Clinical Trials Of Novel Agents Research Articles

Current Real-World Treatment Patterns and Outcomes in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Limited real-world data exist on treatments for relapsed/refractory multiple myeloma (RRMM) since the approval of several new agents. This study assessed treatment patterns and outcomes of patients with RRMM receiving ≥2 lines of therapy in US community oncology practices.Methods: A chart review was conducted in patients ≥18 years with MM diagnosed January 1, 2011-May 31, 2017, from a large electronic medical record database. Patient data were examined from the date of initiation of first-line therapy (1LT) for MM until death, loss to follow-up, or study end date, whichever was earliest. This study was hypothesis generating, thus no statistical tests were performed. Descriptive statistics were used to describe baseline demographic/clinical characteristics, treatment patterns, median progression-free survival (mPFS) and median overall survival (mOS) for the overall RRMM population. Patients were then stratified into “older” vs. “newer” treatment cohorts based on whether the drugs used in each line of therapy were approved before, or after 2013.Results: Of 1005 charts reviewed, 456 patients had received ≥2 lines of therapy and were included in the chart review study (median age at diagnosis: 70.4 years; females: 39.5%, males 60.5%; bone involvement at diagnosis: 66.0%; International Staging System stage within 1 month of diagnosis: I 28.7%, II 27.9%, III 43.4%; 183 (40.1%) patients received 3LT, 75 (16.4%) 4LT, and 29 (6.4%) 5LT. 1LT was dominated by bortezomib (BTZ), lenalidomide (LEN), and the combination of the two, with 93.3% of patients using these agents as 1LT and 69.8% of patients as 2LT. In 3LT and beyond, there was greater use of newly approved drugs (approved since 2013) compared with 1LT and 2LT; pomalidomide (14.8% 3LT, 17.3% 4LT, 17.2% 5LT), carfilzomib (19.1% 3LT, 13.3% 4LT, 17.2% 5LT), elotuzumab (2.2% 3LT, 4.0% 4LT, 3.4% 5LT), panobinostat (0% 3LT, 2.7% 4LT, 3.4% 5LT), daratumumab (6.6% 3LT, 13.3% 4LT, 17.2% 5LT), and ixazomib (0% 3LT, 1.3% 4LT, 3.4% 5LT) with the exception of the BTZ/LEN combination. However, patients receiving either BTZ, LEN, or both in combination as 1LT or 2LT often received the agent(s) as re-treatment in lines 2-6 (46.2%-55.6%). Median time on treatment decreased from 7.5 months in 1LT to ≤2.3 months in 4LT and 5LT, and median treatment-free intervals decreased from 1.6 months between 1LT and 2LT to 0.5 months between 4LT and 5LT. The most common reason for discontinuation was disease progression and drug toxicity/intolerability.The most commonly reported adverse events (AEs) for all lines of therapy were fatigue (71.6%-78.3%), bone pain (38.5%-69.1%) and anemia (53.8%-69.3%). AEs were generally constant across lines of therapy, except for bone pain, anemia, and neuropathy, which broadly decreased with increasing line of therapy. Overall, mPFS ranged from 12.0 months in 1LT to 3.5 months in 5LT and mOS ranged from 48.2 months in 1LT to 5.8 months in 5LT (Figure 1). A trend for increased mPFS and mOS with newer vs. older drugs was observed across treatment lines. The magnitude of the “new” treatment benefit on mPFS was pronounced in 1LT.Conclusions: Forty percent of patients received therapy beyond 2lines demonstrating a great unmet need in the treatment of RRMM. While BTZ and LEN were predominant in 1st and 2nd lines, substantial fragmentation was seen in ≥3 line, highlighting the lack of defined treatment pathways for these patients. The results further indicated that treatments beyond 2LT offer shorter benefit as disease progresses; median time on treatment and mPFS decreased as treatment line increased. Also, median PFS and OS in this real-world analysis were also slightly lower than that observed in recent clinical trials of novel agents, which is consistent with other real-world studies. While there remains a need to replicate these results within a larger dataset where statistical comparisons could be made and confounding factors controlled for, the trends observed in this study suggest improved PFS and OS outcomes may be associated with newly approved treatments. In particular, the trends suggested that newer treatments may have a greater mPFS benefit vs. older treatments if used in earlier lines of treatment.Funding: GSK (HO-17-17767) [Display omitted] DisclosuresWillson:GlaxoSmithKline: Employment, Equity Ownership. Bruno:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GlaxoSmithKline: Employment, Equity Ownership. Nelson:GlaxoSmithKline: Equity Ownership. Stafkey-Mailey:Xcenda: Employment.

Prevalence and Spectrum of Breast Cancer Inherited Mutations in Uganda and Cameroon Women

Background: Breast cancer among indigenous Africans is characterized by higher prevalence of triple-negative disease and poor prognosis. A previous study in Nigeria reported a strikingly high prevalence of deleterious germline mutations in BRCA1 and BRCA2 among Nigerian women with breast cancer. It is unknown if this is true in other sub-Saharan African countries. Aim: The objective of this study is to determine the frequency of germline mutations among an unselected sample of women in Africa. Methods: We conducted a case-control study of breast cancer in Uganda and Cameroon to investigate genetic and nongenetic risk factors for breast cancer. Breast cancer cases were enrolled in two tertiary hospitals in the two countries, unselected for age at diagnosis and family history. Controls who were free of breast cancer were enrolled in the same hospitals and matched to cases on age. A 24-gene sequencing panel was used to test germline mutations in cases and controls. Results: There were 176 cases and 177 controls with a mean age at diagnosis of 46.2 years for cases and mean age at interview of 46.7 years for controls. Among cases, 18.2% carried a pathogenic mutation in a breast cancer gene: 6.3% in BRCA1, 6.3% in BRCA2, 1.7% in ATM, 1.1% in PALB2, 0.6% in BARD1, 0.6% in CDH1, 0.6% in TP53, and 1.2% in any of 17 other genes. Among controls, 2.3% carried a pathogenic mutation in one of the 24 susceptibility genes. Cases were 9.6-fold more likely to carry a mutation compared with controls (odds ratio=9.61, 95% confidence interval: 3.28-38.1; P < 0.001). The mean age of breast cancer cases with pathogenic BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations ( P = 0.03). There was a trend that cases with a positive family history had higher chance of carrying a mutation (33.3%) than cases without (17.1%), but few cases reported a positive family history. Conclusion: Our findings confirm the earlier report of a high proportion of deleterious mutations in BRCA1 and BRCA2 among breast cancer patients in sub-Saharan Africa. As most of these women present with advanced breast cancer, there is an urgent need to improve access to genomic testing and life saving cancer medicines including chemotherapy and clinical trials of novel agents like PARP inhibitors. Given the high burden of inherited breast cancer, genetic risk assessment should be integrated into cancer control plans in sub-Saharan Africa.

Abstract IA18: Progress and future directions in the management of low-grade serous cancer of the ovary

Abstract Low-grade serous carcinoma of the ovary or peritoneum is a rare histologic subtype that may originate de novo or following a diagnosis of a serous borderline tumor. It accounts for approximately 10% of all serous carcinomas. It is distinguished from high-grade serous carcinoma based on the degree of nuclear atypia (mild to moderate versus marked) and mitotic index (< 12 mitoses/10 HPF versus > 12 mitoses/10 HPF). Rarely, low-grade and high-grade serous carcinoma may coexist in the same tumor. Compared to high-grade serous carcinoma, it is characterized by younger age at diagnosis, prolonged survival, and relative chemoresistance. In unsupervised clustering analysis of expression profiles, it tends to cluster with serous borderline tumor. The MAP kinase pathway appears to play a role in the pathogenesis of low-grade serous carcinoma; BRAF mutations occur in approximately 5% of cases, and KRAS mutations occur in 20-40% of cases. NRAS and HRAS mutations also occur less frequently. Preliminary findings suggest that tumors with a mutation in the MAP kinase pathway are associated with improved survival compared to tumors without mutations. Multiple studies have demonstrated relative resistance to conventional chemotherapy in the neoadjuvant, adjuvant, and salvage settings. Thus, a search for more effective therapies has dominated the clinical research of this subtype over the past decade. Bevacizumab has demonstrated objective responses in approximately 40-50% of patients in the salvage setting. The initial trial of a single-agent MEK inhibitor for recurrent low-grade serous carcinoma found a response rate of 15%, but there was no correlation of clinical response with mutational status. Three second-generation randomized MEK inhibitor trials have been conducted: one (in combination with a PI3K inhibitor) closed prematurely for toxicity, one closed prematurely for futility, and a third (GOG 0281) is completing accrual in the next few months. Detailed results of all three trials are not yet available. There have also been reports of objective responses to BRAF inhibitors in patients whose tumor harbors a BRAF mutation. In addition, hormonal therapies are of interest in this subtype given the fact that there are several similarities between low-grade serous carcinoma and ER+ breast cancer: 1) at least 80% of these tumors are ER+, 2) women < 35 years of age have a worse prognosis, 3) anti-estrogen hormonal therapies have activity in the salvage setting, and 4) following primary surgery and chemotherapy, hormonal maintenance therapy appears to be associated with superior outcomes compared to observation. Future directions include understanding further the molecular biology of this subtype through preclinical investigations and additional prospective clinical trials of novel agents, including targeted therapies, combinations of targeted therapies, and hormonal therapies in the neoadjuvant, adjuvant, and salvage settings. Citation Format: David M. Gershenson. Progress and future directions in the management of low-grade serous cancer of the ovary. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA18.

Current questions in bone sarcomas.

Osteosarcoma and Ewing sarcoma, the most common primary bone tumours in young people, are curable in most patients. However, these tumours remain a significant challenge due to the complexity and intensity of treatment and its long-term morbidity and the significant proportion of patients in whom treatment is unsuccessful. This review addresses questions about current management and emerging therapeutic targets for patients with osteosarcoma, Ewing sarcoma and chondrosarcoma, the commonest bone sarcoma but more common in older patients. The largest collaborative international study in osteosarcoma, EURAMOS-1 determined that treatment of patients with resectable disease should not be altered on basis of pathological response to neoadjuvant chemotherapy. In view of little improvement in outcome being evident in recent years, novel therapeutic approaches are required. Putative targets and clinical trials of novel agents are discussed, including emerging targets such as poly (ADP-ribose) polymerase inhibition and isocitrate dehydrogenase inhibition in Ewing sarcoma and chondrosarcoma, respectively. Newer radiotherapy techniques including proton beam and particle ion therapy may be important for local tumour control in selected patients. Collaborative studies are essential to answer current questions and investigate novel therapies in these malignancies to improve outcome and quality of life for patients.

Abstract P6-03-05: Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer

Abstract Background: Image-guided percutaneous needle biopsy of the breast is a common procedure. In breast cancer patients (pts) undergoing core biopsies and surgical resection on the same day, the rate of tumor cell displacement along the needle track has been reported to be up to 50%. However, the clinical significance of this finding in triple negative breast cancer (TNBC) patients (pts) undergoing serial biopsies while receiving neoadjuvant chemotherapy (NACT) is unknown. Here we report the incidence of needle-track seeding (NTS) in a cohort of TNBC pts enrolled on a molecular triaging protocol involving serial biopsies of the index breast lesion. Methods: We reviewed the clinical records of 144 consecutive TNBC pts enrolled on a molecular triaging protocol at MD Anderson Cancer Center. Per protocol, all pts underwent a pre-treatment research biopsy and were initiated on anthracycline based NACT (AC). Pts with inadequate response to front-line NACT were encouraged to undergo additional biopsies of the index breast lesion prior to switching therapies. Serial breast ultrasound (US) was performed to monitor therapeutic response and incidental evidence of needle-track seeding noted on US was documented. Results: Clinicopathological characteristics of the pts are summarized in Table 1. 89% (128/144) of pts had a diagnostic breast biopsy done at another center prior to presenting at MDACC. To date, we have performed 209 US guided biopsies of index breast lesions in 144 pts. 92% (193/209) of these biopsies were done mainly for research purposes. 1.4% (2/144) of pts were found to have evidence of NTS on follow up US. The first pt had a T1N0 (1.9cm), grade 3, invasive ductal carcinoma (IDC) at diagnosis. She underwent a diagnostic biopsy followed by a research biopsy before initiating AC. She was found to have NTS as well as progression of disease (PD) on follow up US after 2 cycles of AC. The second pt had a T2N0 (3cm), grade 3 IDC at diagnosis. She underwent a diagnostic biopsy at another center, followed by a research biopsy before initiating AC. Like the first pt, she was found to have NTS and PD on follow up US after 2 cycles of AC. Both pts are currently on neoadjuvant clinical trials of novel agents. Conclusion: The rate of NTS detected on US in TNBC pts undergoing serial biopsies of index breast lesions while receiving NACT is low and further studies are needed to determine the impact of serial biopsies on long term outcomes in TNBC. Table 1: Patient CharacteristicsCharacteristicN=144Age - Median (years, interquartile range)55 (46-62)Tumor Size Mean (cm, standard deviation)3.4 (2.2)T1 – n(%)35 (24)T2 – n(%)89 (62)T3 – n(%)19 (13)T4 – n(%)1 (1)Clinical Nodal Status Negative – n(%)74 (51)Positive – n(%)70 (49)Grade 1 – n(%)1 (1)2 – n(%)17 (12)3 – n(%)124 (86)Unknown – n(%)2 (1)Histologic Subtype Invasive ductal carcinoma – n(%)121 (84)Invasive lobular carcinoma – n(%)2 (1)Mixed ductal and lobular carcinoma – n(%)3 (2)Metaplastic carcinoma – n(%)13 (9)Not specified – n(%)5 (3)Laterality Right – n(%)72 (50)Left – n(%)72 (50) Citation Format: Yam C, Santiago L, Candelaria RP, Adrada BE, Rauch GM, Hess KR, Litton JK, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Huo L, Thompson AM, Gilcrease MZ, Symmans WF, Moulder SL, Yang W. Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-05.

Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Clinical Trial Availability in Adolescent and Young Adult Patients with Non-Hodgkin Lymphoma

IntroductionIncidence of non-Hodgkin lymphoma (NHL) in adolescent and young adults (AYAs) has increased over the last 25 years. Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, anaplastic large cell lymphoma, lymphoblastic lymphoma, and primary mediastinal B-cell lymphoma are the most common subtypes in patients between the ages of 15 and 19; follicular lymphoma has increased incidence in AYAs who are at least 20 years old.1 Additionally, AYAs with non-Hodgkin lymphoma have increased relapse rates and increased mortality compared to both their childhood and adult counterparts.2 Clinical trials of novel agents often exclude subjects under the age of 18. Because of this, we hypothesized that treatment in adult centers may be associated with increased availability of clinical trials studying novel agents in these at-risk patients.MethodsA keyword search of "Non-Hodgkin Lymphoma" in the database maintained by ClinicalTrials.govwas performed on May 1, 2016. Age groups, sample size, information on the studied agents, and lymphoma subtypes were collected, as well as whether study sites were members of the Children's Oncology Group. Seventeen categories of novel agents were identified; data was collected on any novel agent contained within a trial protocol.ResultsOf the 726 trials in the initial data set, 404 trials were included in our analysis; studies were excluded from the analysis if the study regimen did not contain a novel pharmacologic agent, or if they focused solely on a transplant conditioning regimen. Sixty-one studies (15%) of novel agents were open to enrollment for subjects under the age of 18 (Table 1). Twenty-five (25) of these trials of these utilized cellular therapy (CAR-T cells, donor lymphocytes, and cytotoxic T lymphocytes). Trials of tyrosine kinase inhibitors (7), novel small molecules (7), monoclonal antibodies (5) were the next-most common agents utilized in clinical trials with the remaining agent classes further detailed in Table 2.Of the 343 trials that were limited to patients who were at least 18 years old, 227 (66%) trials allowed the enrollment of subjects with DLBCL, Burkitt lymphoma, anaplastic large cell lymphoma, lymphoblastic lymphoma, follicular lymphoma, and primary mediastinal B cell lymphoma.All agent classes were represented in trials open to patients who were at least 18 years old; however, three agent classes were excluded from clinical trials in the under-18 subset: BiTE immunotherapy, PI3K inhibitors, and pleiomorphic pathway modifiers. Additionally, 178 of 343 trials (51%) included in the analysis that excluded patients under 18 years old had at least one study site which was a member of the Children's Oncology Group.ConclusionsAdolescent and young adult patients with non-Hodgkin lymphoma have higher relapse rates and lower survival rates than both their pediatric and older adult counterparts. The vast majority of trials study novel agents in the NHL subtypes that most commonly affect the adolescent and young adult population. Half of the trials that exclude patients under 18 years old take place at Children's Oncology Group member sites. While this suggests that adolescent and young adult patients treated at Children's Oncology Group member sites may have access to trials studying novel agents, the extent to which AYAs are being enrolled in these trials requires further study.[1]Hochberg, J., Waxman, I.M., Kelly, K.M., Morris, E. & Cairo, M.S. (2009) Adolescent NHL and Hodgkin lymphoma: state of the science. Br J Haematol, 144, 24-40.[2] Bleyer A, O'Leary M, Barr R, Ries LAG (eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD 2006. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Characterization of Real World Treatment Patterns and Outcomes Among Older Adults with Chronic Lymphocytic Leukemia in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries with a median age of 72 years at diagnosis. Data from recent randomized clinical trials of novel agents, such as ibrutinib, have shown significant improvements in overall survival (OS) among older CLL patients. Prior to the introduction of kinase inhibitor therapies, chemoimmunotherapy combinations were the mainstay treatment. However, older individuals and/or those with co-morbid conditions may be less likely to tolerate standard CLL chemoimmunotherapy. While we await real-world outcomes data on how novel agents have continued to change the CLL landscape, little is known about the management and survival among older CLL patients prior to the availability of novel agents in clinical practice. Our study uses comprehensive prescription and medical insurance claims linked with registry data to describe the time to treatment initiation, front line therapy, and survival outcomes in older adults with CLL between 2007-2013--an era that predates the approvals of ibrutinib, idelalisib and obinutuzumab.Methods: The study used the 2007 to 2013 SEER-Medicare linked database. The sample included patients with first primary tumor site as CLL or SLL (ICD-O histology codes 9670 and 9823) diagnosed between 2007 and 2011. This date of first diagnosis of CLL or SLL defines the index date. Patients aged > 65 years with Medicare fee-for-service coverage in the 12 months pre-index and Medicare fee-for-service and prescription drug coverage in the 6-months post-index period or until death were included. Study outcomes included time to first treatment since CLL/SLL diagnosis, type of treatment initiated, and OS since first treatment. The first treatment type was classified into 6 groups (rituximab monotherapy, chlorambucil monotherapy, rituximab + bendamustine, rituximab + fludarabine +/- other treatment, rituximab + other chemotherapy, and other chemotherapy without rituximab). Logistic regression examined factors associated with receiving any treatment within 1- and 2-years of diagnosis. Cox regression examined factors associated with OS. Covariates in both sets of models included age, gender, race, region, low-income subsidy status, anemia/thrombocytopenia at diagnosis, comorbidities, disability status, and year of diagnosis. Cox regressions also included covariates for time to treatment and type of first treatment.Results: We identified 3,214 newly diagnosed CLL/SLL patients. Our sample had a mean age of 78 years (SD: 8), 49% were male, and 30% had anemia and/or thrombocytopenia at diagnosis. Nearly 33% of the patients received at least one CLL treatment over a median follow-up of 1,099 days (IQR: 834-1735 days) from the date of diagnosis. The most common treatments were rituximab monotherapy (26%), fludarabine + rituximab +/- other treatment (23%), and chlorambucil monotherapy (16%). Among those who initiated treatment, the median time to initiation was 791 days (IQR: 127-1344 days) from diagnosis. Logistic regressions indicated that patients aged 75-79 years old (vs. 80+ year olds) and those with anemia and/or thrombocytopenia at diagnosis were significantly more likely to initiate treatment within 1- and 2-years of diagnosis.The median OS from treatment initiation among the 1,047 treated patients was 52.4 months (Figure 1). The estimated 1-year and 2-year OS since treatment initiation was 81% and 69%, respectively. The OS at 2 years was 68% for rituximab monotherapy, 73% for fludarabine + rituximab +/- other treatment, and 59% for chlorambucil monotherapy. Cox regressions showed older age, male gender, disability, higher comorbidity scores, and type of first treatment (chlorambucil monotherapy vs. rituximab as monotherapy or in combination with chemotherapies) to be significantly associated with lower OS.Discussion: About one-third of older individuals who were newly diagnosed with CLL initiated treatment over a median follow-up of 3 years. This real world study shows modest 2-year OS in older CLL patients after initiating treatment in the pre-novel therapy era. While available clinical trials suggest novel CLL agents offer significant improvements in survival for older adults with CLL, future studies should examine CLL outcomes in real world settings to correlate how results obtained in recent landmark clinical trials translate into clinical practice. [Display omitted] DisclosuresMato:Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Mehra:Janssen: Employment, Equity Ownership. Mahler:Janssen Research & Development: Employment. Huntington:Johnson & Johnson: Consultancy; Celgene: Consultancy, Honoraria; Oncosec Medical: Equity Ownership; Geron: Equity Ownership; Pharmacyclics: Honoraria; Exelixis: Equity Ownership. Doshi:Pfizer Inc.: Other: Spouse owns stock in company, Research Funding; Forest Labs: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; PhRMA: Research Funding; National Pharmaceutical Council: Research Funding; Humana: Research Funding; Merck & Co., Inc.: Membership on an entity’s Board of Directors or advisory committees, Other: Spouse owns stock; Shire: Membership on an entity’s Board of Directors or advisory committees; Alkermes: Membership on an entity’s Board of Directors or advisory committees.

Hepatitis B Reactivation with Novel Agents in Non-Hodgkin's Lymphoma and Prevention Strategies.

Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines. Non-Hodgkin’s lymphoma is the most common hematological malignancy, and certain patients undergoing therapy are at increased risk of HBV reactivation. Rituximab, a monoclonal antibody, is well studied in HBV reactivation, but newer agents have been implicated as well. Here, we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation. Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin’s lymphoma. Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation, and HBV reactivation rates have decreased with increased awareness. HBV reactivation is uncommon when using other novel agents. Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients. In conclusion, the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation, especially in patients treated with anti-CD20 antibody. Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. Lastly, large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. To review the evidence base and consider ways of improving the management of nmCRPC. Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.

Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan

Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM.Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS.Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS.Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors for Hospitalization of Children with Sickle Cell Anemia Treated with Hydroxyurea at Maximum Tolerated Dose

Background: Hydroxyurea (HU) is recommended to be offered to children with sickle cell anemia (SCA; HbSS and HbSβ0 thalassemia) beginning at 9 months of age (Yawn, JAMA 2014). Intensifying HU to a maximum tolerated dose (MTD) provides fetal hemoglobin (HbF) levels of >20% (Ware, Blood 2010). Yet, children treated with HU at MTD still experience hospitalizations due to SCA-related complications (Nottage, PLoS One 2013). The ability to identify children at high risk of experiencing SCA-related complications while on HU would enhance clinical management and facilitate performance of clinical trials of novel agents. Our objective was to identify risk factors associated with hospitalization and to develop a prediction model for hospitalization of children treated with HU at MTD.Methods: The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) designed to describe the clinical effects of HU in children with SCA. We have analyzed children who initiated HU per protocol and whose dose was escalated to MTD. Laboratory and clinical data were abstracted at baseline and at 9-12 months after enrollment. The first laboratory values of each interval were considered representative of the period. The primary outcome measure was hospitalization. After a multivariate regression logistic model identified risk factors for hospitalization based on a stepwise selection strategy, a smoothed receiver-operating-characteristic (ROC) curve was generated to predict hospitalization for the composite model and for each individual risk factor using the method of maximum-likelihood fitting of univariate distriubutions. Atlhough HbF was not identified in regression analysis among risk factors, because of its known effects as a disease modifier, it was inserted into the composite model. A prediction model was then generated for the identified risk factors utilizing optimal cutoff values defined by the maximum Youden method.Results: 151 children (mean [SD] age, 8.3 [5.0] years) were analyzed. HU resulted in higher HbF levels (22.6% [9.1] versus 10.1% [7.1]; p<0.0001), lower absolute neutrophil counts (4000/mm3 [2600] versus 7000/mm3 [3800]; p<0.0001), and fewer hospitalizations (7.8% [10/128] versus 28.9% [39/128]; p<0.0001) after 9-12 months compared to baseline.Children hospitalized after 9-12 months of therapy had similar HbF levels compared to those not hospitalized (OR 0.98 [95% CI: 0.9-1.1]; p=0.5), but higher total bilirubin (BiliT) (OR 1.3 [95% CI: 1.0-1.6]; p=0.03), blood urea nitrogen (BUN) (OR 1.3 [95% CI: 1.1-1.7]; p=0.19), and lactate dehydrogenase (LDH) (OR 1.01 [95% CI: 1.002-1.010]; p=0.006) levels. A ROC curve including insertion of HbF showed an area under the curve (AUC) of 0.90 (Figure 1). Optimal cutoffs for risk factors were: BiliT 1.05 mg/dL, BUN 8.5 mg/dL, and LDH 473 units/L. The probability of hospitalization varied in relation to identified risk factors (Table 1).Table 1Predicted probability of hospitalization after 9-12 months of HU at MTD# of risk factorsBiliTHbFBUNLDHProbability of≥1.05(mg/dL)≤20 (%)≥8.5(mg/dL)≥473(units/L)Hospitalization (%)0NoNoNoNo<11YesNoNoNo<1NoYesNoNo1.3NoNoYesNo5.8NoNoNoYes192YesYesNoNo<1YesNoYesNo<1YesNoNoYes2.2NoYesYesNo10NoYesNoYes29NoNoYesYes653YesYesYesNo1.1YesYesNoYes3.8YesNoYesYes15NoYesYesYes774YesYesYesYes25LDH, lactate dehydrogenase; BiliT, total bilirubin; BUN, blood urea nitrogenDiscussion: In this pediatric cohort, HU therapy at MTD produced a robust laboratory response with most children having HbF >20% after 9-12 months. At such high levels of HbF, few children experienced a hospitalization due to its protective effects; however, we identified three laboratory parameters (LDH, BiliT, and BUN) that were predictive risk factors for children who continued to be hospitalized despite high levels of HbF. After 9-12 months of HU therapy at MTD the probability of hospitalization ranged from <1% to 65% for children with HbF of less than <20% and <1% to 77% in children with HbF of >20%. This model may help identify children at risk for complications of SCA while being treated with HU at MTD. [Display omitted] DisclosuresEstepp:Eli Lilly and Company: Research Funding; Daiichi Sankyo: Research Funding. Off Label Use: Off label use of hydroxyurea in children with sickle cell anemia.

Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions.

The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system.

Targeted therapy in cancer.

To describe the emergence of targeted therapies that have led to significant breakthroughs in cancer therapy and completed or ongoing clinical trials of novel agents for the treatment of patients with advanced cancer. The literature was systematically reviewed, based on clinical experience and the use of technologies that improved our understanding of carcinogenesis. Genomics and model systems have enabled the validation of novel therapeutic strategies. Tumor molecular profiling has enabled the reclassification of cancer and elucidated some mechanisms of disease progression or resistance to treatment, the heterogeneity between primary and metastatic tumors, and the dynamic changes of tumor molecular profiling over time. Despite the notable technologic advances, there is a gap between the plethora of preclinical data and the lack of effective therapies, which is attributed to suboptimal drug development for "driver" alterations of human cancer, the high cost of clinical trials and available drugs, and limited access of patients to clinical trials. Bioinformatic analyses of complex data to characterize tumor biology, function, and the dynamic tumor changes in time and space may improve cancer diagnosis. The application of discoveries in cancer biology in clinic holds the promise to improve the clinical outcomes in a large scale of patients with cancer. Increased harmonization between discoveries, policies, and practices will expedite the development of anticancer drugs and will accelerate the implementation of precision medicine. Combinations of targeted, immunomodulating, antiangiogenic, or chemotherapeutic agents are in clinical development. Innovative adaptive study design is used to expedite effective drug development.

Novel Agents for Treatment of Multiple Myeloma

Multiple myeloma (MM) is a neoplasm of clonal plasma cells that closely interacts with the bone marrow (BM) microenvironment. The overall survival of patients with MM has improved dramatically in the last 20 years, due primarily to the development of autologous stem cell transplantation and novel drugs, including a proteasome inhibitor (bortezomib) and immunomodulatory agents (thalidomide and lenalidomide), as well as advances in supportive care. However, this disease remains classified as an incurable hematological malignancy. Understanding the intracellular mechanisms and the interactions between plasma cells and the BM microenvironment has accelerated development of second- and third-generations of “old novel” agents or new agents with novel targeted mechanisms of action, such as monoclonal antibodies, cell cycle-specific drugs, and deacetylase inhibitors. Among them, carfilzomib and pomalidomide have been approved for treating patients with relapsed/refractory MM. Results of ongoing preclinical and clinical trials of novel agents provide hope for continuous improvements and a cure for MM in the near future. (Korean J Med 2015;88:252-257)

Improving outcomes for patients with acute myeloid leukemia in first relapse: a single center experience.

The outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory, with few available effective therapies. Increased understanding of the biology of the disease has led to the identification of novel therapeutic agents, several of which have been evaluated in recently conducted clinical trials. We sought to determine whether the introduction of these agents as well as modern supportive care measures has already translated to better outcomes. We examined the outcomes of 1,056 patients with AML in first relapse treated between January 1993 and December 2013 at our institution. As previously reported, the independent prognostic factors for survival after first relapse included age at relapse, cytogenetics, and duration of first complete remission. Upon multivariable analysis, treatment era was an independent predictor of survival, with significant improvement in overall survival between 2008 and 2013 as compared to prior time periods. Modern supportive care measures as well as participation in clinical trials of novel agents are already improving the outcomes in first relapse.

Advanced Thyroid Cancer Patients in Phase I Clinical Trials: Outcome Assessment and Literature Review.

BackgroundTo describe the basic demographics, analyze the response and survival experience of advanced thyroid cancer subjects treated in Phase I clinical trials. We also reviewed early Phase studies using new targeted agents in thyroid cancer.MethodsWe conducted a retrospective observational study in 32 advanced thyroid cancer patients who participated in 21 Phase I trials at our center between 2002 and 2012. Descriptive statistics and Kaplan Meier analyses were used to examine clinical outcomes and survival.ResultsThe median age of subjects was 57.5 years (range 21-81) at the time of study enrollment; more men (53.1%) than women were enrolled. A large number of study participants were Hispanic Americans. Nearly half (46.8%) of patients had ECOG performance status of zero, 53.1% were ECOG one and above. The most common histological subtypes were papillary (37.5%), medullary (28.1%), follicular (18.7) and anaplastic (15.6%). More than half of patients had ≥ 2 metastatic sites (62.6%). Of the 30 evaluable patients for tumor response, 2 confirmed partial responses (6.6%) were observed, whereas 17 patients had stable disease (SD) as best response. Among patients with stable disease, 10 patients (33.3%) achieved SD lasting ≥ 6 months. The median overall survival from the time of enrollment in a Phase I trial was 16.1 months. No treatment related death was observed among these patients treated with an investigational agent.ConclusionAdvanced thyroid cancer patients with no standard treatment options could participate in early Phase clinical trials of novel agents.

Current status of clinical trials of novel agents for multiple myeloma

Current status of clinical trials of novel agents for multiple myeloma

TM-233 Exerts Anti-Myeloma Activity and Overcomes Bortezomib-Resistance In Human Multiple Myeloma Cells By Targeting NF-κB and JAK/STAT Dual-Signaling Pathways

Although the introduction of bortezomib and immunomodulatory drugs (IMiDs) has led to improved outcomes in patients with multiple myeloma (MM), the disease remains incurable. Bortezomib, a proteasome inhibitor, is widely used in the treatment of MM and has resulted in marked therapeutic effects; however, this therapy is often complicated by peripheral neuropathy (PN), of which grade ≥3 PN is dose-limiting toxicity and can necessitate cessation of therapy. Subcutaneous administration of bortezomib can reduce the incidence of PN; however, among cases of PN that still occur, 24% are grade 2 PN and 6% are grade 3 PN. These data suggest that the incidence of PN higher than grade 2 is not attenuated by the subcutaneous delivery of bortezomib. In addition, patients often become refractory to bortezomib after long-term use. In an effort to identify potent and well-tolerated agents, clinical trials of novel agents (e.g., carfilzomib, pomalidomide, and monoclonal antibody against CS-1) are being conducted both in patients with newly diagnosed MM and in those with relapsed/refractory disease. We previously reported that 1’-acetoxychavicol acetate (ACA) obtained from the rhizomes of the plant Languas galanga induces cell death of MM cells in vitro and in vivo through inhibition of NF-κB-related functions (Cancer Res, 2005; 65: 4417). Subsequently, we developed several ACA analogs based on quantitative structure-activity relationship (QSAR) analysis to develop more potent NF-κB inhibitors, and successfully synthesized a novel benzhydrol-type analog of ACA, named TM-233, that exerted potent growth inhibition against various MM cells (U266, RPMI8226, and MM-1S cells) in a dose- and time-dependent manner when compared with ACA (Chem Pharm Bull., 2008; 56: 1490). Further, TM-233 inhibited constitutive phosphorylation of JAK2 and STAT3 and down-regulated the expression of anti-apoptotic Mcl-1 protein. TM-233 directly bound and activated the transcription of the Mcl-1 gene promoter. Mcl-1 is the downstream molecule of STAT3; therefore, these results suggest that TM-233 induces cell death in MM cells with down-regulated Mcl-1 via modulation of the JAK/STAT pathway. In addition, we examined the DNA-binding activity of NF-κB in TM-233-treated MM cells and found that NF-κB was inhibited by TM-233. Further, Western blotting showed that TM-233 rapidly decreased the nuclear expression of NF-κB but increased the accumulation of NF-κB in the cytosol, suggesting that TM-233 inhibits the translocation of NF-κB from the cytosol to the nucleus. Immunohistochemical analysis confirmed that the p50/RelA dimer of NF-κB was located in the cytosol and not in the nucleus in TM-233-treated MM cells. We then examined the effects of TM-233 on bortezomib-resistant MM cells. Bortezomib-resistant MM cell lines (i.e., KMS-11/BTZ and OPM-2/BTZ) were established by limiting dilution. We found that these cells have a unique point mutation, G322A, in the gene encoding the proteasome β5 subunit (Leukemia 2010; 24: 1506). TM-233, but not bortezomib, inhibited cellular growth and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells in a time- (0-48 hours) and dose- (0-5 μM) dependent manner. Furthermore, the combination of low-dose TM-233 (less than 2 μM) and bortezomib (10 nM) significantly induced cell death in bortezomib-resistant MM cells via inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in MM cells by acting via different mechanisms from those of bortezomib. In conclusion, TM-233 induced cell death in MM cells, and this effect was mediated through the JAK/STAT and NF-κB dual-signaling pathways. These data indicate that TM-233 might be a more potent and more specific NF-κB inhibitor than that of original compound (ACA), and might be able to overcome bortezomib-resistance in MM cells. Therefore, further studies investigating clinical approaches, including combination therapy, are warranted. Disclosures: No relevant conflicts of interest to declare.

Predictors Of Survival Outcomes In Phase I Relapsed Or Refractory Multiple Myeloma Patients

ObjectivesCategorization of response criteria for multiple myeloma (MM) is based on magnitude of change in serum and urine paraprotein values and normalization of free light chain ratio (rFLC). However, the association between improvements in these surrogate markers and patient outcomes is not validated in the phase I setting. Early measures of response would be beneficial for patients and agents to identify those likely to have prolonged disease-free intervals and to validate agent activity for rapid movement to subsequent development. MethodsWe identified 31 trials that met enrollment criteria of phase I, relapsed or refractory disease, and non-transplant study population. Clinical and demographic data collected included age, sex, race, ECOG performance status (PS) at entry, myeloma subtype and isotype, prior therapy, cytogenetics at study entry, date of progression, and date of expiration. Patients with t(4;14), del13, del17p, t(14;16), or t(14;20) were considered to have non-standard risk cytogenetics. Evaluation of the relationship between progression free survival (PFS) and change in plasma cell activity by the rFLC and magnitude of response in serum/urine paraprotein per IMWG criteria was performed. Landmark analyses occurred at cycle 2 and 4, 8, and 12 months. Progression free survival (PFS) at 12 months was the primary outcome of interest. ResultsAmong 87 patients; 47 (54%) were female; 56 (64%) white, 29 (33%) black; 27 (31%) non-standard risk cytogenetics; ECOG PS 1 in 73 (84%); and median prior lines 5 (1-11). Eighty were evaluable for paraprotein changes, 71 for rFLC. Normalization of rFLC at 4 months conferred a PFS advantage (11.3 v 2.8 months, p = 0.038) (Table 1). Normalization of rFLC by 12 months was found to predict PFS (6.1 vs. 2.8 months, p = 0.015) and a longer OS (45 vs. 17.4 months, p = 0.002). Magnitude of response in paraprotein was found to predict and correlate linearly with PFS at all time landmarks (r2 = 0.769 to 0.952). Analysis of PFS by IMWG criteria and by quartiles of 50% changes were both linear (p < 0.001) (Figure 1). [Display omitted] ConclusionThese findings suggest that normalization of the rFLC and magnitude of paraprotein response are viable surrogate disease endpoints in phase I clinical trials of novel agents and combinations. The use of current IMWG criteria in the phase I setting is valuable, but the addition of time of response and alterations of response boundaries should be further evaluated in the setting of improved treatments. Disclosures:Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.