUSIONS: In this study, the primary consideration for prescribing a PRBC transfusion was anemia symptoms in 72.1% of patients, with only 25.2% of patients prescribed a transfusion based exclusively on Hb value. Results indicate that clinical judgment and patient symptoms, not just Hb value, were used in decisions to prescribe PRBC transfusions.

Efficacy and safety of darbepoetin alfa initiated at hemoglobin ≤10 g/dL in patients with stage IV cancer and chemotherapy-induced anemia.

Data on efficacy and safety of darbepoetin alfa (DA) administered at hemoglobin (Hb) ≤10 g/dL are limited. In this analysis, we examined DA's efficacy and safety in patients with Stage IV cancers and chemotherapy-induced anemia (CIA) initiated on DA at Hb ≤10 g/dL. Data for patients with Stage IV cancers and CIA and who initiated DA at Hb ≤10 g/dL were extracted from three phase 3 trials identified in a central database of Amgen-sponsored DA studies in CIA. Efficacy outcomes were assessed by achievement of Hb increases of ≥1 g/dL and ≥2 g/dL and red blood cell (RBC) or whole blood transfusion requirements. Data were analyzed for all patients with baseline Hb ≤10 g/dL, and by the subgroups of patients with baseline Hb ≥9 to ≤10 g/dL versus <9 g/dL. Crude and Kaplan-Meier proportions of patients who experienced each outcome and time (days) to each outcome were summarized by treatment. Meta-analysis (fixed-effects inverse-variance model) was performed to compare outcomes for DA versus placebo. Safety was assessed by occurrence of adverse events. Data from 213 patients were analyzed: DA, n = 115; placebo, n = 98. More patients in the DA versus the placebo subgroup achieved Hb increase of ≥1 g/dL (72% vs. 36%; HR: 2.92, 95% CI: 1.95, 4.39) and ≥2 g/dL (44% vs. 18%; HR: 2.98, 95% CI: 1.71, 5.21) during the first 12 treatment weeks. Median times to Hb increase of ≥1 g/dL and ≥2 g/dL were 36 days and 78 days for DA, respectively. RBC or whole blood transfusions were less common in patients in the DA versus the placebo subgroup (24% vs. 45%; HR: 0.44, 95% CI: 0.27, 0.73). No new safety issues were reported. Our results confirm that DA use in patients with Stage IV cancer and CIA is more effective than placebo at increasing Hb levels and at reducing transfusion needs when DA treatment is initiated at Hb ≤10 g/dL.

The effect of chemotherapy-induced anemia on dose reduction and dose delay.

PURPOSE: To evaluate moderate (grade 2, hemoglobin <10 g/dl) and severe (grade 3+, hemoglobin <8 g/dl) anemia as potential risk factors for DDR in the first line course of chemotherapy. While chemotherapy-induced neutropenia has been shown to be associated with dose delay/reduction (DDR) in several studies, the effect of anemia is less well studied. METHODS: We identified 3955 Kaiser Permanente patients diagnosed with incident non-Hodgkin's lymphoma (n = 574), breast (n = 2043), lung (n = 463), gastric (n = 113), ovarian (n = 204), or colorectal cancers (n = 558) between 2010 and 2012. Generalized linear mixed effects models were used to study the effect of anemia in subsequent cycles, adjusting for demographics, comorbidities, chemotherapy cycle, neutropenia, thrombocytopenia, and liver and renal function. RESULTS: We found that moderate (grade 2) to severe (grade 3-4) anemia increased the risk of DDR in subsequent chemotherapy cycles [odds ratio (OR) = 1.46, 95 % CI (1.32, 1.62) and OR = 2.02 (1.41, 2.89)], respectively, compared to grade 1 or no anemia. Both stage I-III and IV patients with grade 2 or greater anemia were at higher risk for DDR than patients with grade 1 or no anemia [ORstage IV, grade 2 = 1.94 (1.58, 2.38); ORstage IV, grade 3/4 = 2.83 (1.42, 5.62) and ORstage I-III, grade 2 = 1.33 (1.18, 1.49); ORstage I-III, grade 3-4 = 1.81 (1.18, 2.76)]. CONCLUSIONS: These results provide insight into novel risk factors for chemotherapy dose modification that may inform clinicians on management strategies to optimize treatment outcomes.

Patient and health care provider perceptions of cancer-related fatigue and pain.

PURPOSE: In 1997, Vogelzang et al. reported that 61 % of patients with cancer indicated fatigue impacted daily life more than pain, and only 37 % of oncologists shared this perception. We provide an update to this study, which can help prioritize symptom assessment and management in the clinic. Study aims were to determine and compare perceptions of patients with cancer and health care providers (HCPs) of the impact of fatigue and pain. METHODS: A random sample of patients with cancer was recruited in the USA by Harris Poll Online and Schlesinger Associates. Oncology HCPs were recruited by Food and Drug Research, Inc. and Toluna, Inc. RESULTS: From June to November 2012, 550 of 1122 eligible patients (49 %), 400 of 533 eligible oncologists (75 %), and 400 of 617 eligible oncology nurses (65 %) completed a survey. Of patients, 58 % reported that fatigue affected their daily lives more than pain while undergoing treatment with chemotherapy versus 29 % of oncologists and 25 % of oncology nurses that had this perception. Ninety-eight percent of patients reported experiencing fatigue, whereas 72 % of oncologists and 84 % of oncology nurses thought this was the case. Eighty-six percent of patients reported pain while undergoing treatment with chemotherapy, whereas 36 % of oncologists and 51 % of oncology nurses believed this occurred. Nausea and vomiting felt by HCPs were the most concerning symptoms for patients (88 %). CONCLUSIONS: This study shows the importance of assessing symptoms by direct patient report during chemotherapy treatment. HCPs continue to underestimate the prevalence and importance of fatigue and pain for patients with cancer, a finding that may alter the management of treatment-related symptoms and may influence the development of patient symptom management plans.

Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis.

Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81-1.34, random-effects model, 10 studies); the risk difference was - 0.01 (95% CI, - 0.03-0.02). The OR for disease progression was 1.02 (95% CI 0.81-1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy.