eCancer Consult, February 2014

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HNSCC: Outpatient ChemoRT Regimen Offers Outcomes Equal to Inpatient at Lower Cost

An overarching goal of healthcare delivery is to improve the value of care defined as patient outcomes per dollar spent. With that in mind, a recent Cleveland Clinic study of two chemoradiation (ChemoRT) regimens for stage III-IV squamous cell carcinoma of head and neck (HNSCC) compared the outcomes and costs of the protocols.

“The study found that the two definitive regimens, one outpatient and one inpatient—both considered standards of care at Cleveland Clinic and across the country—had equal outcomes but lower costs for the outpatient treatment,” says John F. Greskovich, Jr., MD, radiation oncologist in Cleveland Clinic’s Taussig Cancer Institute and lead author of the study. The findings have the potential to change practice patterns for the better, he says.

“This type of study exemplifies value-based decision-making centered on three factors: clinical benefit to the patient, typically measured by disease-free survival; toxicity of therapy, measured by acute and late toxicities and quality of life; and cost of therapy—cost to the patient and cost to society, including payer costs,” Dr. Greskovich says.

A research first

Researchers evaluated the two arms of a phase 3, definitive ChemoRT trial in which 69 non-nasopharynx HNSCC patients were assigned to concurrent radiotherapy and either an outpatient (cisplatin [CDDP], 100 mg/m2, weeks 1, 4, 7) or an inpatient (CDDP, 20 mg/m2/d and 5FU, 1000 mg/m2/d by continuous intravenous infusion x 4 days, weeks 1,4) regimen. The two arms were well-balanced in pretreatment variables, including HPV-positive status.

“This is the first randomized prospective trial that has been done directly comparing the outcomes and cost of these two regimens commonly used for head and neck cancers,” Dr. Greskovich says.

The study measured local, regional and distant control as well as overall and relapse-free survival outcomes. Researchers compiled revenue and cost data, pulled from Cleveland Clinic’s accounting database, from treatment start date to 6 months post-treatment.

Study findings and significance

“When we looked at outcomes at two years, they were statistically the same in the two arms of the study,” Dr. Greskovich says. “There was no statistical difference between the two treatments with respect to overall survival, relapse-free survival, locoregional or distant control.”

From an economic standpoint, the analysis found that while net income was similar between the two study groups, net revenue and total cost differed significantly. The inpatient group realized $19,338 higher net revenue but also had $18,664 higher total cost per patient, making the outpatient regimen the better value-based therapy, he says. The higher inpatient treatment arm cost largely reflects the cost of planned and unplanned hospitalizations.

Implementing value-based changes

Based on the findings, Cleveland Clinic made a value-based practice change. The change was successfully implemented, with 45 percent, 19 percent and 0 percent of patients treated with the inpatient regimen in 2011, 2012 and 2013, respectively. “Measuring the outcomes and cost of the two treatment regimens for a full cycle of care enabled us to change our practice pattern by appropriately reducing cost without sacrificing tumor outcomes,” Dr. Greskovich says.

The study results are being presented this month at the K. Kian Ang, MD, PhD, FASTRO, Commemorative Plenary Session of the 2014 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Ariz.

Highlights from ASH Annual Meeting

Physicians and investigators from Cleveland Clinic’s Taussig Cancer Institute made major contributions to the American Society of Hematology (ASH) 2013 Annual Meeting in New Orleans, describing their research in more than 30 oral presentations and more than 60 poster presentations. Here we feature condensed abstracts from five of the presented research papers (Cleveland Clinic authors are listed in bold). For complete abstracts, see

Distinct Pattern of Genomic Changes Associated with Smoking in Patients with Myelodysplastic Syndromes (MDS)

David J. Seastone, DO, PhD, Sudipto Mukherjee, MD, PhD, MPH, Zaher K. Otrock, MD, Paul Elson, ScD, Michael K. Keng, MD, Bartlomiej Przychodzen, PhD, Hideki Makishima, MD, PhD, Brittney Dienes, Sean Hobson, Kristin Dodd, RN, Tracy Cinalli, RN, Ramon V. Tiu, MD, Yogen Saunthararajah, MD, Jaroslaw P. Maciejewski, MD, PhD, FACP and Mikkael A. Sekeres, MD, MS

Background: Smoking is a risk factor for development of MDS and for overall survival. The pathogenesis of MDS is a multistep process with environmental and genetic influences. The link between smoking and MDS is thought to be mediated by organic solvents in tobacco. We identified specific molecular abnormalities associated with smoking exposure in MDS patients (pts).

Methods: 151 MDS pts seen from 2000 to 2012 with complete smoking and molecular data were included. We assessed associations between the number of mutations present and demographic and clinical factors. Analysis was performed using next-generation targeted deep gene sequencing with 22 common gene mutations, selected based on the frequency observed in a cohort of MDS patients analyzed by whole exome sequencing. Mutations were considered individually and in functional groups: methylation (TET2, IDH1, IDH2), histone modification (ASXL1, EZH2), and gene splicing (SRSF2, U2AF1, SF3B1).

Results: Overall 68% of pts had at least one mutation of the 22 screened mutations: 32% had a single mutation, 22% had 2, and 13% had 3 to 6 mutations. The most common mutations were in TET2, SF3B1, ASXL1, DNMT3A and U2AF1; 32% of pts had one or more mutation in genes involved in methylation, 19% in histone modification, and 32% with splicing. In univariable analyses, current/ex-smokers were more likely to have at least one of the common mutations than never smokers. The number of mutations increased with smoking exposure, particularly with genes involved with histone modification. Certain mutations increased in prevalence with age, e.g.: pts < 60 had fewer mutations overall than pts ≥ 60, and in particular fewer mutations in methylationassociated genes. Older age and greater smoking history/exposure were both associated with more mutations. Current and ex-smokers and heavier smoking exposure (> 20 pack years) were also associated with worse survival, though current or ex-smokers with < 20 pack years had similar survival to never smokers. Multivariable analyses confirmed smoking as a risk factor for survival.

Conclusion: Smoking is associated with a greater number of molecular abnormalities in MDS pts, and may generate a distinct mutational signature pattern, particularly along histone acetylation pathways. This study identifies specific environmentally mediated pathways in the multistep pathogenesis of MDS.

Influence of Killer Immunoglobulin-Like Receptor (KIR) and HLA Genotypes on Outcomes after Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Patients with AML and MDS: A Report from the Center for International Blood and Marrow Transplant Research Immunobiology Working Committee

Ronald M. Sobecks, MD, Meighan M. Gallagher, BA, Medhat Askar, MD, PhD, Michael D. Haagenson, MS, Tao Wang, PhD, Stephen Spellman, MBS, Stephanie J. Lee, MD, MPH, Marcelo A. Fernandez Vina, PhD, D(ABHI), Carlheinz R. Muller, MD, PhD, Michael R. Verneris, MD, Ann E. Woolfrey, MD, Peter J. Shaw, MD, Daniel J. Weisdorf, MD, Sarah Cooley, MD, Jeffrey S. Miller, MD, and Katharine C. Hsu, MD, PhD

Background: Disease relapse is a significant cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). In the setting of reduced-intensity conditioning (RIC), a graft-versus-leukemia (GVL) effect is critical for successful outcomes in patients (pts) with advanced myeloid malignancies. A GVL effect has been attributed in part to donor-derived alloreactive natural killer (NK) cells, which are regulated by interaction of KIRs with their HLA-class I ligands. Several models of NK reactivity (missing KIR ligand, centromeric haplotype-B content, nontolerized KIR2DS1) have been associated with improved outcomes following HLA-matched, HLA-mismatched, related and unrelated donor HCT, particularly for AML pts given myeloablative conditioning. The effect of KIR-HLA combinations on outcomes after RIC HCT, however, is not known. We retrospectively analyzed donor-recipient KIR/HLA genotypes from 929 URD HCTs facilitated by the National Marrow Donor Program for pts with AML (n = 624) or MDS (n = 305) treated with RIC between 1990 and 2007.

Methods: A total of 664 donor-recipient pairs were 10/10 HLA-matched and 265 were 9/10 HLA-matched. A total of 332 (37%) pts received ATG and 73 (8%) received alemtuzumab. P values less than 0.01 were considered significant. We hypothesized that donor-recipient KIR-HLA interactions may be associated with improved post-transplant outcomes following RIC HCT for AML and MDS.

Results: Pts lacking the HLA-Bw4 ligand for donor inhibitory KIR3DL1 experienced lower relapse following HCT at one year (27% vs. 36%, P = 0.002) and five years (31% vs. 42%, P = 0.003) compared to pts with the Bw4 ligand. The lower risk for relapse was confirmed in multivariate analysis (HR 0.71, P = 0.005). However, there was no significant association of Bw4 ligand with disease-free survival (HR 0.84, P = 0.05) and overall survival (HR 0.97, P = 0.70). Risk for acute GVHD was higher among pts lacking KIR ligands after adjusting for other clinical factors. In particular, pts lacking HLA-C2 for donor KIR2DL1 experienced higher grade 2-4 (HR 1.3, P = 0.005) and 3-4 acute GVHD (HR 1.5, P = 0.002), and pts lacking multiple KIR ligands experienced higher grade 3-4 acute GVHD (HR 1.5, P = 0.007). The analysis was then restricted to AML pts, the population with the greatest reported KIR-HLA effects. Pts whose donors were KIR2DS1+ and HLA-C2C2 (n = 33) had higher transplant-related mortality (TRM) (HR 2.4, P = 0.002) compared to all other pts. There was no significant effect of KIR2DS1 with HLA on relapse. In a multivariate analysis, lack of HLA-C2 in AML pts was associated with higher grade 2-4 (HR 1.4, P = 0.002) and 3-4 acute GVHD (HR 1.5, P = 0.01), and risk for grade 3-4 acute GVHD was higher in pts lacking multiple KIR ligands (HR 1.6, P = 0.005). There were no significant associations between donor homozygosity for the centromeric B-haplotype (cenBB) or overall B-haplotype KIR content and RIC HCT outcomes.

Conclusion: Overall, these results suggest that in the RIC HCT setting, lack of Bw4 ligand for KIR3DL1 is associated with a lower risk of relapse for AML/MDS. This observation corroborates previous findings in myeloablative HCT transplants. Furthermore, tolerance of donor KIR2DS1 by HLA-C2C2 was associated with worse outcome (as manifested by higher TRM) in AML pts. In contrast, it appears that in RIC, HCT homozygosity for the centromeric B-haplotype does not have a significant role in leukemia relapse. The associations of KIR ligands with acute GVHD were not previously observed, suggesting that NK cell alloreactivity depends on multiple variables, including RIC. Further elucidation of the biology of NK cell alloreactivity in the RIC setting may provide guidance for future approaches to help optimize conditions for generating GVL reactions without GVHD and less TRM in this transplant population.

Inhibition of JAK-STAT Pathway as a Therapeutic Option for Myelofibrosis Associated Pulmonary Hypertension

Ali Tabarroki, MD, Daniel Lindner, MD, PhD, Valeria Visconte, PhD, Li Zhang, PhD, Edy Hasrouni, Yvonne Parker, Heesun J. Rogers, MD, PhD, Tracy Cinalli, RN, Kristin Dodd, RN, Gina Rupp, RN, Hien Kim Duong, MD, Alan E. Lichtin, MD, Matt Kalaycio, MD, Mikkael A. Sekeres, MD, MS, Anjali S. Advani, MD, Betty K. Hamilton, MD, Sudipto Mukherjee, MD, PhD, MPH, Yogen Saunthararajah, MD, Stavros E. Mountantonakis, MD, Gustavo A. Heresi, MD, and Ramon V. Tiu, MD

Background: Pulmonary hypertension (PH) is an under-recognized complication of myelofibrosis (MF), occurring in 30 percent of MF patients and associated with poor survival. The pathophysiology of PH in MF has not been elucidated, although in idiopathic PH, the proliferation of pulmonary artery endothelial cells has been linked to activation of the STAT3 pathway. Dysregulation of the JAK-STAT pathway has been implicated in the pathogenesis of MF. Ruxolitinib, a JAK1/2 inhibitor, was approved for management of splenomegaly and cytokine-mediated symptoms in MF. No specific therapy in the management of MF-associated PH has been established. Given the association between MF and PH and the possible pathophysiologic link mediated by JAK signaling, we prospectively followed 19 patients with MF-associated PH and compared their echocardiographic findings and PH-relevant serum biomarker levels pre- and post-ruxolitinib therapy.

Results: Nitric oxide (NO), a primary regulator of vascular endothelial function, is reduced in MF patients with PH compared to normal individuals. Treatment with ruxolitinib resulted in marked increase in NO levels compared to baseline, while no changes in NO levels were observed after treatment with hydroxyurea and lenalidomide. Treatment with ruxolitinib also resulted in reduction of key cytokines that inhibit NO production and induction of cytokines that lead to increase in NO synthesis, supporting the role of cytokines in PH pathogenesis in MF.

Conclusion: Aberrant JAK-STAT signaling in MF mediates PH by dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors. This suggests that inhibition of the JAKSTAT signaling pathway is a novel, viable target for the management of patients with MF-associated PH.

Prospective Study of an Emergency Department Febrile Neutropenia Pathway in Patients with Hematologic Malignancies

Michael K. Keng, MD, Elaine Thallner, MD, MS, Paul Elson, ScD, Christine Zayac, MA, Jennifer Sekeres, PharmD, BCPS, Candice M. Wenzell, PharmD, BCOP, Erika M. Gallagher, PharmD, BCOP, Catherine M. Weber, PharmD, BCOP, Marc A. Earl, PharmD, BCOP, Sudipto Mukherjee, MD, PhD, MPH, David J. Seastone, DO, PhD, Brad Pohlman, MD, Eric Cober, MD, Beth Rodgers, RN, MSN, CEN, Virginia B. Foster, PhD, MPH, Joy Yuhas, RN, MSN, Matt E. Kalaycio, MD, Brian J. Bolwell, MD, and Mikkael A. Sekeres, MD, MS

Background: Febrile neutropenia (FN) is an oncologic emergency associated with high morbidity and mortality, particularly in patients (pts) with hematologic malignancies. Delays in antibiotic administration, which can occur in busy emergency departments (EDs), lead to worse outcomes. We instituted an FN pathway (FNP) in Cleveland Clinic’s (CC) ED to reduce antibiotic delays.

Methods: We compared patients from 06/2012 to 06/2013 to historical pts from 02/2010 to 05/2012. Fever was defined as temperature ≥ 38°C, while neutropenia as absolute neutrophil count < 0.5 x 109/L. All CC cancer pts received a special “Neutropenic Risk Hospital Medical Alert Card,” which they presented upon CC ED registration with fever. The pathway formally recognized “fever with a history of cancer” as a distinct chief complaint and categorized FN as Emergency Severity Index level 2 (equivalent to stroke or myocardial infarction) for immediate triage and care. ED-specific electronic FN order sets were created to facilitate antibiotic, laboratory, and blood culture ordering, with antibiotics administered prior to return of neutrophil count. The primary goal of the FNP is administration of empiric broad-spectrum antibiotics within 120 minutes of ED presentation, per Infectious Diseases Society of America guidelines. The primary outcomes measured were time intervals related to it, e.g. time to blood draw, physician assessment, and antibiotic order/ administration. All reported times were from ED registration.

Results: FNP study pts had significantly shorter time to having blood drawn (median 38.5 vs. 70 minutes, p < 0.0001), seeing a doctor (median 44 vs. 71 minutes, p = 0.0002) and to receiving antibiotics (median 79 vs. 228 minutes, p < 0.0001). Time to admission was also shorter for FNP study pts, though study pts (4.2 vs. 6.0 hours, p < 0.0001) were less likely to be admitted than historical controls (83% vs. 97%, p = 0.005), p < 0.0001). For FNP pts admitted to the hospital, there was a non-significant decrease in length of stay, ICU admission and length of ICU stay compared to historical controls. Comparing the two FNP groups treated or not treated per the order set, those treated using the order set had shorter times to antibiotics being ordered (median 28.0 vs. 60.5 minutes, p < 0.0001) and administered (100% vs. 90%, p = 0.02). ED order set pts also had a higher rate of antibiotic use. Correct antibiotic use, antibiotic overuse, hospital and ICU admission rates, time to hospital admission, and length of hospital stay were all similar between the two groups (all p ≥ 0.28).

Conclusion: The FNP significantly decreased time from ED registration to all set time-points, including time to antibiotics by almost threefold, compared to historical controls in pts with hematologic malignancies. Rate of hospitalization was significantly lower, and ICU and length of stay numerically lower. The FNP is an effective clinical tool to provide prompt antibiotic administration to FN pts and likely represents a significant mechanism for improved outcomes and cost savings to patients with hematologic malignancies presenting with FN.

Somatic Mutational Screen for Improved Prediction of the Outcomes of Epigenetic Therapy in Myelodysplastic Syndromes (MDS)

Swapna Thota, MD, Paul Lakin, Holleh Husseinzadeh, MD, Hideki Makishima, MD, PhD, Bartlomiej P. Przychodzen, PhD, Brittney Dienes, Kathryn M. Guinta, Naoko Hosono, MD, PhD, Tomas Radivoyevitch, PhD, Mikkael A. Sekeres, MD, MS, Yogen Saunthararajah, MD and Jaroslaw P. Maciejewski, MD, PhD

Background: Hypomethylating agents decitabine and azacitidine are standard treatments for MDS. However, individual treatment responses vary from complete remissions (CR) to complete refractoriness. In general, at least months of therapy are needed prior to assessing response. Thus, patients may be subjected to prolonged exposure to ineffective therapy, suffering toxicities without clinical benefit, while potentially more effective alternative treatments are delayed. Currently, there are no reliable phenotypic or mutational markers for predicting response to hypomethylating agents. With the availability of whole exome sequencing (WES) for more routine analysis, we theorized that somatic mutational patterns may help identify patients who would most benefit from these drugs, thereby maximizing response rate by rational patient selection.

Methods: We screened 168 patients with MDS who received either azacitidine or decitabine for the presence of somatic mutations. Only those who received sufficient therapy, i.e., completed at least 4 cycles, were selected for outcome analysis. WES and targeted deep nextgeneration sequencing for a subset of 60 genes most frequently affected by somatic mutations in MDS was applied to 94 evaluable patients. Overall, the most frequently mutated genes include: TET2, IDH1/IDH2, SRSF2, ASXL1, SF3B1, RUNX1, EZH2/EED/SUZ12, SETBP1, CBL and PPFIA2. For some analyses we also divided mutations into functional gene families; e.g., DNMT family (DNMT1, DNMT3A, DNMT3B), PRC2 family (EZH2, EED, SUZ12, JARID2, RBBP4, PHF1), IDH family (IDH1, IDH2), CBL family (CBL, CBLB), and RAS family (NRAS, KRAS, HRAS, NF1, NF2, RIT1, PTPN11), among others.

Results: The most common molecular abnormalities in responders included the presence of complex karyotype, del7q/-7, del5q and mutations in DNMT3, ASXL1 and others. Similarly, the most common defects found in refractory included the U2AF1/2 family of genes. When compared and selected by the lowest p value, the top mutations in terms of predicting response were SRSF2 (OR 2.4), cohesin (5.1), ATM (OR 5.6) and PHF6 (OR 4.22). Mutations predicting non-response include RAS (OR 0.3), U2AF1/2 (OR 0.4) and LUC7L defects (OR 0.53). To generate better predictors, we combined mutations in “either/or” fashion.

For instance, the presence of either SRSF2 and cohesin, or cohesion and PHF6 mutations, will be considered predictors of response, and the presence of either RAS/U2AF1 and/or cohesin/ATM and SRSF2 are predictors of refractoriness.

Conclusions: Mutational patterns may be helpful in identifying patients who may benefit from hypomethylating therapies. Identification of the most predictive genes could guide development of molecular marker based selection of patients for hypomethylating agent therapy, but will require ongoing analysis and additional prospective testing for validation.

Transformed Diffuse Large B-Cell Lymphoma (DLBCL) Patients Treated with Salvage Rituximab, Ifosfamide, Carboplatin and Etoposide (R-ICE) Have Superior Overall Survival than Patients with De Novo DLBCL

Kathleen B. Fenner, MSHS, Lisa Rybicki, MS, Deepa Jagadeesh, MD, MPH, Robert M. Dean, MD, Brad Pohlman, MD, Mitchell R. Smith, MD, PhD, and Brian T. Hill, MD, PhD

Background: Approximately 30% of diffuse large B-cell lymphoma (DLBCL) patients (pts) relapse following initial immunochemotherapy. DLBCL usually arises without a history of lymphoma (de novo), but it can also transform from antecedent indolent lymphoma. There exist limited data regarding the outcomes of the two subpopulations of transformed and de novo DLBCL pts treated with second-line chemotherapy regimens. We sought to compare the outcomes of relapsed/refractory transformed and de novo DLBCL pts after receiving frontline rituximab, cyclophosphamide, doxorubcin, vincristine and prednisone (R-CHOP) and second-line rituximab, ifosfamide, carboplatin and etoposide (R-ICE) chemotherapy prior to planned autologous stem cell transplant (ASCT). The analysis was performed on an intent-to-treat basis.

Methods: This retrospective review compared 100 consecutive DLBCL pts (89 de novo and 11 transformed) at the Cleveland Clinic between 2000 and 2012. Inclusion criteria were age greater than or equal to 18 with relapsed/refractory DLBCL; prior treatment with R-CHOP; and second-line R-ICE chemotherapy. Baseline characteristics were compared for categorical variables using the Chi-square test or Fisher’s exact test; continuous and ordinal categorical variables were compared using the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) in transformed and de novo relapsed/refractory DLBCL pts were estimated using the Kaplan-Meier method and compared using the log-rank test. Stepwise multivariable analysis with a variable entry criterion of P < 0.10 and a variable retention criterion of P < 0.05 was used to identify multivariable prognostic factors.

Results: The majority of pts had advanced stage (III or IV) disease at the time of diagnosis of DLBCL (62.5% for transformed and 68.5% for de novo pts, P = 0.59). There was a male predominance in both groups, transformed (72.7%) and de novo (61.8%), P = 0.48. The median age at second-line was comparable between transformed and de novo pts (62 vs. 58 years respectively, P = 0.66). The period of time between R-CHOP and R-ICE was significantly longer in transformed pts than those with de novo DLBCL (30.1 vs. 11.3 months, respectively, P < 0.001). The number of cycles of R-ICE was comparable between the two groups and most commonly was three. The percentage of pts who proceeded to a planned ASCT was comparable for transformed and de novo pts (45.5% vs. 47.2% respectively, P = 0.97). The molecular subtype for cases in which data were available was germinal center in six of seven (85.7%) transformed pts and 32 of 46 (69.6%) de novo pts as determined by the Hans immunochemistry algorithm (P = 0.66). Transformed pts had a statistically significant improvement in OS compared with de novo pts (77.8% vs. 27.4% five-year OS, respectively, P = 0.034). Death due to relapsed disease was comparable for both groups (50% transformed vs. 38.5% de novo). Transformed pts had marginally better PFS outcomes after five years (51.4%) than de novo pts (26.9%, P = 0.18). In a multivariable analysis, transformed DLBCL was associated with a statistically significant odds ratio (OR) of 0.23 (95% C.I. 0.05 - 0.95)1.05 - 17.8) for OS (P = 0.043). ASCT was associated with improved OS in multivariable analysis (OR = 0.57 (C.I. 0.33 - 1.00), P = 0.05).

Conclusion: Contrary to expectation, transformed DLBCL pts previously treated with R-CHOP have superior OS after second-line R-ICE than pts with de novo DLBCL. This may result from a relatively longer period of time between initial treatment and the need for second-line and possibly an enrichment for cases with the more favorable germinal center molecular type. Improvements in second-line treatment for de novo relapsed/refractory DLBCL with novel agents are needed.

Taussig Cancer Institute Clinical Trials

Disease: Brain and lung
A Randomized, Double Blind, Phase 2, Dose-Ranging Study to Evaluate the Safety and Efficacy of Veliparib and Whole Brain Radiation Therapy Versus Placebo and Whole Brain Radiation Therapy in Subjects with Brain Metastases from Non-Small Cell Lung Cancer
Objective: The primary efficacy endpoint is overall survival

Disease: Blood & Marrow Transplant (BMT) and Multiple Myeloma
A Study of Low-dose Lenalidomide after Non-myeloablative Allogeneic Stem
Objective: Identify the maximum tolerated dose (MTD) and safety of lenalidomide up to 10mg following non-myeloablative allogeneic stem cell transplant for multiple myeloma

CASE 1812
Disease: Prostate
High-Dose Stereotactic Radiation for Prostate Cancer
Objective: To assess treatment related gastrointestinal (GI) and genitourinary (GU) toxicity for patients who undergo SBRT for localized prostate cancer. Our hypothesis is that toxicity will not be excessive (defined as greater than 15% for either GI or GU) compared to the historical standard of fractionated IMRT with image-guidance (which results in 5% grade 3 GU and 5% grade 3 GI toxicity).

CASE 4113
Disease: Breast
A Pilot Study for Evaluating the Neural Substrates of Cognitive impairments and movement-related fatigue in women undergoing adjuvant chemotherapy (CARES)

  1. To determine the feasibility of cognitive testing, TMS and rsF-MRI pre and post adjuvant chemotherapy
  2. To determine if cognitive deficits are related to changes in fc and white matter damage in women who have received adjuvant chemotherapy for breast cancer
  3. To determine if fatigue is related to excitability of motor cortices, white matter damage and fc in women treated with adjuvant chemotherapy for breast cancer Subjective (Brief Fatigue Index or Inventory, BFI)

Disease: Hematologic Malignancy
Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects with EphA3-Expressing Hematologic Malignancies

  1. Dose Escalation Phase: The primary objective is to determine a possible maximum tolerated dose (MTD, defined in Section 7.1.1) for KB004 when administered up to 700 mg once weekly by IV infusion to subjects with hematologic malignancies.
  2. Cohort Expansion Phase: The primary objective is to characterize preliminary clinical activity based on the International Working Group (IWG) criteria specific to that hematologic malignancy. Patients must have EphA3+ disease as assessed by IHC

MEI 1913
Disease: Myelodysplastic Syndrome (MDS)
A Phase II Randomized, Double-Blinded, Placebo-Controlled Study of Pracinostat in Combination with Azacitidine in Patients with Previously Untreated International Prognostic Scoring System (IPSS) Intermediate Risk 2 or High-Risk Myelodysplastic Syndrome (MDS)
Objective: Estimate the relative efficacy, as measured by complete remission (CR) within 180 days following randomization of pracinostat plus azacitidine versus placebo plus azacitidine.

Disease: Breast
A Phase III Clinical Trial Comparing Trastuzumab Given Concurrently with Radiation Therapy and Radiation Therapy Alone for Women with HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy

  1. The primary aim is to determine the value of trastuzumab given during radiation therapy (RT) compared to RT alone in preventing the subsequent occurrence of ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS (IIBCR-SCR-DCIS) in women with HER2-positive DCIS resected by lumpectomy.
  2. The primary endpoint is time from randomization to IIBCR-SCR-DCIS defined as ipsilateral invasive breast cancer, ipsilateral skin cancer recurrence, or ipsilateral DCIS. An IIBCR-SCR-DCIS event is defined as recurrent tumor in the ipsilateral breast parenchyma, skin of the ipsilateral breast or ipsilateral DCIS occurring after lumpectomy. In the determination of time to an IIBCR-SCR-DCIS, no statistical censoring will be performed with respect to any previous local, regional, distant recurrences or second primary cancers.

Disease: Breast
A Randomized Phase III Trial of Adjuvant Therapy comparing chemotherapy alone (Six Cycles of Docetaxel plus cyclophosphamide of four cycles of doxorubicin plus cyclophosphamide followed by weekly Paclitaxel) to chemotherapy plus Trastuzumab in Women with Node-Positive of High-Risk Node Negative HER2-Low invasive Breast Cancer.
Objective: The primary objective of this trial is to show that the addition of trastuzumab to chemotherapy (either TC [Groups 1A and 2A] or AC -> WP [Groups 1B and 2B]) improves IDFS. Patients will be entered in one of these two chemotherapy cohorts based on the investigators preference, which must be indicated prior to randomization.

SEGE 2412
Disease: Lymphoma
A randomized, double-blind, placebo-controlled, phase 3 study of brentuximab vedotin and CHP (A + CHP) versus CHOP in the frontline treatment of patients with CD30-positive mature T-cell lymphomas
Objective: To compare the progression-free survival (PFS) as determined by an independent review facility (IRF) between the 2 treatment arms.

SWOG 1207
Disease: Breast
Phase III Randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk hormone receptor-positive and HER2/NEU negative breast cancer. E^3 Breast Cancer Study- Evaluating Everolimus with Endocrine Therapy
Objective: The primary objective of this study is to compare whether the addition of one year of everolimus (10 mg daily) to standard adjuvant endocrine therapy improves invasive disease-free survival (IDFS) in patients with high-risk, hormone-receptor (HR) positive and HER2-negative breast cancer.

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