Absence Of Measurable Disease Research Articles

TIPS-03 A PHASE 1 STUDY OF GALLIUM MALTOLATE (GAM) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)

Abstract Glioblastoma remains the most aggressive malignant brain tumor with universally poor prognosis. New treatments are needed which target novelpathways. GBM cells have significantly greater requirements for iron and display markedly higher levels of transferrin receptors for iron uptake and ferritin for iron storage than surrounding normal astrocytes. The increased intracellular iron pool drives GBM activity. Previously, we showed that since gallium shares certain chemical properties with iron, it can inhibit malignant cell growth by disrupting tumor iron homeostasis. Recently, we reported that GaM is cytotoxic to GBM cell lines and stem cells but not to microvascular endothelial cells. In rodent orthotopically implanted human GBM xenografts, orally administered GaM reduced tumor volume and prolonged animal survival. These preclinical studies form the basis for our Phase 1 study which evaluates GaM in patients with recurrent GBM. The trial will follow a 3 + 3 phase 1 dose escalation design. Three to six patients at each dose level will receive GaM 500 mg/d, 1000 mg/d, or 1500 mg/day for a minimum of two 28-day cycles. Patients age >= 18 years with histologically confirmed GBM or molecular GBM with recurrent measurable disease are eligible. In the absence of measurable disease, pathologic confirmation of recurrence is required. Primary objectives are to determine a maximum-tolerated dose and recommended Phase 2 dose. Safety/tolerability will be assessed. Secondary objectives include disease assessments and evaluation of PFS and OS. Correlative studies planned are sequential blood levels of gallium, iron, Tf, ferritin, and hepcidin. Available tumor tissues will be examined for the expression iron biomarkers by immunochemistry. The study is currently enrolling. Patients will receive study drug until disease progression, unacceptable adverse events, patient withdrawal, or death. To date, 5 patients received GaM 500 mg/d without DLT and 4 patients started GaM 1000 mg/d.

Ongoing Symptoms and Reduced Health Measures in Unicentric Castleman Disease Patients Despite Perceived-to-be Curative Surgical Excision

Unicentric Castleman disease (UCD) is one of several subtypes of Castleman disease that share characteristic histopathology. While UCD involves one region of enlarged lymph nodes (LN) and milder symptoms, idiopathic multicentric CD (iMCD) involves multiple regions of enlarged lymph nodes and cytokine-driven organ dysfunction. UCD symptoms can occur due to compression of neighboring structures or inflammatory cytokine production. Complete excision of the enlarged LN is reported in the literature to be curative in 84-96% of UCD patients. However, many UCD patients describe persistence or worsening of symptoms post excision despite normal laboratory values and absence of measurable disease. To better characterize and describe the experience of individuals diagnosed with UCD, we administered surveys to UCD patients to capture information about general quality of life (QOL), specific health measures, and ongoing UCD symptoms.All patients enrolled in the ACCELERATE Natural History registry who either self-reported a UCD diagnosis or were suspected to have a UCD diagnosis were invited to participate in the Rand36-item Short Form survey, the EQ-5D-5L, the MCD Symptom Score survey, all of which are validated instruments, as well as an additional form regarding ongoing symptoms. Among the 107 UCD patients invited to participate, 51 (48%) responded. Descriptive analyses were conducted on all 51 respondents with a self-reported UCD diagnosis. Subsequently, a subset consisting of 25 respondents, who had been reviewed by a panel of physicians that confirmed a UCD diagnosis (confirmed subcohort, CS), was analyzed.Mean (SD) EQ-5D-5L health index score (100 being perfect health, 0 being worst health imaginable) of the 51 patients was 67.6 (19.9), compared to a representative sample of the US population whose score was 80.4. Patients reported having poor health over the prior 4 weeks, with low scores indicating high levels of fatigue (38.8) and poor general health (47.7). These are notable and comparable to scores for fatigue (52.2) and general health (57.0) among a separate cohort of patients with diabetes, hypertension, coronary heart disease, and/or depression.Strikingly, 57% of patients reported continuation of symptoms post-LN excision, with an additional 16% being unsure. Only 29% reported complete symptom resolution, with the remainder reporting partial resolution (29%), stable disease (20%), worsening disease (12%), or unsure (10%). Nearly all 51 respondents underwent their LN-excision >1 year prior (93%). Fatigue (61%) and night sweats (39%) were most commonly reported in patients with continued symptoms. In fact, 27 patients (53%) reported ongoing symptoms on the day of survey completion with 93% of those patients reporting fatigue that day. Of note, sub-group analyses of the CS revealed similar findings, with a potential trend towards slightly better overall health with mean (SD) health index score 72.6 (14.5), fatigue (44%) and night sweats (36%), and ongoing symptoms reported in 40%. Of the patients in the CS, all had a complete resection, with 3 demonstrating subsequent lymphadenopathy in new regions ranging from 6 months to 5 years after their initial excision.Overall, these data suggest that UCD patients who have had resection of disease continue to experience symptoms that affect QOL. Patients reported lower QOL than a representative national average, as well as health measures comparable to a separate cohort of individuals with chronic health conditions. Of note, the full cohort of self-reported individuals consistently reported lower scores compared to the subset of patients with confirmed UCD (not statistically tested). Of the 26 non-confirmed cases, 8 did not achieve criteria to meet UCD and 18 have not yet been reviewed by our physician panel. A different undiagnosed disorder may be the root cause of symptoms in a portion of these patients and others may be experiencing symptoms due to a co-occurring disorder. These results may be confounded by reporting bias and may not be representative of the full UCD population. Nevertheless, these data suggest that perceived-to-be curative excision does not result in symptom-free outcomes in a substantial proportion of patients and that symptom management may be required beyond excision. Future work is needed to correlate these findings with clinical, laboratory, and experimental data to further elucidate mechanisms and treatment options. DisclosuresFajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’.

Multiple Myeloma Oligosecretory Relapse, a Non-Negligible Phenomenon. Frequency, Clinical Characteristics and Outcomes in a Single Center

Introduction:Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials.Methods:Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP > 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups.Results:One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A).Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p<0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively.Conclusions:Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. [Display omitted] DisclosuresAvivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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.

Long-term results of the GEINO 1401 TRIAL: Randomizing patients to stop or to continue temozolomide until 12 cycles.

2013 Background: We previously presented our results of the GEINO 1401 trial that randomized patients diagnosed with glioblastoma and treated with chemoradiotherapy and adjuvant temozolomide (TMZ) followed by six cycles of TMZ, to receive an extended use of TMZ up to 12 cycles or to control. We found no differences in 6-months neither progression free survival (PFS) nor overall survival (OS). In this report we actualize our results and analyse long-term survivor patients (LTSP). Methods: The trial NCT02209948 randomized (ratio 1:1) 159 patients diagnosed with glioblastoma who had been treated with standard therapy to stop treatment or to continue up to 12 cycles of TMZ. Patients were stratified based on their O6-methylguanine-DNA-methyltransferasa (MGMT) methylation status and presence or absence of measurable disease at inclusion. We update here OS outcomes and analyse the data of LTSP defined as an OS over 30 months from diagnosis. Results: At a median follow-up of 20 months, 82.4% of the patients had died and 89.9% had progressed. The median OS from randomization was 22.0 months for the control arm and 18.2 for the experimental arm: HR 0.957 (95%CI 0.806-1.136, p = 0.615). At 2 years from randomization there were a 61% of survivors in the TMZ group and 62% in the control group. There were a 49.7% of LTSP showing no differences between TMZ and control group. We found a higher prevalence of methylated MGMT in LTSP, but no differences were shown in patients with or without measurable disease at inclusion, status of IDH and the use of bevacizumab after progression. Conclusions: Adding 6 cycles of TMZ after the first 6 adjuvant cycles confers no additional benefit in OS. Nearly 50% of the patients included in GEINO 1401 who had been previously treated with TMZ 6 cycles without progressing were LTSP. Clinical trial information: NCT02209948.

MEK Inhibition with Trametinib in Patients with Non-Langerhans Cell Histiocytosis

Background: Activation of the MAPK pathway through BRAF mutations or other molecular alterations is a hallmark of the non-Lagerhans cell histiocytosis (non-LCH) such Erdheim-Chester disease (ECD) or Rosai-Dorfman disease (RDD). Conventional clinical molecular testing of tumor tissue fails to identify targetable molecular alteration in about one third of patients with non-LCH. Targeting the MAPK kinase pathway in non-LCH with small molecule inhibitors can be effective in patients with BRAF or other MAPK molecular alterations. Methods: Patients with non-LCH with any, unknown or pending molecular profile (tumor tissue targeted next generation sequencing [NGS], plasma cell-free [cf] DNA targeted NGS) were treated with trametinib, an oral inhibitor of MEK1/2 kinase. Treatment outcomes such as response per RECIST 1.1 or RANO in case of central nervous system involvement, time on therapy and adverse event (AE) were analyzed. Results: Total of 16 patients with ECD (n=12) or RDD (n=3) or ECD/LCH (n=1) were started on oral trametinib dose of 1 mg to 2 mg daily. Of these 16 patients, 3 patients were found to have BRAF V600E mutation in tumor and/or plasma cfDNA, 7 patients had other alteration(s) putatively activating the MAPK pathway (CAPZA2-BRAF fusion [n=1], RAF1 amplification [n=1], GNAS mutation [n=3], HMGA2 rearrangement [n=1], NF1 mutation [n=1], KRAS mutation [n=1] and MAP2K1 mutation [n=1]) and 2 patients had no results from molecular testing. Patients were treatment-naïve (n=9) or received 1 (n=3) or 2 (n=4) prior systemic therapies. To date, 5 (31%) patients had either partial (n=4) or complete response (n=1); 8 (50%) patients had stable disease (n=4) or non-CR/non-PD (n=4) in the absence of measurable disease and 3 (19%) did not have response assessed. At the median follow up of 10.1 months the median progression-free survival has not been reached as only two patients progressed on therapy while 14 remain progression-free for 1.1+ to 36+ months. The therapy was overall well tolerated with grade 1 rash being the most frequent AE. AE &gt; grade 2 included mucositis (n=2), rash (n=2), dizziness (n=1), uveitis (n=1) and decrease in ejection fraction (n=1) and two patients discontinued therapy because of AEs. Conclusions: MEK inhibitor trametinib demonstrated encouraging activity in patients with non-LCH irrespective of underlying molecular profile. Further studies of trametinib in patients with non-LCH are warranted. Disclosures Janku: Ideaya: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees; Primmune Therapeutics: Consultancy; PureTech Health: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Deciphera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Piqur: Research Funding; Bristol-Myers Squibb: Research Funding; IFM Therapeutics: Membership on an entity's Board of Directors or advisory committees; Synlogic: Membership on an entity's Board of Directors or advisory committees; Sotio: Consultancy; Astex: Research Funding; FujiFilm Corporation and Upsher-Smith Laboratories: Research Funding; Astellas: Research Funding; BioMed Valley Discoveries: Research Funding; Plexxikon: Research Funding; Symphogen: Research Funding; Bayer: Research Funding; Agios: Research Funding; Proximagen: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tovagene: Consultancy, Other: Ownership interests; Immunomet: Consultancy. OffLabel Disclosure: We will discuss trametinib (FDA approved for melanoma) to be used in non-LCH

Hyperprogressive disease in patients with metastatic genitourinary tumors treated with immune checkpoint inhibitors.

448 Background: Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients (pts) treated with immune checkpoint inhibitors (ICI). The rate and outcome of HDP in pts with metastatic renal carcinoma (RCC) and urothelial carcinoma (UC) are unknown. Here, we report the percentage of HPD in a cohort of pts with GU malignancies treated at our center and explore associations with clinical variables. Methods: Medical records from pts treated in phase I-III clinical trials with ICI alone or in combination between July 2013 and June 2018 were retrospectively reviewed. We defined HPD according to the radiologic VHIO´s criteria (ASCO 2018). Associations between HPD and categorical or continuous variables were evaluated using Fisher exact test and Wilcoxon test respectively. OS were estimated with the Kaplan-Meir method. Statistical analyses were performed using the R statistical software (R version 3.5.0). Results: Overall, 104 pts received therapy with ICI. Of these patients, 16 were not included for the analysis (6 pts with absence of measurable disease, 6 pts did not have CT scan available after the clinical progression and 4 pts treated with ICI plus chemotherapy). Thus, 88 pts were included for the analysis, 29 (33%) with RCC and 59 (67%) with UC. Median follow-up was 7.4 months. Median age was 66.5 years (range 29-91 y).Twenty-three pts (26%) were treated with ICI monotherapy and 65 pts (74%) in combination (anti-CTL4, antiangiogenics, PARP inhibitors, FGFR inhibitors). Forty-seven pts (53%) received ICI as second-line therapy or later. By RECIST v1.1, 26 (30%), 19 (21%) and 43(49%) pts had a best response of progressive disease, stable disease or partial+complete response, respectively. We identified 9 pts (10%) who meet the HPD criteria, 2 pts with RCC and 7 with UC. HPD was associated with anemia at baseline (p = 0.058). Pts with HPD had a trend toward lower overall survival (OS) compared with pts with non-HPD (8.87 vs 4.77 months; p = 0.065). Conclusions: These findings demonstrate that HPD is a phenomenon seen in a significant proportion of pts with RCC and UC and should be taken in account. We found that HPD is associated with poor OS and the anemia at baseline was correlated with HPD.

