Absence Of Disease Progression Research Articles

A phase I, first-in-human, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma.

TPS11626 Background: Ewing sarcoma (ES) is a rare cancer that affects children and young adults. Patients with recurrent/refractory ES have a poor prognosis (5-year survival 10-15%) with no improvement despite advances in cytotoxic and targeted therapies. Genomic rearrangements resulting in fusion proteins and over-expression of ets family transcription factors occur in 95% of ES. In particular, the EWS-FLI1 oncogenic fusion creates a constitutively active transcription factor that drives the malignant ES phenotype. Strategies to target the EWS-FLI1 fusion protein have been limited by lack of specificity. A promising approach is to target the interaction of the ets transcription factor with its critical protein partner, RNA helicase A (RHA). TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RHA. TK216 demonstrates potent anti-proliferative effects on ES cell lines and xenografts. Methods: We initiated a Phase 1, first-in-human, open-label, multi-center, dose-escalation/dose-expansion trial of TK216 in patients with recurrent/refractory ES who are ≥12 years of age (ClinicalTrials.gov: NCT02657005). TK216 is dosed based on body surface area and administered as a continuous intravenous infusion for 7 days followed by 14 days rest every 21 days. Treatment may continue in the absence of disease progression. One intrapatient dose escalation is allowed. Enrollment of 6 to 8 cohorts using a 3+3 dose-escalation design is anticipated. During dose expansion, a total of 18 patients with ES will be accrued at the recommended Phase 2 dose (RP2D). The primary objective of the study is to determine the maximum tolerated dose and RP2D of TK216. Secondary objectives are to assess the safety profile, pharmacokinetics, pharmacodynamics, and antitumor activity of TK216. Molecular assays will be performed to characterize EWS-FLI or EWS-ets abnormalities in archival tumor tissue. The overall response rate, duration of response, progression-free survival, and overall survival will be determined in the expansion cohort. Nine patients have been enrolled since June 2016. Accrual to cohorts 1, 2, and 3 completed and cohort 4 opened in January 2017. Clinical trial information: NCT02657005.

Real life outcome of advanced melanoma patients who discontinue pembrolizumab (PEMBRO) in the absence of disease progression.

9539 Background: PEMBRO improves survival of patients (pts) with advanced melanoma. Optimal duration of treatment in responding pts hasn’t been established. Methods: 12 European hospitals collected data from 509 pts treated with PEMBRO outside an interventional clinical trial. Outcome was evaluated for pts who discontinued PEMBRO in the absence of progressive disease [PD]. Results: After a median follow up of 56 wks [range 1-135], median PFS was 22 wks [95% CI 18-26] and median OS was 70 wks [95% CI 59-81] for the total population. PEMBRO is ongoing in 66 [13%] pts, 344 [68%] pts stopped PEMBRO because of PD, and 99 [19%] pts discontinued PEMBRO without evidence of PD (of which 65 [13%] pts upon pt/MD decision, 26 [5%] pts due to a PEMBRO-related AE of grade < 4 and 8 [2%] pts due to a grade 5 PEMBRO-unrelated AE). Pts discontinuing PEMBRO without PD had a significant [ P <.005] better ECOG PS, less advanced tumor stage, less frequent brain metastases and more often a normal LDH at baseline. There was no significant difference between pts stopping due to AE or upon pt/MD decision. The median time on treatment for the 65 pts who stopped PEMBRO upon pt/MD decision was 55 wks [range 9-112].Their best objective response rate [BORR] was 80% [31 [48%] CR, 21 [32%] PR, 12 [18%]SD, 1[2%]NE]. After a median follow-up of 26 wks [range 1-75] after the last PEMBRO dose, 3 [5%] pts progressed (after 9, 14 and 15 wks). PEMBRO was reintroduced in 1 patient resulting in a CR. The median time on treatment of the 26 pts who stopped PEMBRO due to an AE in the absence of PD was 27 wks [range 1-103]. Their BORR was 77% [9 [35%] CR, 11 [42%] PR, 5 [19%] SD, 1 [4 %] NE]. After a median follow-up of 50 wks [range 12-109] following the last PEMBRO dose, 9 [35 %] pts progressed. Median time to PD was 26 wks [range 7-108]. PD was not correlated with BOR. PEMBRO was reintroduced in 4 pts resulting in 1 CR, 1 PD, 1 SD and 1 NE. Conclusions: In this real life experience, advanced melanoma pts who discontinue PEMBRO treatment upon pt/MD decision, in the absence of PD or AE, were at low risk for short-term recurrence. Pts stopping PEMBRO due to an AE in the absence of PD (having a shorter exposure to PEMBRO and longer FU after discontinuing treatment) seem to have a higher risk for subsequent PD.

