Rowland, K. M.

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.

9513 Background: Hot flashes are a major problem in many women for which better treatment options are needed. Given the known efficacy of gabapentin for decreasing hot flashes, it was decided to evaluate pregabalin, with hopes that it would work better and/or with fewer toxicities. Methods: A three-arm, double-blinded, placebo-controlled randomized trial was developed. Women with bothersome hot flashes (at least 28/week) were randomized to receive either a placebo or target pregabalin oral doses of 75 mg bid or 150 mg bid (starting at 50 mg/d and then increasing the dose at weekly intervals to 50 mg bid, then 75 mg bid, and then, in the higher dose arm, 150 mg bid); patients were treated for 6 weeks. Hot flash numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flash diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intra-patient difference in hot flash score between baseline and week six, comparing the higher dose pregabalin arm and the placebo arm. With the planned sample size of 55 patients per arm, there was an 80% power and two-sided 5% Type I error rate to detect a difference of 0.54 standard deviations, or 1.08 hot flashes per day, or 2.7 units of hot flash score per day. Results: 207 patients were randomized between 6/20/2008 and 8/21/2008. The study arms were well balanced. Mean/median daily hot flash scores and frequencies for all pts at baseline were 15.7/13.4 and 8.3/7.7, respectively. The table shows the decreases in hot flashes from the baseline to the sixth treatment week. Larger numbers illustrate greater hot flash reductions. Toxicity information, quality of life information, and information regarding the effects of hot flashes on subjective symptoms will be available at the meeting time. Conclusions: Pregabalin reduces hot flashes in women. There appears to be similar effects with both studied doses. [Table: see text] No significant financial relationships to disclose.

8556 Background: In the original PARMA trial it was demonstrated that salvage chemotherapy with DHAP followed by autologous bone marrow transplant resulted in increased overall survival over salvage chemotherapy with DHAP alone in patients with aggressive lymphomas. The current study was designed to assess safety and feasibility of ROAD as a salvage chemotherapy regimen which could be administered as an inpatient or outpatient. Methods: Patients received immunochemotherapy on the following schedule: rituximab 375 mg/m2 weekly × 4, oxaliplatin 130 mg/m2 on day 2, Ara C 2000mg/m2 x 2 doses on day 2 and dexamethasone 40 mg on days 2–5, with OAD repeated at 3 week intervals (up to 6 cycles). Patients were considered for autologous stem cell transplantation after 2 cycles if eligible. Eligible histologies included diffuse large B cell lymphoma, mantle cell lymphoma and transformed lymphoma in first relapse. Results: 50 patients were accrued from Aug 2006 through Jul 2008: 5 patients were deemed ineligible after central pathology review. Baseline characteristics of eligible patients included median age 69 (range 23 - 77), 53% were male, 53% had advanced stage at relapse, LDH was elevated in 58% and all patients had an ECOG PS of 2 or less. Patients received a median of 2 cycles of therapy (range 1–6) with 39/45 receiving treatment in cycle 2, with 12 patients continuing beyond 2 cycles. 31 patients experienced grade III/IV hematologic toxicity and 22 patients had grade III/IV non-hematologic toxicity, primarily febrile neutropenia. One patient developed grade III nephrotoxicity due to disease progression. Twenty patients received their treatments exclusively as outpatients. 26 responses were seen in the 45 eligible patients (58%, 95% CI: 44–74%), with 20 responding patients proceeding to autologous SCT. Conclusions: ROAD is a safe and effective salvage chemotherapy regimen for relapsed aggressive lymphoma, including as a preparatory regimen prior to stem cell transplant. It appears to have similar response rates to R-DHAP in a similar patient population, but without the potential nephrotoxicity (data from prior published study from NCCTG). ROAD can be safely administered as an inpatient or outpatient. No significant financial relationships to disclose.

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.

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.

9005 Background: Hot flashes can be a major problem in men with prostate cancer; effective non-hormonal options are needed. Methods: A four-arm, double-blinded, placebo-controlled randomized trial was developed to evaluate gabapentin for hot flashes. Men with bothersome hot flashes (at least 14/week) related to androgen deprivation therapy were randomized to receive either a placebo or gabapentin doses of 300 mg qd, 300 mg bid or 300 mg tid; men were treated for 4 weeks. Hot flashes numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flashes diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intrapatient difference in hot flash score between baseline and treatment termination. With the planned sample size of 50 evaluable patients per arm, the study provided 80% power to detect a difference in change from baseline at 4 weeks between each gabapentin arm and the placebo arm of 1.3 hot flashes per day or 3.3 points in hot flash score. Results: 223 patients were randomized between 12/21/2001 and 11/10/2006. The study arms were well balanced. The following table illustrates the percentage of baseline hot flash scores and frequencies during the fourth treatment week, compared to the baseline week for 179 eligible patients, utilizing the data available at time of this abstract preparation. Patients receiving 900 mg/d dose of gabapentin also reported significantly less hot flash distress and more hot flash control satisfaction than did the placebo group. The gabapentin was remarkably well tolerated, without any statistically significantly worse patient-reported side effects on the gabapentin arms. Conclusion: Gabapentin at the 900 mg/d dose can reduce hot flashes, in men receiving androgen deprivation therapy for prostate cancer. No significant financial relationships to disclose. [Table: see text]