Population Based Observational Study Demonstrates Significant Increase in Watch-and-Wait for Newly Diagnosed Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is associated with a poor prognosis relative to other indolent B-cell lymphomas where clinicians have traditionally been reluctant to adopt watch-and-wait (W+W) strategies. US registry data from 2004 to 2011 demonstrated 6% of new diagnoses were observed beyond 3 months from diagnosis (Cancer 2016; 122: 2356-63), although other studies have demonstrated higher rates of W+W with no detriment to patient survival.Currently no consensus exists on how to determine suitability for W+W. The MCL Biobank Observational Study was set up to capture clinical behaviour across the United Kingdom and to characterise patients enrolled to W+W compared to those who receive upfront systemic therapy. The study remains open to recruitment.Method: From January 2015 to April 2017 222 patients from 49 centres in the United Kingdom enrolled to the study. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible, with no specific exclusion criteria. Baseline data was recorded at entry including investigator decision to start systemic therapy or enter W+W. Clinical updates were provided at 6 month intervals.In contrast to previous studies W+W was defined as a period lasting at least 1 year from date of diagnosis.Results: All patients were followed-up for a minimum of 1 year. The median age was 70 (range 32-90), 69.4% were male and 47.1% were MIPI high risk.At 1 year follow-up 60 patients (27.0%) were on W+W, 141 (63.5%) received systemic therapy, 16 (7.2%) received isolated radiotherapy and 5 (2.3%) received palliative care. At 2 year follow-up 16 of 85 patients (18.9%) remained on W+W. There were no deaths recorded in patients on W+W. Estimated 2-year survival of the whole population was 80.6%.Univariate analysis comparing baseline characteristics of patients on W+W with those receiving systemic therapy showed no significant difference in age (median age 71.7 vs 69.0; p=0.48), baseline WCC (median 8.0 x 109/L vs 8.9 x 109/L; p=0.09) or performance status (ECOG >1 OR 0.7; p=0.51) meaning the MIPI was not predictive of suitability for W+W (MIPI high risk OR 1.18; p=0.61). Positive predictors for W+W included measures of low disease proliferation: LDH ratio <1.0 (p=<0.001), Beta-2-microglobulin < 3.5 mcg/ml (p=0.011) and Ki67 <30% (p=0.001). In addition, female sex (p=0.010) predicted for indolent behaviour. Measures of high disease burden were generally negative predictors including presence of B symptoms (p=0.001), haemoglobin <100 g/L (p=0.014) and stage IV disease (p=<0.001). The absence of measurable disease on CT was predictive of W+W (p=0.009), although measurable disease was identified in the majority of cases (70.2%) illustrating most patients on W+W were not the leukaemic, non-nodal subtype.Conclusion: This study demonstrates that adoption of W+W in the United Kingdom significantly exceeds use in previous observational studies and highlights a fundamental shift in clinical approach. The results show that conservative management can be reasonably adopted in a significant proportion of patients. Patients with low disease burden appear best candidates and markers of cell turnover may aid clinical judgement. The MIPI does not have a role in this setting. Longer follow-up will establish if W+W confers survival benefit. DisclosuresPettitt:Celgene: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Gilead: Research Funding; Napp: Research Funding; GSK/Novartis: Research Funding; Chugai: Research Funding. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees.

Abstract OT2-01-06: Phase III study of palbociclib (PD-0332991) in combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to aromatase inhibitors. “The PEARL study” (GEICAM/2013-02)

Abstract Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer patients. However, endocrine resistance is a major clinical challenge.Treatment options at recurrence/progression to AIs include sequential endocrine-based therapiesin monotherapy or in combination with a targeted agent or chemotherapy. Preclinical data suggest that ER+/HER2- BC is dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in overcome endocrine resistance. Palbociclib (P) is an oral novel CDK4/6 inhibitor that is synergistic with ET in preclinical and clinical studies. Initially this study was designed to demonstrate the clinical benefit of P plus exemestane (E) vs capecitabine (C) (cohort1). Recent studies revealed that the acquisition of ESR1 mutations is a major mechanism of resistance to the treatment of AIs in the metastatic setting. Retrospective analyses show that patients with ESR1 mutation derived no benefit from sequential AI monotherapy. In contrast, preclinical and clinical data indicated that SERD, fulvestrant (F), is active in ESR1 mutant tumors. Hence the choice of endocrine partner with P is particularly important to create optimal synergy in endocrine resistance setting. The current design added cohort 2 of P plus F vs C. The overall study goal is to prospectively answer the question of optimal endocrine partner with P and its efficacy/safety over chemotherapy in endocrine resistant setting. Trial Design:This is an international (5 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to ET (cohort 1: E 25 mg daily, cohort 2: F 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus P (125 mg daily x3 weeks every 4 weeks) vs. C (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2- MBC are eligible if resistant to previous AI (letrozole or anastrozole in cohort 1 or any AI in cohort 2) defined as:recurrence while on or within 12 months after the end of adjuvant treatment orprogression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease. The primary objectives are to demonstrate that P plus F is superior to C and that P plus ET is superior to C inwomen whose tumor had estrogen receptor ESR1 wild type in terms of Progression-Free Survival (PFS); secondary objectives are PFS regardless the ESR1 mutational status, overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarkers. The study will recruit approximately 302 patients in cohort 1 and 300 patients in cohort 2. The study started recruitment in March 2014; 290 patients have been included so far (289 cohort1 + 1 cohort 2). Analysis of primary endpoint is planned in Sep2019 (ClinTrials.gov reference NCT02028507. Citation Format: Martín M, Kahan Z, Carrasco E, Bartlett CH, Casas M, Gil-Gil M, Muñoz M, Ciruelos EM, Ruiz-Borrego M, Margelí M, Antón A, Bermejo B, Morales S, Gal-Yam E, Koehler M, García-Sáenz JA, de la Haba J, Chacón I, Zielinski C. Phase III study of palbociclib (PD-0332991) in combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to aromatase inhibitors. “The PEARL study” (GEICAM/2013-02) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-06.

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial

mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2) on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. Novartis Pharmaceuticals.

Abstract OT1-1-05: Phase III study of palbociclib in combination with exemestane vs. capecitabine, in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to non-steroidal aromatase inhibitors (NSAI): PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006)

Abstract Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer (BC) patients. AIs have become the treatment of choice in postmenopausal patients. The high response rates with ET in these patients are partially undermined by the resistance developed by most of them over time. On early disease recurrence/progression to AIs, the treatment options include other AI, estrogen-receptor antagonists or chemotherapy (being capecitabine one of the best options). Preclinical data suggest that ER+/HER2- BC are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in delaying/reverting endocrine resistance. Palbociclib is an oral novel CDK4/6 inhibitor that seems to be synergistic with ET in preclinical and clinical studies. Trial Design: This is an international (6 countries) randomized phase III study. Patients are randomized 1:1 to exemestane (25 mg daily) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2- MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) defined as: recurrence while on or within 12 months after the end of adjuvant treatment or progression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or lytic bone lesions in the absence of measurable disease. The primary objective is Progression-Free Survival (PFS); secondary objectives are overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarker’s defined changes. The study will recruit 348 patients to detect a difference of 2.75 months in the median PFS (from 6 to 8.75 months; hazard ratio= 0.686), with a power of 80% and a 5% two sided significance level. The study started recruitment in March 2014 and 14 patients have been included so far (ClinTrials.gov reference NCT02028507). Citation Format: Miguel Martín, Semir Beslija, Eva Carrasco, Zsuzanna Kahan, Ma José Escudero, Istvan Lang, Begoña Bermejo, Moshe Inbar, José Ignacio Chacón, Dan Jinga, José Ángel García-Saenz, Juan de la Haba, Serafín Morales, Miguel Gil, Laura Murillo, Antonio Antón, Manuel Ruiz-Borrego, Christoph Zielinski, Günther Steger, Bella Nisenbaum. Phase III study of palbociclib in combination with exemestane vs. capecitabine, in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to non-steroidal aromatase inhibitors (NSAI): PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-05.

409TiP - Phase III Study of Palbociclib in Combination with Exemestane Vs. Capecitabine, in Hormonal Receptor (Hr) Positive/Her2 Negative Metastatic Breast Cancer (Mbc) Patients with Resistance to Non-Steroidal Aromatase Inhibitors (Nsai): Pearl Study (Geicam/2013-02_Cecog/Bc.1.3.006)

ABSTRACT Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer (BC) patients. AIs have become the treatment of choice in postmenopausal patients. The high response rates with ET in these patients are partially undermined by the resistance developed by most of them over time. On early disease recurrence/progression to AIs, the treatment options include other AI, estrogen-receptor antagonists or chemotherapy (being capecitabine one of the best options). Preclinical data suggest that ER + /HER2- BC are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in delaying/reverting endocrine resistance. Palbociclib is an oral novel CDK4/6 inhibitor that seems to be synergistic with ET in preclinical and clinical studies. Trial design: This is an international (6 countries) randomized phase III study. Patients are randomized 1:1 to exemestane (25 mg daily) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR + /HER2 MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) defined as: recurrence while on or within 12 months after the end of adjuvant treatment or progression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or lytic bone lesions in the absence of measurable disease. The primary objective is Progression-Free Survival (PFS); secondary objectives are overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarker's defined changes. The study will recruit 348 patients to detect a difference of 2.75 months in the median PFS (from 6 to 8.75 months; hazard ratio= 0.686), with a power of 80% and a 5% two sided significance level. The study started recruitment in March 2014 and 10 patients have been included so far (ClinTrials.gov reference NCT02028507). Disclosure: C.H. Bartlett: Employee of Pfizer and hold Pfizer stock; M. Koehler: Employee of Pfizer and hold Pfizer stock; C. Zielinski: Honoraria and Advisory Boards from Roche. All other authors have declared no conflicts of interest.

Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial

Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Amgen.

Abstract OT2-6-04: Dovitinib, a receptor tyrosine kinase inhibitor in combination with fulvestrant in postmenopausal endocrine resistant human epidermal growth factor receptor 2 negative (HER2-) / hormone receptor-positive (HR+) breast cancer: A phase II, randomized, double blind, placebo-controlled study