First-in-man dose escalation and pharmacokinetic study of CAP7.1, a novel prodrug of etoposide, in adults with refractory solid tumours

AimAn open-label, phase I dose-escalation trial was performed in adult patients with various solid cancers to identify the maximum tolerated dose (MTD), to assess the safety, pharmacokinetic profile and anti-tumour activity of the new prodrug CAP7.1. The prodrug is converted to its active moiety etoposide via carboxylesterases in selective cells leading to a better tolerability and higher efficacy in therapeutic resistance cells and children with refractory neuroblastoma. Patients and methodsEligible adult patients with advanced, refractory, solid malignancies received CAP7.1 as intravenous infusion on 5 consecutive days. Doses were escalated in four cohorts consisting of three to six patients, with a starting dose of 45 mg/m2/day. Treatment cycles were repeated in 21-day intervals in the absence of disease progression and prohibitive toxicity. The safety, pharmacokinetics and efficacy were evaluated, and the MTD and dose-limiting toxicity (DLT) were determined. ResultsNineteen patients were assigned to four CAP7.1 dose cohorts (45, 90, 150 and 200 mg/m2/day). CAP7.1 was well tolerated. Haematotoxicity was observed at the two highest dose levels including three DLTs (two febrile neutropenia and one sepsis) only and were reversible with adequate therapy. No organ toxicity was observed. Non-haematological toxicities (mild-moderate) consist mainly of nausea, fatigue, vomiting, pyrexia and alopecia. One partial response and 11 stable diseases were observed as supporting signs of efficacy. ConclusionMTD of CAP7.1 was reached at the dose of 200 mg/m2. A favourable safety profile and initial anti-tumour efficacy of CAP7.1 in therapeutic refractory tumours warrant further evaluation in clinical studies.

Long term responders to palliative chemotherapy for advanced biliary tract cancer.

Patients with advanced biliary tract cancer (BTC) are often treated with palliative chemotherapy (PC). Standard PC since 2010 is a cisplatin/gemcitabine doublet, with median overall survival (OS) of 11.7 months from the ABC-02 trial. Prior to this, our institutional standard was gemcitabine and fluoropyrimidine. The ABC-02 study used 8 cycles of PC as standard with treatment stopped even in the absence of disease progression, but some patients may benefit from continuing PC longer than 8 cycles. Patients treated with at least 2 cycles of PC for advanced BTC in Princess Margaret Cancer Centre between 1987 and 2015 were included, and divided into 2 groups for analysis-long-term responders (LTR) who received 9 or more cycles, and controls (2-8 cycles). Data was collected on demographics, clinicopathological features, PC regimen, toxicities, and survival. The primary outcome measure was OS, with secondary analyses including progression-free survival (PFS) and toxicity rates between groups. A total of 382 patients were identified, 123 who met the criteria for LTR and 259 who were included as controls. The baseline demographic and clinical characteristics were similar, although more patients in the control group had gallbladder cancer or extrahepatic cholangiocarcinoma than LTR (P=0.024), and more patients in the LTR group were treated with combination chemotherapy regimens (93% vs. 82% in controls, P=0.003). The LTR patients had significantly longer PFS (median 13.3 vs. 4.1 months, P<0.001) and longer OS than controls (median 22.1 vs. 9.2 months, P<0.001). In LTR patients, 15% had a break from chemotherapy of 3 months or more and restarted the same regimen. The LTR patients reported higher rates of nausea, cutaneous and hematologic toxicity, but also more frequently went on to receive second-line chemotherapy (47% vs. 33%, P=0.007). In multivariable analysis of OS, LTR, good performance status and intrahepatic site of cancer were associated with better survival. From this institutional dataset, a significant proportion of patients continued chemotherapy past 8 cycles, and appeared to derive benefit from longer duration of treatment. Toxicity rates were higher in this group, but manageable as evidenced by second-line treatment rates. Discontinuation of chemotherapy for reasons other than toxicity or progression may result in loss of disease control and impact survival in this population; these data suggest the use of continued chemotherapy to disease progression in patients with advanced BTC is a favorable option.

Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome.

Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial. A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome. Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study, <10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:272-285 IMPLICATIONS FOR PRACTICE: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

The Influence of Psychosocial Constructs on the Adherence to Active Surveillance for Localized Prostate Cancer in a Prospective, Population-based Cohort

To evaluate the influence of psychosocial factors such as prostate cancer (PCa) anxiety, social support, participation in medical decision-making (PDM), and educational level on patient decisions to discontinue PCa active surveillance (AS) in the absence of disease progression. The Comparative Effectiveness Analysis of Surgery and Radiation study is a prospective, population-based cohort study of men with localized PCa diagnosed in 2011-2012. PCa anxiety, social support, PDM, educational level, and patient reasons for discontinuing AS were assessed through patient surveys. A Cox proportional hazards model examined the relationship between psychosocial variables and time to discontinuation of AS. Of 531 patients on AS, 165 (30.9%) underwent treatment after median follow-up of 37 months. Whereas 69% of patients cited only medical reasons for discontinuing AS, 31% cited at least 1 personal reason, and 8% cited personal reasons only. Patients with some college education discontinued AS significantly earlier (hazard ratio: 2.0, 95% confidence interval: 1.2, 3.2) than patients with less education. PCa anxiety, social support, and PDM were not associated with seeking treatment. We found that 31% of men who choose AS for PCa discontinue AS within 3 years. Eight percent of men who sought treatment did so in the absence of disease progression. Education, but not psychosocial factors, seems to influence definitive treatment-seeking. Future research is needed to understand how factors unrelated to disease severity influence treatment decisions among patients on AS to identify opportunities to improve adherence to AS.

The efficacy and safety of pegylated liposomal doxorubicin monotherapy and combination therapy with carboplatin in Korean patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer: a single-institution experience

ObjectiveThis study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer.MethodsThis retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m2) between 1st December 2014 and 31th July 2016.ResultsThe mean number of chemotherapy cycles was 3.8 (range, 2 to 9) in the PLD monotherapy group and 7 (range, 2 to 13) in the PLD combined with carboplatin (PLD-C) group. In overall response rates and clinical beneficial rates, PLD monotherapy group shows 5.0% and 17.5%, and PLD-C group shows 33.3% and 75.0%. The mean progression-free survival (PFS) was 5 and 13 months in the PLD monotherapy and PLD-C groups, respectively. At 6 months after treatment initiation, absence of disease progression was confirmed in 6 (15%) and 10 (83.3%) patients in the PLD monotherapy and PLD-C groups. Hematological adverse events (e.g., neutropenia and thrombocytopenia) were more common in the PLD-C group (P<0.001, P=0.004). The incidence of anemia and non-hematological adverse events, including mucositis, hand-foot syndrome, and allergic reactions, was similar in both groups.ConclusionThis study demonstrated the efficacy and safety of PLD monotherapy and PLD-C combination in Korean patients with ROC. This study would be helpful to consider the degree of worry about side effects and treatment expectations after treatment. Further retrospective studies with larger samples are required to confirm the efficacy of PLD monotherapy in Asian patients with platinum-resistant ROC.

ED13.04 Systemic Induction Therapy of Malignant Pleural Mesothelioma

ED13.04 Systemic Induction Therapy of Malignant Pleural Mesothelioma

The use of O-(2-18F-fluoroethyl)-L-tyrosine PET in the diagnosis of gliomas located in the brainstem and spinal cord.