8565 Background: Previous studies using low-dose (250 ug/dose) aerosolized sargramostim (granulocyte macrophage colony stimulating factor: aero-GM-CSF) for the treatment of metastatic melanoma, revealed anecdotal clinical responses that appeared to correlate with an increase in the number of tumor specific cytotoxic T lymphocytes (CTL) in blood. Herein, we address whether or not further dose escalation of aero-GM-CSF is safe, results in greater increase of melanoma specific CTLs, and affects clinical outcomes. Methods: A 5+5 dose escalation clinical trial was conducted to determine the dose of aero-GM-CSF that would increase in the frequency of peripheral blood melanoma specific CTLs in HLA-A2+ patients with metastatic melanoma to the lungs. Aero-GM-CSF was administered twice daily on days 1–7 and 15–21 of a 28 day cycle at doses of: 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 ug per cohort. If at most 2 of 5 patients at a dose level reported a 5-fold increase in CTLs, dose escalation occurred. If not, 5 additional patients were treated at that dose. Dose escalation continued until =2 of 5 patients at a dose level developed severe toxicity, at least 7 of the 10 patients at a dose level reported a 5-fold increase in CTLs, or all dose levels were exhausted. Results: The study accrued 40 patients from August 2002 to July 2006. Four patients cancelled participation prior to treatment. One patient was replaced (500 ug) as he died within 13 days of registration. Among the 35 remaining patients, median age was 58 (23–84), 72% were male, and 72% had a PS=0. Dose escalation was not terminated due to toxicity. Toxicities = grade 3 (at least probably treatment related) included: grade 3 fatigue (1) at 1,000 ug; and grade 3 cough (1), and grade 4 dyspnea (1) at 1,750 ug. At the 2,000 ug dose, most patients (4 of 5) exhibited a greater than 2-fold increase in melanoma specific CTLs. Two of these patients remain on treatment: one with partial response at 14.0 months and the other with stable disease at 6.5 months. A 5-fold increase in tumor specific CTLs was not achieved in any patient. Conclusions: Aero-GM-CSF therapy administered at up to 2,000 ug/dose appears safe and seems to correlate with increased frequencies of tumor specific CTLs in a dose-dependent fashion. Further dose escalation followed by clinical efficacy testing is warranted. No significant financial relationships to disclose.

Abstract Background: HF occur in about 75% of midlife women and are associated with quality of life disruption and premature endocrine therapy discontinuation among breast cancer survivors. Estrogen therapy, effective for HF, is contraindicated in hormone receptor-positive breast cancer (BC). Previous studies have suggested that Oxy could be effective in managing HF. Methods: This randomized, placebo (P)-controlled trial enrolled women who had experienced HF ≥28 times per week over &gt;30 days and of sufficient severity to seek treatment. Patients (pts) were randomized to receive oral Oxy at two doses: 2.5mg BID for 6 weeks (Oxy2.5), 2.5mg BID for a week with subsequent increase to 5mg BID (Oxy5), or matching P, in equal ratios. Baseline and monthly questionnaires were administered including a HF diary, the HF related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in weekly HF score and frequency from baseline to end of study compared using Kruskal-Wallis tests. Results: 150 pts were accrued between 2/23/2017-3/5/2018. 4 pts cancelled before starting treatment and were excluded from analyses. This interim report includes the first 104 pts for which at least one post-baseline evaluation was available. Baseline characteristics were well-balanced between the arms. Sixty-two percent were on tamoxifen or an aromatase inhibitor for the duration of the study. Pts on both Oxy doses had a significantly greater reduction in HF score and frequency compared to P. Pts on Oxy2.5 had a mean change in HF score of -10 (SD 7.4) vs -5.1 (SD 9.7) with P, p=0.003; and a mean change in average weekly number of HF of -4.6 (SD 3.1) vs -2.3 (SD 3.9), p=0.002. Pts on Oxy5 had a mean change in HF score of -16.2 (SD 5.1) vs -5.1 (SD 9.7) with P, p&lt;0.001; and a mean change in average weekly number of HF of -7.0 (SD 4.0) vs -2.3 (SD 3.9), p&lt;0.001. Repeated measures mixed models confirmed that, after adjusting for baseline values, both Oxy arms had significantly lower HF scores and frequency compared to P (p&lt;0.001). HFRDIS revealed that pts in both Oxy arms experienced improvement in the following HF interference measures: work, social activities, leisure activities, sleep, relations, life enjoyment, and overall quality of life. Pts on Oxy5 also had improvement in HF interference with mood. Pts on Oxy2.5 experienced more stomach pain (p=0.031), diarrhea (p=0.007), nausea (p=0.04), headaches (0.032), episodes of confusion (0.012), dry mouth (p=0.003) and dry eyes (0.027) compared to P. Pts on Oxy5 experienced more constipation (0.004), dry mouth (0.001) and difficulty urinating (0.004) compared to P. There were no differences in study discontinuation due to adverse effects between either Oxy arm and P (Oxy2.5 vs P, p=0.653; Oxy5 vs P, p=0.483). Conclusions: Oxy is superior to P for management of HF. Oxy2.5 and 5 were both associated with significant improvements in HF scores and frequency as well as improvement in HF interference with several quality of life measures. While pts on Oxy experienced more side effects than pts on P, rates of discontinuation due to adverse events were low. This study was supported by the Breast Cancer Research Foundation. Citation Format: Leon-Ferre RA, Novotny PJ, Faubion SS, Ruddy KJ, Flora D, Dakhil C, Rowland KM, Graham ML, Le-Lindqwister N, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of oxybutynin (Oxy) for hot flashes (HF): ACCRU study SC-1603 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS6-02.