Abstract Background: Overcoming endocrine resistance is a critical goal in the treatment of HR+ breast cancer. Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with endocrine resistance. Up to 8% of patients with HER2–/HR+ breast cancer have amplification of the FGFR1 gene. Dovitinib, a potent inhibitor of FGFR, as well as vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification. The objective of this study is to determine if dovitinib in combination with fulvestrant can improve outcomes in postmenopausal patients with endocrine resistant HER2-/HR+ breast cancer. Trial design: This multicenter, randomized, double-blind, placebo-controlled, phase II trial (NCT01528345) will enroll postmenopausal patients with HER2–/HR+ locally advanced or metastatic breast cancer. Patients are randomized 1:1 (stratified by FGF amplification [FGFR1, FGFR2, or FGF3] and presence of visceral disease) to receive intramuscular fulvestrant (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Eligibility criteria: Postmenopausal women with HER2-/HR+ breast cancer (N = 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting are eligible. Other key inclusion criteria are: ECOG performance status ≤1; and adequate bone marrow and organ function; measurable disease as per RECIST 1.1 or ≥ 1 nonmeasurable lytic or mixed bone lesions in the absence of measurable disease. Patients with current or past evidence of CNS or leptomeningeal metastases, HER2 overexpression, and those who received previous treatment with fulvestrant or FGFR inhibitors are excluded. Specific aims: The primary endpoint is progression free survival (central review). Secondary endpoints include overall response rate, duration of response, overall survival, time to deterioration of ECOG performance status, patient-reported outcome scores, safety, and assessment of plasma pharmacokinetic concentrations of fulvestrant and dovitinib. Additionally, the pharmacodynamics of dovitinib on FGFR-associated angiogenic pathways and potential predictive biomarkers of response will be explored. Statistical methods: Analysis of primary endpoint will be carried out in FGF amplified subpopulation, FGF non-amplified subpopulation and the full population, using Bayesian methodology. Target accrual: Enrollment is ongoing. Target accrual is 150 patients (90 FGF amplified patients and 60 FGF non-amplified patients). Contact: For further information about the study please contact Gogov Sven (sven.gogov@novartis.com)/ Stephanie Deudon (stephanie.deudon@novartis.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-04.

Abstract OT2-6-09: 4EVER - A phase IIIb, multi-center, open label study for postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer (BC) treated with everolimus (EVE) in combination with exemestane (EXE)

Abstract BACKGROUND The double blind, placebo-controlled BOLERO-2 trial demonstrated a significant doubling of progression free survival (PFS) with EVE and EXE compared to EXE alone for postmenopausal women with hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC after recurrence/progression on non-steroidal aromatase inhibitors (NSAI) (Baselga J, et al. NEJM. 2012). The 4EVER study further evaluates the combination of EVE+EXE in a broader population to obtain greater insights and presents an extensive exploratory translational research program. SPECIFIC AIMS/TRIAL DESIGN 4EVER is a German multi-center, open-label, single-arm trial. 300 patients will receive EVE (10 mg/d)+EXE (25 mg/d) within clinical practice. The primary objective is to assess the overall response rate (ORR), the secondary objectives include PFS, overall survival, safety, quality of life (QoL), health utilities and health care resources. The exploratory biomarker objectives include pharmacogenetics, bone-turnover biomarkers, presence and molecular characteristics of circulating tumor cells, correlation of response to EVE+EXE with proteomics, and the influence of age, performance status, cancer activity and inflammation on anxiety and depression. Exploratory biomarkers are assessed at baseline and after 4, 12, and 24 weeks of treatment. ELIGIBILITY CRITERIA: Main inclusion criteria are postmenopausal women with metastatic or locally advanced ER+, HER2- BC, not amenable to curative treatment by surgery or radiotherapy, refractory to NSAI and with at least one lesion that can be accurately measured or bone lesions lytic or mixed (lytic+sclerotic) in the absence of measurable disease. STATISTICAL METHODS/TARGET ACCRUAL: The study is designed as an open-label, single-arm, phase IIIB trial to assess the efficacy and safety of EVE plus EXE in postmenopausal women with hormone receptor positive breast cancer progressing following prior therapy with NSAI. The primary objective is to estimate the ORR. Therefore, no statistical hypothesis or model is underlying the analysis. The ORR, i.e. best overall response of complete response (CR) or partial response (PR), as well as individual response categories CR, PR, stable disease (SD), progressive disease (PD) or unknown will be summarized using frequency tables together with their associated two-sided exact 95% confidence intervals (Clopper-Pearson method). The full analysis set will be used for the primary efficacy analysis. The primary efficacy and safety analysis will be conducted on all patient data at the time all patients who are still receiving study drug will have completed at least 24 weeks of treatment (or discontinued prematurely). The study plans to randomize 300 patients over a 1-year accrual period. The expected trial duration from activation to reporting of ORR is about 2 years. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-09.

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Liver, Bladder, Cervical, and Gastric Cancers

Updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. Published reports relevant to use of tumor markers for 4 cancer sites--liver, bladder, cervical, and gastric--were critically reviewed. Alpha-fetoprotein (AFP) may be used in conjunction with abdominal ultrasound for early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis or cirrhosis associated with hepatitis B or C virus infection. AFP concentrations >200 microg/L in cirrhotic patients with typical hypervascular lesions >2 cm in size are consistent with HCC. After a diagnosis of HCC, posttreatment monitoring with AFP is recommended as an adjunct to imaging, especially in the absence of measurable disease. Although several urine markers have been proposed for bladder cancer, none at present can replace routine cystoscopy and cytology in the management of patients with this malignancy. Some may, however, be used as complementary adjuncts to direct more effective use of clinical procedures. Although carcinoembryonic antigen and CA 19-9 have been proposed for use gastric cancer and squamous cell carcinoma antigen for use in cervical cancer, none of these markers can currently be recommended for routine clinical use. Implementation of these recommendations should encourage optimal use of tumor markers for patients with liver, bladder, cervical, or gastric cancers.