Despite an increasing number of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET studies in supratentorial gliomas, studies regarding the usefulness of 18F-FET PET in brainstem and spinal cord gliomas to date remain scarce. Thirty-six 18F-FET PET scans were performed in 29 patients with brainstem (n = 29 scans) or spinal cord glioma (n = 7 scans). In 32 of 36 PET scans, a dynamic acquisition was performed. Fifteen scans in 15 patients were performed to assess newly diagnosed lesions, and 21 scans were obtained during follow-up: for diagnosing tumor progression (n = 15 scans in 14 patients) as well as for treatment monitoring (n = 6 scans in 3 patients). Four patients underwent additional serial scans (range, 1-2), and 3 of these 4 patients were examined for more than one indication. Maximum and mean tumor/brain ratios (TBRmax/mean) of 18F-FET uptake (20-40 min post injection) as well as kinetic 18F-FET uptake parameters were determined. Final diagnoses were confirmed histologically (54%) or by clinical follow-up (46%). In all newly diagnosed high-grade (n = 3 patients) and in 5 of 11 patients with low-grade gliomas, 18F-FET uptake was increased (TBRmax ≥2.5 and/or TBRmean ≥1.9). In 2 patients with newly diagnosed gliomas without MR contrast enhancement, 18F-FET PET nevertheless showed increased metabolism. At suspected progression, the combination of TBRs with kinetic 18F-FET parameters correctly identified presence or absence of progressive disease in 9 of 11 patients (82%). This preliminary study suggests that 18F-FET PET adds valuable diagnostic information in brainstem and spinal cord glioma, particularly when the diagnostic information derived from MRI is equivocal.

Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study

Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study

DA-EPOCH-R in Primary Mediastinal B-Cell Lymphoma; Analysis of End of Therapy FDG-PET and Outcome

Background: Primary mediastinal B-cell lymphoma (PMBL) is a distinct diffuse large B-cell lymphoma that occurs in adolescents and young adults. Retrospective studies suggest dose-intensive therapy is more effective than R-CHOP, and support a role for mediastinal radiation following R-CHOP. We demonstrated that DA-EPOCH-R is effective and obviates the need for mediastinal radiation, thus eliminating the risk of long-term toxicities (NEJM 2013;368:1408-16). End of therapy (EOT) FDG-PET is often performed to assess residual mass activity. The clinical value of EOT negative FDG-PET is under investigation in an international study in which FDG-PET negative patients are randomized to receive radiation or observation following immunochemotherapy (IELSG 37). All patients with an EOT positive FDG-PET receive mediastinal radiation. Herein, we investigate the predictive value of EOT FDG-PET following DA-EPOCH-R and provide updated results from the National Cancer Institute (NCI) and Stanford University Hospital publication of PMBL (NEJM 2013;368:1408-16).Methods: Ninety-two patients with newly diagnosed PMBL were treated with DA-EPOCH-R (Table 1). DA-EPOCH-R was administered for 6-8 cycles as previously described and no patients received up-front radiation. EOT FDG-PET was performed in 76 (83%) patients and scored retrospectively according to Deauville criteria with scores 4 to 5 called positive and scores 1 to 3 called negative. Patients with EOT positive FDG-PET scans were followed with serial scans to distinguish persistent disease from resolving inflammatory changes. The NCI and Stanford cohorts showed no significant differences in outcome and were therefore combined for analysis of event free survival (EFS) and overall survival (OS). Analyses of EFS and OS in patients with Deauville positive and negative EOT FDG-PET scans were also performed.Results: Patient characteristics were similar in the NCI and Stanford cohorts (Table 1). Overall, the median age was 31 years (range, 18 to 68), 59% were female, 59% had mediastinal masses > or = 10 cm and 20% of patients had stage IV disease. At a median follow-up of 5.3 years, the EFS and OS are 90% and 94%, respectively (Figure 1). Of 76 EOT FDG-PET scans performed, 25 (33%) were positive (Deauville score 4 or 5) and 51 (67%) were negative (Deauville score 1 to 3). Only 1 (2%) patient with an EOT negative FDG-PET scan relapsed (at 1 year), and 5 (20%) patients with an EOT positive FDG-PET scan had residual disease and received further therapy. EOT FDG-PET had a sensitivity and specificity of 83% and 71%, respectively, and a positive and negative predictive value of 20% and 98%. Comparison of outcome for EOT FDG-PET negative and positive patients at 5.3 years was 92% and 80% for EFS (p= 0.043), respectively, and was 94% and 91% for OS (p= 0.37) (Figure 2). Serial monitoring of false positive EOT FDG-PET scans showed reduction or occasionally stabilization of SUV, which is consistent with inflammatory causation. There were no events in the 16 patients without evaluable EOT FDG-PET scans resulting in an EFS of 100%. This EFS, however, was not significantly different than that of patients with evaluable EOT FDG-PET scans.Conclusions: DA-EPOCH-R (without radiation) is highly effective in PMBL and has an EFS of 90% with long-term follow-up. An EOT negative FDG-PET has a negative predictive value of 98%. Even among patients with an EOT positive FDG-PET, 80% are cured of disease and achieve long-term remission. These results demonstrate that EOT Deauville 4-5 FDG-PET scans following DA-EPOCH-R do not accurately identify patients with residual disease in most cases and should not be used to justify mediastinal radiation. In the absence of disease progression on CT scans, patients with EOT positive FDG-PET scans should be carefully monitored with short interval (e.g. 4-6 weeks) repeat FDG-PET scans to assess progressive SUV changes and need for biopsy before instituting further therapy. [Display omitted] [Display omitted] [Display omitted] DisclosuresAdvani:Kyowa Hakko Kirin: Consultancy, Honoraria; Infinity: Research Funding; FortySeven: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Sutro: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Stanford University: Employment; Millennium: Research Funding; Kura: Research Funding; Celgene: Research Funding; Regeneron: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Agensys: Research Funding.

