Kugler, J. W.

9531 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a prevalent dose limiting toxicity for several important cancer treatment agents. CIPN can impair function and cause distress. There are no proven pharmacologic treatments for established CIPN currently. This double blind randomized placebo controlled trial evaluated a compounded topical gel for this problem. The novelty of this treatment is that it might incorporate several agents with different mechanisms of action to provide relief locally without negative systemic effects. Methods: Patients with CIPN (rated ≥4 out of 10) for at least one month, related to previous and/or concurrent exposure to neurotoxic agents, were randomized to baclofen 10 mg, amitriptyline HCL 40 mg and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) vs placebo (PLO) to determine its effect on numbness, tingling, pain, and motor function. Exclusion criteria included other causes and/or current treatment for peripheral neuropathy. The primary endpoint was the baseline adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results: Between February and May 2008, 208 patients were enrolled onto this trial. Four week data are shown in the table below, higher numbers being better. The percentage of patients that had improvements of at least 10, on a 100 point scale, in the motor subscale was statistically significantly higher in the BAK-PLO arm, p=.04. There were no unwanted toxicities associated with the BAK-PLO that were significantly different from placebo and no evidence of CNS or systemic toxicity. Conclusions: Topical treatment with BAK-PLO appears to moderately improve symptoms of CIPN. This topical gel was well tolerated without systemic side effects. [Table: see text] No significant financial relationships to disclose.

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.

7544 Background: NCCTG N0028 was a trial that determined the MTD of RT that could be given with carboplatin & paclitaxel was 74 Gy/34 fractions. This secondary analysis was performed to determine the survival of pts treated on this trial. Methods: Eligible pts had medically or surgically unresectable NSCLC, PS=0–1, weight loss <10% in the prior 3 months(mo), no prior therapy, adequate laboratory & pulmonary functions. Included were 25 pts with clinical stages I (4pts), II (1 pt), IIIa (12 pts), & IIIb (8 pts). Treatment included: weekly I.V. paclitaxel (50mg/m2) & carboplatin (AUC=2) during RT. The RT included 2 Gy daily to an initial dose of 70 Gy. The total dose was increased in 4 Gy increments until the MTD was determined. RT was delivered with 3-D treatment planning but no elective nodal RT. Three pts received 70 Gy, 18 pts received 74 Gy, & 4 pts received 78Gy. Results: Pts were followed until death or from 10–67 mo (median: 28mo) in those alive at last evaluation. The median survival (MS) of the entire cohort was 42mo. The 5 stages I-II pts had a MS of 53 mo & the 20 stage III pts had MS of 42mo. Conclusions: Standard dose RT is unable to sterilize disease in the majority of pts with unresectable NSCLC. While the addition of chemotherapy has significantly improved survival of these pts, the MS is generally 15–24 mo. These preliminary results suggest higher than standard doses of RT may improve disease control & prolong survival. A phase III trial comparing standard-dose RT(60Gy) to high-dose RT (74Gy) is open and should more definitively address the issue of RT dose with concurrent chemotherapy for unresectable NSCLC. Future technological improvements in imaging & targeting will provide methods to safely administer even greater RT doses which will likely further improve disease control. No significant financial relationships to disclose.

4025 Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. We recently demonstrated the protective effect of CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO 2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative sNT. Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires were used to differentially assess the effect of CaMg on acute (effect on sNT on days 1–4 after oxaliplatin) and chronic sNT (area between curves over whole course of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6 FOLFOX4) were available for analysis. Apart from a strong reduction in muscle cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold liquids, throat discomfort) on days 1–4 after oxaliplatin of any treatment cycle. In contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers (p=0.06), and muscle cramps over the course of therapy (p=0.01). Conclusions: In our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic, cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires. No effect was noted on phenomena associated with acute sNT. CaMg can be recommended as neuroprotectant against oxaliplatin-related chronic sNT, oxaliplatin's dose-limiting toxicity. [Table: see text]