Treatment of Chinese patients with advanced gastric cancer with FOLFIRI followed by FOLFOX7 or the reverse sequence.

TPS207 Background: A well-recognized standard first-line or salvage chemotherapy regimen for advanced or metastatic gastric cancer has not been established until now. Two regimen sequences—folinic acid, 5-fluorouracil (FU), and irinotecan (mFOLFIRI) followed by folinic acid, FU, and oxaliplatin (mFOLFOX7; arm A), and mFOLFOX7 followed by mFOLFIRI (arm B)—were evaluated for their antitumor activity and toxicity in Chinese patients (pts) with locally advanced or metastatic gastric cancer. Methods: Previously untreated pts between age 18 and 75 with an ECOG performance status of 0-2 and life expectancy > 4 months were eligible if they had histologically proven gastric or gastroesophageal junction adenocarcinoma with at least one site of unidimensionally measurable disease (RECIST), adequate bone marrow function (hemoglobin ≥90 g/L, absolute neutrophil count of ≥2.0×109 cells/L, and platelet count of ≥100×109 cells/L), hepatic function (alkaline phosphatases ≤3 upper limits of normal [UNL], total bilirubin ≤1.5 UNL, AST and ALT ≤3UNL) and renal function (creatinine ≤135umol/L). Previous adjuvant chemotherapy, if given, must have been completed at least 6 months before inclusion. Pts were randomized (1:1) according to the following sequences: a 2-hour infusion of folinic acid 200 mg/m2 followed by 46-hour infusion of FU 2,400 mg/m2 every 2 weeks, either with irinotecan 150 mg/m2 or with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. Toxicity evaluations were based on the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0. Radiological evaluations were conducted at base line and after every two courses. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). Primary endpoint was progression-free survival. Secondary endpoints were overall survival, response rate, and safety. Randomization was performed using a minimization technique, stratifying patients by center and by presence or absence of measurable disease. The planned sample size is 100 in each arm, considering two-sided log-rank test to have 80% power to detect a 20% difference in the proportion of patients without progression at 8 months. No significant financial relationships to disclose.

Differences in lung cancer clinical trial accrual between a public and university medical oncology clinic.

9082 Background: Historically, fewer than 5% of adult cancer patients enter clinical trials. Several studies have suggested socioeconomic disparities in research participation. To evaluate these factors, we prospectively studied patterns of lung cancer clinical trial enrollment by patients treated at both a public clinical facility and an academic cancer center. Methods: From April 2008 through November 2009, we prospectively collected demographic, disease, and clinical trial participation data for lung cancer patients who were either newly referred or established with progressive disease at oncology clinics at Parkland Health and Hospital System, the primary public medical facility in Dallas County, and the Simmons Cancer Center, both of which are associated with the University of Texas Southwestern Medical Center. Univariate analysis and multivariate logistic regression were performed. Results: A total of 229 patients met criteria for analysis. Of these, 52% were female and 67% were seen in the private clinic. Thirty-eight patients (17%) enrolled in a clinical trial. Trial participation was significantly associated with clinical setting (25% for academic versus 10% for public; p=0.04), but was not significantly associated with gender (26% for men versus 15% for women; p=0.11) or disease stage (23% for stages III-IV versus 11% for stages I-II; p=0.18). Reasons for non-participation included inadequate performance status (11% vs. 28% academic vs. public), presence of brain metastases (9% vs. 12%), lack of study availability (8% vs. 17%), receiving treatment elsewhere (13% vs. 0%), presence of comorbidities (16% vs. 6%), patient preference (14% vs. 6%), absence of measurable disease (4% vs. 3%), and clinician preference (16% vs. 10%). Of these, inadequate performance status (P=0.009), lack of study availability (p=0.05), and patient receiving treatment elsewhere (p<0.001) were significantly associated with clinical setting. Conclusions: In this patient cohort, participation rates in lung cancer clinical trials were significantly higher at an academic cancer center than at a public hospital. Study availability for patient with poor performance status may in part account for this association. No significant financial relationships to disclose.