Oncolytic Reovirus Immune Priming: A Phase 1b Study of Reolysin with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Background: While novel agents have improved the outcome for multiple myeloma (MM), the disease remains incurable. Our preclinical work has shown that MM cells from relapsed/refractory patients are very sensitive to the combination of Reolysin (a proprietary formulation of an oncolytic reovirus) and bortezomib (BZ), resulting in synergistic levels of endoplasmic reticulum (ER) stress. A pilot phase 1 study showed that Reolysin was well tolerated in relapsed/refractory MM patients and was associated with prolonged stable disease.Methods:Relapsed/refractory MM patients including patients refractory to BZ were included. This is a phase 1b study of 3 escalating doses of Reolysin (cohort 1; 3 x1010 TCID50, cohort 2; 4.5 x1010 TCID50, and cohort 3; 9 x1010 TCID50). Reolysin is given on days 1, 2, 8, 9, 15, and 16. Patients receive 40 mg dexamethasone and 1.5 mg/m2bortezomib on days 1, 8, and 15. Cycles are repeated every 28 days in the absence of disease progression or unacceptable toxicity.Results:Eight patients have been enrolled, seven were male and the median age was 55 (range, 33 - 66). The median number of prior therapies was 4 (range 1 to 6). All patients were previously exposed to BZ, and 6 patients were previously exposed to both an immunomodulatory agent and carfilzomib. Most patients had ISS stage I disease at study entry (n=5), 2 had stage II and 1 had stage III. The combination was well tolerated and most treatment-related toxicities were transient and easily managed with supportive care. The most common treatment-related toxicities were grade 1 diarrhea (n=4), grade 1 fatigue (n=4), grade 1 flu-like symptoms (n=5) and grade 1 headache (n=4). No dose limiting toxicities occurred in cohort 1 or 2. Three patients completed 1 cycle of treatment only, 2 completed 3 cycles, and 1 patient completed 4 cycles. One patient remains on treatment. Reasons for treatment discontinuation included disease progression (n=4), clinical deterioration (n=1) and patient withdrawal (n=2). Six patients were evaluable for response, 3 patients had stable disease lasting at least 3 cycles whereas 3 patients had progressive disease at the end of cycle 1. Ex vivo treatment of primary MM cells and MM cell lines (U266 and RPMI-8226) with Reolysin revealed a dramatic induction of PD-L1 expression as measured by qRT-PCR and flow cytometry. Furthermore, ex vivo treatment of MM patient mononuclear cells with Reolysin resulted in NK and T cell activation. These results suggest that the addition of an anti-PD-1 or anti-PD-L1 agent may augment the anti-MM activity of Reolysin.Conclusions: The combination of Reolysin, BZ and dexamethasone is well tolerated in a heavily pretreated MM patient population. Cohort 3 is currently enrolling at the 9 x1010 TCID50 dose level of Reolysin. The potential anti-MM effects of immune activation following Reolysin infusion may be mitigated by MM expression of PD-L1. Additional cohorts exploring the tolerability, efficacy and pharmacodynamics of the combination of Reolysin, BZ or carfilzomib, dexamethasone and an immune checkpoint inhibitor will be added following completion of cohort 3. DisclosuresKelly:Pharmacyclics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Coffey:Oncolytics Biotech: Employment. Gill:Oncolytics Biotech: Employment.

