Citations

8032 Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.

6122 Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p<0.0001). All FACT-Leu domains except social/family were worse in pts with fatigue and those with higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and usual activities domain scores worsened in severity as ECOG worsened and for pts with fatigue (all p<0.011). BFI data indicated that global fatigue, fatigue severity and fatigue-related interference worsened by ECOG severity and were associated with clinician-reported fatigue (all p<0.0001). Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.

e16572 Background: The Bowel Function Questionnaire (BFQ) has been used in clinical trials to document patient-reported symptoms following pelvic radiation therapy (RT). This study evaluated the importance patients placed on the symptoms included in the BFQ as measured by a Content Validity Questionnaire (CVQ). Methods: Patients treated with pelvic RT assessed symptoms and importance at baseline, after completion of RT (4 weeks), and 12 and 24 months. BFQ measured quality of life (QOL) and symptoms of: nocturnal bowel movements, incontinence, greater than one bowel movement in 30 minutes, need for protective clothing, inability to differentiate stool and gas, liquid bowel movements, urgency, cramping, and bleeding. Bowel movement frequency was also assessed. Symptoms were rated via the CVQ as “not very important,” “moderately unimportant,” “neutral,” “moderately important,” or “very important." Summary statistics were compiled. Fisher Exact, Chi-Square and Wilcoxon methodology compared BFQ and CVQ results. Results: 125 patients participated. All symptoms were rated as moderately important or very important by most patients.Measures of bowel function of greatest importance (moderately or very important) at baseline were ability to control bowel movements (94%), not having to wear protective clothing (90%), and not having rectal bleeding (93%). In general, patients gave similar ratings of symptom importance at all time points in the study and ratings were independent of whether the symptom was experienced. With the exception of the need for protective clothing, the presence of a symptom at 4 weeks was associated with significantly worse QOL (p-values < 0.001 to 0.005). Conclusions: The BFQ has excellent content validity. Patients rated most symptoms measured by the BFQ as moderately important or very important, indicating the BFQ is an appropriate tool for symptom assessment during and after pelvic RT. With the exception of the need for protective clothing, the presence of every symptom measured by the BFQ was associated with worse QOL. These criteria make them appropriate targets for future research to mitigate radiation-related bowel dysfunction.

1610 Background: Low dose computed tomography (LDCT) scans have reduced lung cancer deaths by 20.3% in high risk populations, although there is an unknown balance between the benefits and harms of LDCT scans as a screening tool. Our purpose was to compare health-related QOL issues among lung cancer patients who were initially detected by LDCT scans; 4 comparison groups included: lung cancer diagnosed by a screening chest X-ray, as an incidental finding from procedures taken for other medical reasons, or based on symptoms indicative for lung cancer and routinely diagnosed, and individuals who were LDCT screened but found no lung cancer (controls who participated in Mayo’s lung cancer CT screening trial). Methods: A total of 1,658 lung cancer patients (cared at Mayo Clinic) in the 4 groups (37, 151, 389, and 1081 respectively) and 488 controls were compared on following patient-reported outcomes (collected via validated tools): overall QOL, four symptoms (cough, pain, dyspnea, fatigue), mental/ physical/ emotional/ social/ spiritual QOL, and other concerns (e.g., family/ friends/ financial/ legal). A clinically significant deficit was defined as at least 10-points in difference (or <50 points) on a 0-100 scale. The rates of deficits were compared via Fisher’s exact tests and average QOL values via Kruskal-Wallis tests. Results: Overall QOL and individual symptoms were significantly worse (p<0.05) in all lung cancer groups than in controls, except for pain. LDCT-screened patients reported the greatest deficit among the 4 lung cancer groups in physical (41%), emotional (24%), social (38%), and spiritual QOL (24%); whereas chest X-ray detected patients had the least deficit in overall QOL (22%) and pain (32%). All 4 lung cancer groups experienced much worse fatigue (52-64%) than the controls (32%). Conclusions: Our preliminary results suggest that LDCT-screening detected lung cancer patients reported a different QOL profile from other lung cancer patients and non-lung cancer controls. The clinical course, smoking behavior, and QOL related health issues associated with LDCT screening for lung cancer warrant thorough investigation.

17511 Background: There is no published data regarding BMI changes in survivors of adult lymphoma. Methods: In October of 2004, we mailed a 23-page survey to 95 randomly selected patients from a population of 2,485 of patients from the Mayo Tumor Registry who had survived lymphoma from 5 to 20 years. 56 completed the survey for a 68% participation rate. Body mass index (BMI) was calculated using clinical height and weight in the medical record at the time of diagnosis and self-reported weight in the survey response. Physical activity was self-reported. Based on their pattern of response, patients were categorized into a stage of change of current exercise (precontemplation, contemplation, preparation, action, or maintenance). Mood disturbance (depression, anxiety, and distress) and quality of life (QOL) were self-reported using the CES-D, POMS, STAI, FACT-G, and LASA questionnaires. Scores were transformed to a scale of 0–100 (higher score meaning higher functioning) to allow comparisons with a difference of 10 points considered significant. Results: The median age at completion of the questionnaire was 62 years (range: 25–85). The median time since diagnosis was 11 years (range: 6–20). Regular fitness, defined as a stage of change for exercise of action or maintenance, was reported by 48% of the respondents. The median BMI at diagnosis was 25.6 and the median at time of questionnaire was 27.0, which is a statistically significant change. Change in BMI, BMI at diagnosis, and BMI at time of questionnaire had no correlation with level of physical activity. Obese patients had a mean score of 72 points on the LASA, which was significantly lower than normal and underweight patients (mean 86) and overweight patients (mean 84). Conclusions: A small, but significant increase in body mass index was noted in long-term lymphoma survivors from the time of diagnosis to long-term follow-up. Patients who were obese at time of diagnosis may have lower quality of life down-the-road, as measured by the LASA years following treatment. This data represents the first information about body mass index in survivors of adult lymphoma. Further larger studies are needed to confirm these preliminary data and to evaluate other aspects of health behavior in long-term survivors of lymphoma. No significant financial relationships to disclose.

6116 Background: Analyses of patient-reported outcomes rely on the dependability of patients to complete and submit assessments in a timely manner – not all data is obtained. In recent work focusing on quality of life (QOL) data and imputation, it has been found that most methods do not alter study results. But how much data can be missing before study results are affected? Methods: Missing data was investigated using a 2-arm study (109 patients) who completed Linear Analogue Self Assessments at 4 intervals. Patients (11%) had missing data at the second interval. Existing data was analysed for differences in scores between arms, then cases were randomly deleted to create increasing percentages (12%-20%) of missing data. Ten simulations were conducted per percent. Imputation methods applied were carrying forward the last value (LVCF), average value (AVCF), and maximum value (MVCF). Student’s t-tests were performed between arms for each simulation. Results: Imputation did not alter results of our study data which was statistically significant (SS) between arms for overall QOL (p=0.036) and spiritual well-being (SWB) (p=0.006), and not statistically significant (NS) for mental well-being (MWB) (p=0.174). After data deletion and t-test calculations, AVCF did not impact results. For overall QOL, data deletion changed the p-value to NS in 1 of 10 simulations starting at 12% missing data and 5 of 10 simulations starting at 16% missing data. No matter what percentage of missing data, imputation produced a SS p-value over 80% of the time. Data deletion and subsequent imputation did not affect the study decision for SWB. For MWB, all differences between arms were NS prior to imputation. After imputation, there was at most a 7% disagreement in conclusions. LVCF and MVCF performed equally in all simulations. Conclusions: For this particular study, when p-values are close to the study-defined alpha, the increase in missing data can change the study results and imputation methods are more likely to determine SS differences. The further the p-values are from the study alpha, there is little effect from increasing missing data or applying imputation. These results are for one particular study and further research is needed. No significant financial relationships to disclose.

6075 Background: Failing to meet patient expectations for participating in treatment decisions impacts satisfaction with care, but it is unknown whether this translates into QOL deficits. As part of a larger survey of cancer survivors conducted by the American Cancer Society (ACS), data were gathered on the role patients in Minnesota preferred and the role actually experienced during the treatment decision-making process. Methods: Patients who were diagnosed with one of the ten most common cancers in 2000 completed a survey containing the Profile of Mood States (POMS), the SF-36, and the Control Preferences Scale (CPS). Fisher’s exact tests compared role preference distributions across demographic categories. Two-sample t-tests compared the POMS and SF-36 scores between patients whose preferred role preference was concordant with the role experienced and those with discordant preferred and actual roles. Results: 33% of the 599 consenting patients preferred an active role in treatment decision-making, 52% preferred a collaborative role, and 13% preferred a passive role. The actual roles experienced were 33% active, 50% collaborative, 17% passive. Over 88% of patients had concordant preferred and actual roles. Patients with concordant roles had higher SF-36 physical scores (45 vs 40, p=0.004), higher vitality (50 vs 42, p=0.005), less fatigue (70.2 vs 60.1, p=0.001), better concentration (84 vs 79, p=0.008) and better overall mood (77 vs 73, p=0.006). Role preference differed across gender (p=0.0002) in that more women preferred a collaborative role than men (57.8% vs 45.5%) and fewer women preferred a passive role (9% vs 17.3%). Patients under age 50 experienced more active roles in treatment decisions than those aged 50+ (p=0.04). Patients reporting an active actual role had higher SF-36 physical scores (p=0.005) and higher POMS vigor subscale scores (p=0.04). There were no differences in QOL scores for preferred roles. Conclusions: Patients who experienced discordance between their preferred role and their experience reported substantial QOL deficits in both physical and emotional domains. Oncologists can improve patient satisfaction with care and QOL by meeting patient expectations with respect to the amount of input they have in making treatment decisions. No significant financial relationships to disclose.