1020 Background: Trastuzumab-containing regimes have dramatically improved outcome of patients with HER2+ breast cancer. Efforts to improve efficacy and tolerability of combination regimens with this monoclonal antibody are important for patient care. Thus, we conducted a multi-institutional phase II study of a triplet combination in patients eligible to receive either first- or second-line treatment for HER2+ metastatic breast cancer (MBC). Methods: A phase II study designed to test that the true confirmed response rate (CRR) was at most 45% versus a true CRR of at least 65% was done (March 2005-June 2008). This design required that at least 25/45 confirmed responses in evaluable patients for the treatment to be considered promising. Patients received capecitabine 825 mg/m2 po (days 1–14), vinorelbine intravenously (IV) 25 mg/m2 days 1 and 8 every 3 weeks and trastuzumab IV 8mg/kg day 1, week 1, and then 6 mg/kg q 3 weeks. Tissue and blood have been collected for future studies on biomarkers. Results: 47 women were accrued, one patient cancelled participation prior to receiving any study drug, and another had a major protocol violation. 45 patients were evaluable and 30 (67%) achieved a confirmed response, (26 patients, 58% had a confirmed partial response and 4 patients, 9% had a confrimed complete response). Median progression free survival was 11.3 months (95% CI 8.4–23.2 months), median overall survival was 27.2 months (95% CI: 26.6-NA months), and among the 30 responders, the median duration of response time was 15.5 months (95% 7.7–26.1 months). The most common grade 3 events include neutropenia 61%, fatigue 13%, skin reaction-hand-foot 11%, and leukopenia 11%. Alopecia was not noted with this regimen. Conclusions: This triplet combination is effective, safe, and is promising in patients with HER2+ MBC. A phase III study should be conducted to compare the best doublet with this triplet combination whether this would lead to better clinical outcomes. [Table: see text]

8534 Purpose: Tumor necrosis factor (TNF) is a putative mediator of the cancer anorexia/weight loss syndrome. This study was designed to determine if etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton TNF receptor linked to the Fc portion of human IgG1) could palliate this syndrome. Methods: 63 evaluable patients were randomly assigned to etanercept 25 mg SQ twice/week versus a comparably-administered placebo, both of which were to be given for at least 12 weeks. All patients had an incurable malignancy, acknowledged loss of weight and/or appetite as a concern, and reported weight loss of > 5 pounds over 2 months and/or a daily intake of < 20 calories/kg body weight. The above sample size provided 81% power to detect a 24% difference in the percentage of patients who gained >/= 10% of baseline weight. Results: At baseline, groups were comparable on age, gender, tumor type, and degree of weight loss. Over time, weight gain was minimal in both groups; no patient gained >/= 10% baseline weight. Appetite questionnaires (the NCCTG Anorexia/Cachexia Questionnaire and FACT-AN) revealed negligible improvements in both groups. Median survival was comparable: 175 days versus 148 in etanercept-treated and placebo-exposed patients, respectively (p=0.82). Finally, preliminary data on adverse events showed that etanercept-treated patients had higher rates of neurotoxicity (29% versus 0%) but lower rates of anemia (0% versus 19%) and thrombocytopenia (0% versus 14%). Infection rates were negligible in both groups. Clinical correlative data on TNF genotyping will be available at the time of the meeting. Conclusion: This TNF inhibitor does not appear to palliate the cancer anorexia/weight loss syndrome. The study was supported by CA37404, the American Institute for Cancer Research, and Amgen. No significant financial relationships to disclose.

6006 Background: In March 1998, the Common Toxicity Criteria version 2.0 was implemented and introduced the collection and reporting of attribution of adverse events to study treatment. Collection and reporting of attribution adds time and cost to the clinical trial process, and its use while reporting adverse events (AE) in the literature has varied. We investigate whether attribution adds value to the interpretation of AE data. Methods: Patients on the placebo arm of trial 97–24–51 (CAI vs. Placebo) were chosen since the true relationship of the event to the study treatment is known (“unrelated”). Attribution was collected per CTCv2.0 and categorized as “not related” (not related or unlikely) and “related” (possible, probable, or definite). All reported AEs and the maximum severity for a given AE were evaluated. Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Changes in attribution over time for the same event were computed. Results: 84 patients on the placebo arm experienced a total of 1013 AEs. 47% of AEs were reported as “related” with 36% reported as possibly related. Known CAI AEs were more likely to be reported as “related” (p = 0.005). Pulmonary AEs were more likely to be reported as “not related” (p = 0.0006). No patterns were observed by gender, age, PS, severity or treatment cycle of AE. When the same event was reported on the same patient in multiple cycles, the attribution category changed at least once 36% of the time with 25% changing from “related” to “unrelated” or vice versa. Conclusion: Almost 50% of events on a placebo arm of a phase III trial were reported as being attributed to study treatment and 25% of the time the same event was not consistently attributed. These data suggest that attribution is difficult to determine, unreliable, and thus its value in large phase III trials is questionable. [Table: see text] No significant financial relationships to disclose.

