Strand, Carrie

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Abstract Background: In the treatment of ER+/HER2- metastatic breast cancer (MBC), randomized phase II/III trials testing selective estrogen receptor degraders (SERDs), proteolysis-targeting chimeras (PROTACs), complete estrogen receptor antagonists (CERANs) and selective ER modulators (SERMs) (mostly compared to fulvestrant) have demonstrated modest (1-2 months) improvements in progression-free survival (PFS), mainly limited to patients with ESR1-mutated MBC. In these studies, the median PFS (mPFS) ranges from 3 to 6 months, with shorter mPFS in patients with prior progression on CDK 4/6 inhibitor (CDK 4/6i). Here we report the final results of a randomized phase II study that compared Z-endoxifen (Endx) 80 mg/day with tamoxifen (Tam) 20 mg/day in postmenopausal women with estrogen receptor (ER)- positive/ HER2-negative MBC, and report outcomes according to ESR1, PIK3CA, PTEN and AKT alterations (Alliance A011203; NCT02311933). Methods: Postmenopausal women with unlimited prior endocrine regimens (including CDK 4/6i) and up to two chemotherapy regimens for MBC, with tumor biopsy confirmation of ER+ (>10% nuclear staining) and negative for HER2 amplification/overexpression were eligible. Prior adjuvant Tam was allowed if relapse was > 1 year following Tam completion. Patients randomized to Tam could cross over to Endx at progression. The primary end point was PFS analyzed by the interval censored data analytic approach. ctDNA was analyzed for ESR1 and PIK3CA/PTEN/AKT alterations using Guardant360 CDx 74-gene next-generation sequencing-based assay (Guardant Health). Results: Among 108 women who preregistered, 76 (Endx: 40; Tam: 36) were randomized and eligible. Patients were heavily pretreated; all patients had prior exposure to an aromatase inhibitor (AI), 50% had ≥ 2 AI based regimens in the metastatic setting and 50% in each arm had received fulvestrant. Approximately half on each arm received at least one chemotherapy regimen in the metastatic setting. Prior CDK 4/6i therapy was imbalanced (48% on Endx and 28% on Tam). Endx did not significantly prolong PFS compared to Tam (median PFS [mPFS] 4.3 vs 1.7 months; HR 0.72, p=0.168). Because arms were imbalanced according to prior CDK 4/6i exposure, we performed an unplanned analysis demonstrating that Endx improved PFS relative to Tam in CDK 4/6i-naïve patients (mPFS 8.3 vs 2.1 months; HR 0.39, p=0.0097) but not in patients treated with prior CDK 4/6i (mPFS 3.0 vs 1.5 months). In the subset of patients who consented for ctDNA testing (n=28), the mPFS for those with either an activating alteration in the PIK3CA/PTEN/AKT pathway or with an ESR1 mutation was similar as the overall trial. For the 24 patients who progressed on Tam and crossed-over to Endx, the median PFS was 3.5 months (range 1.5-15.0 months) with a 6-month clinical benefit rate of 33.3% (8/24; 90% CI: 17.8-52.1%). Conclusions: Endx did not meet the prespecified threshold for concluding that it significantly improved PFS relative to Tam in a cohort of heavily pretreated MBC. However, the observations of a > 6-month improvement in mPFS in CDK 4/6i-naïve patients, anti-tumor activity following crossover to Tam, and mPFS estimates similar to other novel endocrine agents in development all support the ongoing development of Endx. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN) and 5P50CA116201. Clinicaltrials.gov Id: NCT02311933. https://acknowledgments.alliancefound.org. Citation Format: M. P. Goetz, V. Suman, J. Reid, T. Dockter, C. Strand, W. F. Symmans, J. Hawse, A. Storniolo, J. Doroshow, J. M. Collins, H. Streicher, M. M. Ames, A. Tarnower, O. M. Hahn, J. N. Ingle, L. Carey, A. Partridge. Final results from the Randomized Phase II study of Z-Endoxifen and Tamoxifen in Endocrine Refractory, Estrogen Receptor Positive, HER2 negative Metastatic Breast Cancer (Alliance A011203) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-07.

Abstract The aim was to assess whether subject’s participation in early-phase chemoprevention trials was satisfactory and identify features associated with subjects’ satisfaction. Thirteen trials that investigated a range of candidate agents from 2006 to 2021 by the Cancer Prevention Network were included. The five-item “Was It Worth It?” (WIWI) questionnaire was administered to all subjects at the end of each trial’s intervention or at early termination. Satisfied overall was defined as a participant response of “yes” to the first three questions. Six hundred ninety-one participants from the United States, Canada, Puerto Rico, and Honduras enrolled on a trial. Six hundred fifty-two (94.4%) completed the WIWI questionnaire. Of these, 493 (75.6%) were White, non-Hispanic/Latino; 39 (6.0%) Black, non-Hispanic/Latino; 98 (15.0%) Hispanic/Latino; and 8 (1.2%) of another race/ethnicity. One hundred ninety-three were women (29.6%), 121 (17.5%) were ≥65 years, and 517 (79.3%) participated in a placebo-controlled trial. Eighty-five percent indicated being satisfied overall. Compared with White, non-Hispanic/Latino, the odds of not satisfied overall were 2.96 times higher for Black/Asian/>1 race, non-Hispanic/Latino (P < 0.001) and 0.40 times lower for Hispanic/Latino (P = 0.004). The odds of not satisfied overall was 1.9 times higher when the number of preintervention adverse events experienced was ≥1 (P = 0.012), 1.8 times higher when the percentage of the intervention duration with adverse events was >5% (P = 0.024), and 7.4 times higher for subjects who terminated the intervention early (P < 0.001). These findings can inform the design of future chemoprevention trials and help investigators improve accrual, retention, adherence, and diversity in this underexplored research setting. Prevention Relevance: The five-item “WIWI?” questionnaire, which captures the participant-reported experience of trial participation, gives the subject a voice in the development of new chemopreventative agents. This study in 652 subjects looked at satisfaction with participation in early-phase chemoprevention trials for higher-risk, cancer-free men and women. See related Spotlight, p. 7

9503 Background: Neoadjuvant ± adjuvant immunotherapy improves event-free survival relative to adjuvant immunotherapy alone for patients with high-risk resectable stage III melanoma. However, the optimal regimen balancing efficacy and tolerability is not known. T-cell immunoglobulin and ITIM domain (TIGIT) is a promising immune checkpoint but its therapeutic potential in stage III melanoma is underexplored. Methods: In this phase II trial, patients with resectable, macroscopic stage III melanoma received four 21-day neoadjuvant cycles of 1200mg IV atezolizumab (atezo, anti-PD-L1) + 600mg IV tiragolumab (tira, anti-TIGIT), followed by therapeutic lymph node dissection (TLND) and eight 21-day adjuvant cycles of 1200mg IV atezo. Primary endpoints were pathologic response (of all patients initiating neoadjuvant therapy) and recurrence-free survival (RFS) from the time of TLND in patients who were operated on per protocol and received adjuvant therapy. Secondary endpoint was adverse events (AEs); exploratory endpoints included event-free survival (EFS) and distant metastasis-free survival (DMFS). Results: Thirty-four patients, median age 59 years, were accrued and initiated neoadjuvant atezo/tira. 76.5% had >1 metastatic lymph node involved at baseline and 73.5% presented with Stage IIIC disease. All 34 patients were evaluable for AEs, pathologic response and EFS. Four patients were diagnosed with metastatic disease during neoadjuvant treatment, while 30 had TLND per protocol and 28 received adjuvant treatment and were evaluable for RFS and DMFS. Major pathologic responses (MPR, ≤10% viable tumor) were observed in 16/34 patients (47.1%, Table). With 19.9 months median follow-up from registration, 12-month EFS was 72.0% (95% CI 57.9 to 89.5%). With 16 months median follow-up from operation, 12-month RFS was 73.3% (n=28, 95% CI 56.9 to 94.5%), while 12-month DMFS was 86.0% (n=28, 95% CI 72.2 to 100%). In the 16 patients with an MPR, 2 did not receive adjuvant treatment and were followed for 33.3 and 10.8 months without recurrence/death. In the remaining 14 patients, 12-month RFS and 12-month DMFS were both 91.7% (95% CI 77.3 to 100%). 5 patients (14.7%) experienced any grade 3+ AE with 2 (5.9%) at least possibly related to the neoadjuvant regimen. Conclusions: Among patients with high-risk resectable stage III melanoma, neoadjuvant atezo/tira was a promising regimen with a favorable safety profile and warrants further study. Identification of predictive biomarkers will allow for optimization of neoadjuvant therapy for individual patients. Clinical trial information: NCT03554083 . Pathologic response. N=34 Major Pathologic Response 16 (47.1%) Pathologic complete response (no viable tumor) 13 (38.2%) Near-pathologic complete response (0.1−10% viable tumor) 3 (8.8%) Pathologic partial response (>10.0−50% viable tumor) 2 (5.9%) Pathologic non-response (>50% viable tumor) 12 (35.3%) No per protocol operation 4 (11.8%)

The National Comprehensive Cancer Network (NCCN) recommended surveillance imaging intervals for uveal melanoma (UM) based on the risk of distant metastasis. The objective of this research is to evaluate if patients, treated at our tertiary cancer center, who had scans consistent with these guidelines, had improved overall survival (OS). This was a single-center, retrospective study of UM patients, who developed metastatic disease. Patients were grouped into risk-of-metastasis cohorts (low, medium, and high-risk) based on the UM NCCN guidelines v1.2023. The frequency of scans was reported within annual intervals for 5 years within the low-risk cohort and for 10 years within the medium-risk cohort, and within 6-month intervals for the first 5 years and then annually in years 6–10 within the high-risk cohort. Conditional landmark analyses were used to evaluate the relationship between OS and consistency with guidelines. Scan frequency was evaluated against socioeconomic status. Of the 740 UM patients identified (1997–2020), 110 experienced metastasis and comprised our analysis population (20 low-risk; 67 medium-risk; and 23 high-risk). The median time to death (95% confidence interval) from diagnosis of metastasis was similar between the low, medium, and high-risk cohorts at 1.2 (1.0, 2.0), 2.0 (1.7, 2.6), and 1.6 (1.3, 2.3) years, respectively. For each cohort, the OS results were similar between those who followed guidelines vs. not at each annual landmark time. Living in disadvantaged areas did not impact imaging frequency (all P > 0.05). Imaging at intervals outlined by the NCCN guidelines v1.2023 did not impact OS for patients who developed metastatic UM.

Background Neoadjuvant treatment has become standard for patients with high-risk operable stage III melanoma, but the optimal regimen is unknown. Targeted therapy approaches yield high pathological response rates, while immunotherapy regimens show favorable recurrence-free survival (RFS). NeoACTIVATE was designed to address whether a neoadjuvant combination of both targeted therapy and immunotherapy might leverage the benefits of each. Methods We tested neoadjuvant treatment with 12 weeks of vemurafenib, cobimetinib, and atezolizumab for patients with BRAF-mutated (BRAFm) melanoma (cohort A) and cobimetinib and atezolizumab for patients with BRAF-wild-type (BRAFwt) melanoma (cohort B), regimens which we have shown generate a substantial major pathological response. After therapeutic lymph node dissection, patients received 24 weeks of adjuvant atezolizumab. Here, we report survival outcomes and their association with biomarkers assayed among the gut microbiome and peripheral blood immune subsets. Results With 49 months median follow-up, the median RFS was not reached for cohort A and was 40.8 months for cohort B. At 24 months after operation, 2 of 14 cohort A patients and 4 of 13 cohort B patients had experienced distant relapse. