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Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

Context Preliminary trials report that Scrambler Therapy, a form of electroanalgesia, may improve discomfort from chemotherapy-induced peripheral neuropathy (CIPN). Objective The objective of this phase II, randomized controlled trial was to evaluate the efficacy of Scrambler therapy vs. transcutaneous electrical nerve stimulation (TENS) in treating CIPN. Methods Fifty patients were accrued for the first half of this two-part, crossover trial consisting of a 2-week treatment period with either Scrambler or TENS, followed by an 8-week observation period, and then crossover treatment. Twenty-two patients proceeded to the crossover phase. The primary means of assessment was patient-reported outcomes, including symptom severity scales and Global Impression of Change questionnaires. Symptoms were assessed daily during the treatment period and weekly during an 8-week observation period. Results A 50% or greater reduction in primary symptom (pain or tingling) score on the last day of treatment was achieved by 6 of 10 Scrambler-treated patients (60%) and 3 of 12 TENS-treated patients (25%) after crossover (P = 0.11). By day 4 of treatment, the two arms diverged with respect to mean change in primary symptom score; this effect was largely carried through to the end of the two-week treatment period. Similarly, Scrambler therapy appeared better than TENS when assessed by Global Impression of Change for neuropathy, pain, and overall quality of life. Conclusions Similar findings from the initial randomization and crossover phases of this study support further evaluation of the efficacy of Scrambler therapy in alleviating CIPN symptoms. Evaluation in a larger, randomized controlled trial with standardized treatment is warranted.

Introduction Optimal treatment for older adults with stage III non-small cell lung cancer (NSCLC) remains unclear. Here we hypothesized that sequential chemoradiation therapy (sCRT) is better tolerated than concurrent (cCRT) but confers acceptable efficacy. We evaluated these strategies in older adults utilizing Alliance for Clinical Trials in Oncology data. Materials and methods Pooled analyses from 6 first-line stage III NSCLC CRT trials (Cancer and Leukemia Group B 8433, 8831, 9130, 30106, 30407, 39801) were used to compare toxicity and survival outcomes with cCRT versus sCRT in patients age ≥ 65 years. Grade 3–5 adverse events (AEs), progression-free and overall survival (PFS; OS) are reported with adjustment for covariates. Results Four hundred older adults, of whom 106 (26.5%) had received sCRT and 294 (73.5%) had received cCRT, comprised the cohorts. Virtually all had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (99%). More grade 3–5 AEs were observed at any time-point with cCRT than sCRT (94.2% versus 86.8%; 95% confidence interval for difference in proportions, 1.3%, 15.5%) and this finding remained after adjusting for length of study treatment (P = 0.018). Comparable PFS and OS were observed with sCRT versus cCRT (median: 8.0 versus 9.2 months; median: 11.9 versus 13.4 months, respectively) even after adjustment for age, sex, ECOG PS, body mass index, pretreatment weight loss, stage, and cisplatin-based therapy (P = 0.604 and P = 0.906, respectively). Discussion These data show that sCRT was associated with less toxicity than cCRT with no associated statistically significant decrease in efficacy outcomes and that sCRT merits further study in this population.

This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC).We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3-5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation.730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p = 0.25). A trend emerged with increased odds of a grade 3-5 adverse event for patients ≥65 years versus65 years (OR = 1.52; 95% CI = (0.99, 2.31); p = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = -5%; 95% CI = (-9, 0.2); p = 0.06) for those ≥65 years versus65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p = 0.21) for patients ≥65 years versus65 years. A cutpoint of 70 years yielded similar results.These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC.

12007 Background: Up to 96% of patients with high grade glioma (HGG) report moderate to severe fatigue. Armodafinil, the R-enantiomer of modafinil, is a psychostimulant with low potential for abuse that has shown potential for improving severe fatigue in HGG patients. Methods: In this phase III double blinded placebo-controlled study, adults with HGG and moderate to severe fatigue, > 4 weeks after completing radiotherapy, were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo for a total of 8 weeks. The primary outcome was efficacy in treating severe fatigue. Secondary outcomes included evaluation of tolerability, neurocognitive function, and quality of life. Patients were evaluated at baseline, 4 and 8 weeks. Results: A total of 328 patients were enrolled between 6/3/13-3/1/19. There were 103 (150 mg arm), 97 (250 mg arm) and 97 (placebo arm) evaluable patients with primary endpoint data available. The median age was 60 years (20-85) with a median Brief Fatigue Inventory (BFI) worst fatigue score of 8 (6-10). 60.3% were male, 80.5% received concomitant chemotherapy, and 39.7% were on corticosteroids. The global fatigue score at end of weeks 4 and 8 were lower than at baseline (p0.05) or week 8 (p>0.05) between arms. More patients reported insomnia on the 250 mg arm (p=0.0083). Conclusions: There is no meaningful benefit of the use of armodafinil to reduce moderate to severe fatigue in patients with HGG. In certain cases there may be benefit of armodafinil 150 mg to aid concentration without the risk of insomnia.Support: UG1CA189823;U10CA180868 (NRG). Clinical trial information: NCT01781468 .

Few older cancer patients are enrolled in cancer clinical trials. This article assesses whether the development and conduct of older‐patient‐specific trials is justified, comparing outcomes of patients enrolled in trials purposely designed for older cancer patients versus age‐unspecified trials., Background. Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older‐patient‐specific trials, defined as those designed for older patients with cancer, with those enrolled in age‐unspecified trials. Materials and Methods. We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985–2012. Results. Among 2,277 patients, 1,014 had been enrolled to older‐patient‐specific and 1,263 to age‐unspecified trials. The median age (range) in the older‐patient‐specific trials was 72 (65–89) years compared with 68 (65–84) years in the cohort of older patients in age‐unspecified trials; p < .0001. A greater percentage of patients 75 years or older had enrolled in older‐patient‐specific trials compared with the cohort of age‐unspecified trials: 26% versus 6% (p < .0001). Median overall survival (OS) was 12.8 years (95% confidence interval [CI], 11.9–13.7) and 13.5 years (95% CI, 12.9–14.1) for older‐patient‐specific and age‐unspecified trials, respectively. OS was comparable (hazard ratio [HR], 1.08; 95% CI, 0.92–1.28; p = .34; referent: age‐unspecified trials), after adjusting for age, estrogen receptor status, tumor size, and lymph node status. Similar findings were reached for recurrence‐free survival. A lower rate of grade 3–5 adverse events (hematologic and nonhematologic) was reported in older‐patient‐specific trials (43% vs. 58%; p < .0001). Sensitivity analysis with chemotherapy only trials and subset analysis, adjusted for performance score, yielded similar OS results. Conclusion. Older‐patient‐specific trials appear to address this underrepresentation of older patients with ostensibly comparable outcomes. Clinical trial identification numbers. NCT00003088 (CALGB 9741); NCT00024102 (CALGB 49907); NCT00068601 (CALGB 40401); NCT00005970 (NCCTG N9831) Implications for Practice. This work underscores the importance of clinical trials that focus on the recruitment of older patients with cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent clinical problem, with limited effective therapies. Preliminary non-randomized clinical trial data support that Scrambler Therapy is helpful in this situation. Patients were eligible if they had CIPN symptoms for at least 3 months and CIPN-related tingling or pain at least 4/10 in severity during the week prior to registration. They were randomized to receive Scrambler Therapy versus transcutaneous electrical nerve stimulation (TENS) for 2 weeks. Patient-reported outcomes (PROs) were utilized to measure efficacy and toxicity daily for 2 weeks during therapy and then weekly for 8 additional weeks. This study accrued 50 patients, 25 to each of the 2 study arms; 46 patients were evaluable. There were twice as many Scrambler-treated patients who had at least a 50% documented improvement during the 2 treatment weeks, from their baseline pain, tingling, and numbness scores, when compared with the TENS-treated patients (from 36 to 56% compared with 16–28% for each symptom). Global Impression of Change scores for “neuropathy symptoms,” pain, and quality of life were similarly improved during the treatment weeks. Patients in the Scrambler group were more likely than those in the TENS group to recommend their treatment to other patients, during both the 2-week treatment period and the 8-week follow-up period (p

Introduction Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7– 3.2) in older patients and 3 months (95% confidence interval: 2.9–3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusions TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.

Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

10034Background: Breast cancer incidence increases with age, but older patients tend to be underrepresented in clinical trials. To address this underrepresentation, this study examined the role of ...

10016Background: Pilot data support that Scrambler therapy may benefit patients with Chemotherapy-induced peripheral neuropathy (CIPN). Methods: Patients with CIPN for at least 3 months were eligib...