Identification of the causes that influence recruitment in oncology clinical trials (OCT)

e17562 Background: Prediction of patient recruitment in OCT is one of the most important variables to guarantee timely closure of the trial. Earlier data analysis and conclusions define further research or discontinuation of the development of a given drug. Methods: Retrospective analysis of the recruitment and clinical records of all the patients of the COR that were contacted to participate in an OCT from 2006 to 2008 to identify the causes according to which patients did not participate. Results: Total of candidates 346, 175 women (50.6%). Average age 60 years (range 36 to 89). 42 patients (12%) rejected to participate in an OCT. 80 patients (23%) were screening failures (SF). 59 patients (17%) for not fulfilling an inclusion criteria (IC). Non appropriate stage or absence of measurable disease at screening (35%), abnormal labs (14%) and state of receptors or biomarkers (9%). Total of clinically unpredictable IC SF was 57.5%. 21 patients (6%) were SF due to an exclusion criteria (EC). Presence of distant metastases (12,5%), abnormal labs (2.5%) and abnormal EKG (2.5%). Total of clinically unpredictable EC SF was 19%. Conclusions: 35% of candidate patients did not participate. The most frequent cause was SF (23%). 76.5% of these SF were impossible to determine when informed consent was signed. 12% of patients rejected to participate for different reasons. Our results did not identify a predominant modifiable reason to improve recruitment. For future feasibility analyses our estimation of 35% dropout will be considered standard. [Table: see text] No significant financial relationships to disclose.

Results of a phase II evaluation of nanoparticle albumin bound paclitaxel (nab-paclitaxel) in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer

5525 Background: Patients (pts) with recurrent ovarian, peritoneal, or fallopian tube cancer generally have a poor outcome with current therapies. There are no reports of albumin-bound paclitaxel (nab-paclitaxel) in pts with platinum sensitive recurrent disease. We are reporting our preliminary efficacy and toxicity results with nab-paclitaxel in this group. Methods: 47 pts were enrolled (44 available for analysis). Main inclusion criteria: histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2–3 if stage I) and measurable disease by RECIST or elevated CA-125 (&gt;70 units/mL) in the absence of measurable disease; nonepithelial disease was excluded. Pts received 260 mg/m2 of nab-paclitaxel IV over 30 minutes Day 1 of each 21-day cycle. Pts continued until progressive disease (PD) up to a maximum of 6 cycles. Results: Median age was 65.5 years (range, 42- 84), Stage IIIC (53%) or IV (23%); ECOG PS=0 (87%), and prior surgery (94%). For evaluable pts the overall response rate (ORR) was 50% (13 CR and 9 PR in 44 pts). In pts followed by RECIST only, the ORR was 27% (1 CR and 2 PR in 11 pts). In pts with only CA-125, it was 64% (5 CR and 2 PR in 11 pts). In pts meeting both RECIST and CA-125 criteria, the ORR was 54.5 % (7 CR and 5 PR in 22 pts. Median time to response was 1.8 months (range, 1 to 2.1). The most frequent Grade 3–4 treatment-related toxicities were: neutropenia (8.7%) and fatigue, diarrhea, and dyspepsia (2.2%, each); alopecia (Grades 1–2) occurred in 84.8%. All other adverse events were Grade 1–2. To date, 46 pts are surviving; one death was related to progressive disease. Conclusions: Nab-paclitaxel was very active in this group of pts with recurrent ovarian, peritoneal, or fallopian tube cancer. The ORR was 50%. Toxicities were minimal and manageable. Response and survival analysis and review of the methods of disease assessment are ongoing. Further studies of nab-paclitaxel are warranted. This research was supported, in part, from a research grant from Abraxis BioScience, Inc., Santa Monica, CA. [Table: see text]

Phase II study of nab-paclitaxel plus carboplatin in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancer

15033 Background: This open-label, non-randomized study was designed to determine the efficacy and safety of nab-paclitaxel (a 130-nm albumin-bound particle form of paclitaxel) plus carboplatin in patients with metastatic ovarian or primary peritoneal carcinoma following platinum-based chemotherapy. Methods: Eligible patients had to have either measurable disease (based on RECIST criteria) or pretreatment CA-125 levels ≥2 times the upper limit of normal in the absence of measurable disease. Patients also had to have good performance status, adequate hepatic/renal function, peripheral neuropathy ≤ grade 1, and life expectancy ≥6 months. Patients may have received prior chemotherapy for ovarian cancer, including taxane-containing regimens, provided the treatment was completed at least 6 months before enrollment. nab-Paclitaxel 100 mg/m2 was administered IV over 30 minutes on days 1, 8, and 15 every 28 days. Carboplatin AUC6 was administered IV over 1−2 hours on day 1 every 28 days. Treatment continued for 6 cycles (or longer in the absence of unacceptable toxicity). Planned sample size was 43 patients (39 evaluable). Efficacy was determined by changes in tumor size for patients with measurable disease or changes in CA-125 levels for those with non-measurable disease. Results: To date, 10 patients have been enrolled, 2 of whom completed 2 treatment cycles; both patients had a 50% reduction in their disease (partial response). One patient had grade 4 neutropenia; grade 3 hematologic events were neutropenia (2 patients), thrombocytopenia (3), and anemia (1). Severe headache and severe nausea were reported for 2 patients each; all 4 events required medication. Conclusions: Preliminary results suggest that nab-paclitaxel 100 mg/m2 plus carboplatin AUC6 will have antitumor activity in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancer and that treatment appears to be well tolerated. Updated response and toxicity data from this study will be presented. No significant financial relationships to disclose.