526 Background: Antidepressants do not adequately alleviate all HFs. Based on placebo-controlled data demonstrating that GABA is an alternative therapy for HFs, this trial was initiated to test whether the combination of an antidepressant and GABA was better than GABA alone in PTS with inadequate HF control on an antidepressant alone. Methods: Eligible PTS on antidepressants with bothersome HFs were randomized to two groups. PTS kept a daily HF diary during a baseline wk (while continuing their antidepressant). Following the baseline wk, all PTS were given GABA 300 mg at hs for 3 days, then BID for 3 days, and then TID for 22 days. One group continued their antidepressant while the other group was weaned off it over several days. PTS continued a daily HF diary during this 4-wk period. Efficacy was measured using the mean daily HF number and score; the latter measured by assigning points (1–4, for mild to very severe) to each HF and then adding the points for a given time. The study design provided 80% power to detect a difference in the changes from baseline at 4 wks between the two groups of 1.2 HFs/day, or 3 points/day in HF scores. Results: 115 PTS were randomized and given GABA. PTS continuing their antidepressant reported a 48% mean reduction in HF score after 4 wks, vs 49% for PTS stopping it (p=0.97). Mean HF numbers were reduced 50% and 47%, respectively (p=0.54). 16 other symptoms and quality of life items were measured by PT-completed weekly questionnaires, with the only suggestive changes from baseline between the two arms being more mood troubles after 2 wks of treatment (p=0.06) and more nervousness after 4 wks of treatment (p=0.01) in PTS stopping their antidepressant. Also, a mild temporary increase in dizziness after 1 wk of treatment was observed in the same group (p=0.08) suggestive of an antidepressant withdrawal reaction. Conclusion: This trial failed to provide any evidence that the combination of GABA and an antidepressant decreased HFs any more than did GABA alone in PTS who had inadequate HF control with an antidepressant alone. The 50% reduction in HFs in both arms is commensurate with the efficacy of GABA delineated in other published reports. No significant financial relationships to disclose.

6517 Background: In NCCTG CTs a subset of AEs are assessed at each patient (pt) evaluation based on the known safety profile of agents(s). The NCCTG routinely pre-fills the “known” AE list onto CT Case Report Forms (CRFs). Newly identified AEs may expand the AE assessment list for ongoing CTs. Our survey of NCCTG AE data (JCO 2005), demonstrated that 85% of AEs reported were pre-filled on CRFs, of which, 83% did not actually occur (Grade 0). Extending this work, we evaluated the influence of pre-filling AEs on CRFs, relative to the final AE rates reported. Methods: Our non-random sample contains 507,899 AEs collected from 1/99–6/06 on 74 NCCTG CTs, 13 of which had AEs added to the CRF pre-fill list during the CT (2,604 pts, 3 Ph I/II, 8 Ph II, 2 Ph III, 9 investigational agents). Results: An average of 2.8 AEs (range 1–6) were added to CRFs for ongoing CTs, primarily for Oxaliplatin induced AEs. 58% (21/36) of AEs added during a CT were not reported prior to the addition, 22% (8) were not reported afterwards. 5 CTs had significantly higher AE rates (p<0.01) after expanding the AE list, most notably for required blood chemistries (SGOT/alk phos/creatinine/bilirubin 14.2 vs 0.72%). Overall, the same AEs were 4-fold (range 0–25) as likely to be reported when pre-filled on the CRF. Regardless of pre-filling, only 6% of the newly required AEs were Gr 3+. Conclusions: Our data suggest a significant difference between the AE rates reported if included in the CT CRF assessment list. This may significantly influence the reported results of a CT, explaining differential AE rates reported across CTs of the same agent(s). A prospective study is planned to formally evaluate this observation. Supported by NIH Grant CA25224. No significant financial relationships to disclose.