A Phase 2 Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Llmphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with High-Risk Genomic Features

BACKGROUND: Patients (pts) with CLL/SLL are at high risk for infections, and pts with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated activity in treatment-naïve CLL/SLL, can potentially restore immune system dysfunction associated with CLL/SLL. We present results from an NCI/CTEP-sponsored, randomized phase 2 study (NCI 8834) of low-dose lenalidomide designed to assess the ability of lenalidomide to restore immune synapse response and humoral immunity, as well as delay progression of asymptomatic, genetically high-risk, early-stage CLL/SLL.METHODS: Pts with genetically high-risk CLL/SLL (unmutated IGHV, deletion(17p)/(11q), and/or complex abnormal karyotype) were eligible if they were treatment-naïve, did not meet IWCLL 2008 criteria for initiating therapy, age ≥ 18 but < 80 years, ECOG ≤ 2, no history of autoimmune cytopenia, no venous thromboembolic event ≤6 months prior, and adequate end-organ function. Pts were randomized to receive lenalidomide either concurrent with (Arm A) or sequential to (Arm B) 2 doses of 13-valent protein-conjugated pneumococcal vaccine (Prevnar-13) administered 2 months apart (see figure). Lenalidomide was dosed at 2.5 mg/day during the first 28-day cycle to reduce risk for tumor flare and increased to 5 mg/day for the second and subsequent cycles as tolerated. Treatment continued for at least 24 cycles in the absence of disease progression or irreversible Grade ≥ 3 adverse event (AE). Anti-pneumococcal antibody titers, the primary endpoint of the study, were measured in each arm at 1 and 2 months after the second dose of vaccine and every 6 months thereafter. Secondary endpoints included clinical response, IWCLL 2008 response after 24 cycles, and progression-free survival (PFS).RESULTS: 49 pts were randomized. Median age at enrollment was 59 (range 40-70) years, median time from diagnosis 1.26 (range 0.15-9) years, and ECOG = 0 in 96%. Baseline clinical and genetic risk factors were similar between the 2 arms (see table). In general, AE were mild and manageable. Gr ≥3 AE were uncommon and included (in ≥10% pts): neutropenia in 10 (20%) and hypophosphatemia in 6 (12%). The most common treatment-emergent Gr 1/2 AEs included neutropenia in 27 pts (55%), diarrhea in 26 (53%), rash in 25 (51%), and thrombocytopenia in 23 (47%). Gr 1/2 infections were reported in 17 (35%), but only 1 Gr 3 infection (pneumonia) was observed. Gr 1/2 tumor flare was observed in 2 pts (4%). There were no thromboembolic events. Seroprotection against 7 pneumococcal serotypes (1, 3, 4, 5, 14, 19F, and 23F) was measured 4 weeks after the second dose of vaccine. All but 4 pts (3 in Arm A, 1 in Arm B) achieved seroprotection against ≥1 serotype, and the median number against which seroprotection was achieved was 3 (range: 0-7) in both arms. Mean IgG/IgM/IgA levels at baseline were 722/109/49, and improved to 820/136/51 and 947/197/59 after 12 and 24 cycles of treatment, respectively. Disposition of study patients and treatment responses are summarized in the table; after median 31 cycles received, 59% of patients remain on treatment. 75% of patients achieved a clinically assessed disease response, and of the 34 patients that completed IWCLL response assessment after 24 cycles of therapy (including CT scans and bone marrow biopsy), 9 achieved a PR, 23 SD, and 2 PD. Median PFS has not yet been reached; 1 year PFS was 88% (95%CI 74-94), 2 year PFS was 78% (63-88), and estimated 3 year is PFS 72% (95%CI 56-83).CONCLUSIONS: Low-dose lenalidomide can be administered to asymptomatic, genetically high-risk, early-stage CLL patients with modest toxicity and high rates of durable clinical response. Some anti-pneumococcal vaccine response was achieved by nearly all treated patients on both schedules. Lenalidomide effectively prevented and/or reversed the expected progression of hypogammaglublinemia, which may explain the low incidence of infection, and near absence of severe infection, observed here. [Display omitted] [Display omitted] DisclosuresJones:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Novartis Oncology: Consultancy; Innate Pharma: Research Funding; Pharmacyclics: Consultancy. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial

Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma. Novartis and Myeloma UK.

FEATURES OF IMMUNE STATUS IN ADOLESCENTS WITH COXARTHROSIS

Purpose: To Study immune status in patients with coxarthrosis consequent to treatment of congenital hip dysplasia and Perthes' disease as well as to determine additional variables indicating arthrosis progression.Materials and methods: The authors analyzed results of preoperative immune examination of 13 male patients aged 11,4±0,7 years (10-13) with coxarthrosis of type I-II developed consequently to treatment of hip dysplasia and Perthes' disease. Based on obtained anatomical and functional outcomes the authors divided the patients into two groups. First group included 8 patients with postoperative improvement of joint function and absence of disease progression. Second group (5 patients) was featured by functional deterioration and arthrosis advancing.Results: Patients of the second group demonstrated statistically significant elevation in certain parameters of humoral (circulating immune complex) and cellular immunity (CD3+HLA-DR (%), CD3+HLA-DR (109/l)) as well as interleukin-6.Conclusion: Obtained results have proven that initial immune parameters (IL-6, circulating immune complex, lymphocytes with activation markers) can be used as additional variables for decision making in regard to option and advisability of reconstructive joint preserving procedures in patients with coxarthrosis consequent to treatment of hip dysplasia and Perthes' disease.

Durable disease control in patients with metastatic breast cancer treated with single agent capecitabine.

e12522Background: Capecitabine is effective chemotherapy in metastatic breast cancer (MBC) and is usually given as a third line chemotherapy. Since there is no cumulative dose, if tolerability is good treatment can be given for long time until disease progression. However there are limited data of treatment duration in patients with MBC treated with single agent capecitabine. Methods: At the Institute for Oncology and Radiology of Serbia, a cohort of 24 MBC patients treated with single agent capecitabine and durable disease control have been analyzed. Durable disease control is defined as absence of disease progression during at least 24 months of continuous capecitabine treatment. All patients had progression during or after antracycline and taxane based chemotherapy +/-hormonal therapy +/-trastuzumab therapy. Lapatinib was not available at the time of treatment initiation in 3 patients with HER2 3+ MBC Dose of capecitabine ranged from 1500-2000 mg/m2 bd, days 1-14, q3w; tolerability and clinical evaluat...

Tosedostat Plus Low Dose Cytarabine Induces a High Rate of Responses That Can be Predicted By Genetic Profiling in Elderly AML

Background: Older (age ≥60 years) patients with acute myeloid leukemia (AML) have poor outcomes and intensive induction chemotherapy is frequently unsuitable. Thus, new safe and effective therapies are urgently needed. Tosedostat, a new, orally bioavailable inhibitor of members of the M1 and M17 classes of aminopeptidases, was proven to be effective in both de novo and relapsed AML. We hypothesize that the addition of tosedostat to cytarabine may improve the response rate and remission duration over what is expected with chemotherapy or tosedostat alone.Methods: This was a phase II, prospective, multicenter study, designed according to Fleming's method. Fixing the lowest acceptable rate as 10% and the successful rate as 25%, with a significance level alpha=0.05 and a power 1-beta =0.80, the sample size was estimated in 33 patients. Thirty-three patients (median age 75 years) received Tosedostat 120 milligrams orally once daily until disease progression, coupled with intermittent low-dose cytarabine given subcutaneously at 20 milligrams twice/day for 10 days. Courses of cytarabine were repeated every 4 weeks in the absence of disease progression or unacceptable toxicity, up to 8 cycles. Global gene expression profiling (GEP, Affymetrix Human Gene 2.0 Array) was performed on purified AML blasts of 29 patients from peripheral blood or bone marrow at diagnosis before treatment initiation. Unsupervised clustering was generated using a hierarchical algorithm based on the average-linkage method. Principal component analysis (PCA) and supervised gene expression analysis was performed by using GeneSpring GX 12.0 (Agilent, USA).Results: The characteristic of enrolled patients are listed in table 1 Induction-period mortality was 12%, with 4 deaths occurring in aplasia. According to intent-to-treat, the CR rate was 48.5% (16/33 patients); 2 additional patients obtained a partial response, for an overall response rate of 54.6%. In addition, 4/33 patients remained in stable disease for a median time of 9 months (range: 4-14). Seven patients did not respond and died with progressive disease after having received a median of 2 cycles of cytarabine and 45 days of tosedostat. In responding patients, the median time to best response was 74 days (range 22-145). Responding patients (CR+PR) had a longer median overall survival than non-responders (P=0.018). Six out of 18 (33%) responding patients are still in CR after a median follow-up of 425.5 days (range 208-758); 5 additional patients are alive with stable disease. Twenty-two patients died [while in aplasia (4), in CR (1), due to resistant disease (9) or due to progressive disease (8) after a median CR duration of 192 days (87-535)]. 29 patients had GEP analysis, and a molecular signature associated with the clinical response (CR vs. no CR) was identified. By supervised analysis, 212 genes differentially expressed based on the clinical response (complete remission (CR) vs no CR) were identified (Mann-Whitney, p<0.05; fold change >2). The 212 genes differentially expressed were significantly associated with six relevant biological functions and pathways: β-catenin (βcat); TNFα signaling pathway via NFκB; ERB2; STK33/SKM (serine/threonine kinase 33 expression using the SKM cell line); inflammatory response; and epithelial-mesenchymal transition pathways.Conclusions: The tosedostat and low-dose cytarabine combo produced a CR rate superior to what expected (45.4% versus 25%), and thus met the primary endpoint of study. Further, potential biomarkers were identified by GEP. Specifically, the achievement of CR could be efficiently predicted by the gene expression patterns with an overall accuracy exceeding 90%. A validation analysis is currently being conducted on additional 14 patients in order to confirm the ability of GEP to identify potential responders to TST. The study was registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) n.2012-000334-19.Acknowledgments: CTI is gratefully acknowledged for providing Tosedostat for the patients. The study was supported in part by AIL Pesaro Onlus.Table 1CharacteristicN = 33Median age, years (range)75 (62-85)Median WBC count, × 109/L (range)3.05 (0.26-24.53)Blasts, % (range)60 (20-96)Cytogenetic risk group*, nNot evaluable3 (9%)Intermediate Karyotype17 (52%)Unfavourable Karyotype13 (39%)AML, nDe novo16 (48%)Secondary, n17 (52%) DisclosuresFanin:Novartis Farma: Speakers Bureau.

A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma

A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma

A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck

Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.