5028 Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 103 to 106 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 109 TCID50. No significant financial relationships to disclose.

LBA9006 Purpose: Many patients who receive EGFR inhibitors develop an acneiform rash, and anecdotal reports suggest tetracycline is effective in treating it. To our knowledge, however, no rigorous trials have ever been published to substantiate this approach. This double- blinded, placebo-controlled trial was conducted to assess the role of tetracycline in preventing EGFR inhibitor-induced rash and/or reducing its severity. Methods: 61 patients were randomly assigned to tetracycline 500 mg orally twice a day×4 weeks versus an identical, similarly prescribed placebo. Eligibility criteria required all patients to have begun an EGFR inhibitor </= 7 days prior with no rash at study entry. Patients were to be followed for 8 weeks. Physician assessments of rash incidence, severity, and adverse events, occurred at 4 and 8 weeks. Patients completed a weekly rash diary, quality of life questionnaire (SKINDEX-16), and EGFR inhibitor compliance questionnaire. Thirty patients per group provides 90% power to detect a difference in rash incidence (the primary endpoint) of 40% between groups and of rejecting the null hypothesis of equal proportions with a type I error of 5% (2-sided). Results: Treatment arms were balanced on baseline characteristics, drop out rates, and rates of discontinuation of the EGFR inhibitor. Rash incidence was comparable across arms. Physicians reported that 16 tetracycline-treated patients (70%) and 22 placebo-exposed patients (76%) developed a rash (p=0.61). However, tetracycline appears to have lessened rash severity. By week 4, physician-reported grade 2 rash occurred in 17% of tetracycline-treated patients (n=4) and 55% of placebo- exposed patients (n=16); (p=0.04). Tetracycline-treated patients reported better scores on certain quality of life parameters (SKINDEX-16), such as skin burning or stinging, skin irritation, and being bothered by a persistence/recurrence of a skin condition. Adverse events were comparable across arms. Conclusion: Tetracycline did not prevent EGFR inhibitor-induced rashes. However, diminished rash severity and improved quality of life suggest this antibiotic merits further study. No significant financial relationships to disclose.

9116 Background: Hot flashes affect 75 % to 90 % of women transitioning to menopause and are a major cause of morbidity among breast cancer survivors. Levetiracetam, a popular anticonvulsant, is a centrally active agent that anecdotally appeared to reduce hot flashes in clinical practice. This phase II trial sought to evaluate the efficacy of levetiracetam in reducing hot flashes among women with a history of breast cancer or women who did not wish to take estrogen therapy for fear of an increased risk of breast cancer. Methods: Women who were experiencing bothersome hot flashes (≥ 14 times per week, for ≥ 1 month) were eligible. A single arm pilot study design based on previous work was used with a planned sample size of 30 patients. The patients did not receive any study medication during the first week (baseline week). At the beginning of the second week, patients were started on levetiracetam (500 mg), and were to increase the dose by 500 mg each week to a goal of 1,000 mg twice daily. Hot flash diaries were completed daily. The primary endpoint was hot flash score (frequency times average severity). The change from week 1 (baseline) to week 5, the last treatment week, was analyzed by paired t-test and related Wilcoxon procedures. Results: A total of 30 women were enrolled onto this study in eight months. All patients were eligible. 19 women completed all 4 weeks of the study treatment and provided complete data. After treatment with levetiracetam for 4 weeks, mean hot flash scores were reduced by 57% (95% CI 39%-75%), while mean hot flash frequencies were reduced by 53% (95% CI 38%-68%), reductions being greater than what would be expected with a placebo. There were significant improvements, compared to baseline week data, in sweating, hot flash distress, and satisfaction with hot flash control. Eight subjects stopped the study drug due to treatment related adverse events (grade I/II), with the most frequently reported being somnolence, fatigue and dizziness. Conclusions: While levetiracetam appears to be a promising therapy for the treatment of hot flashes, further study is needed to better substantiate the toxicity and efficacy of this drug before it can be more definitively recommended for use in clinical practice. No significant financial relationships to disclose.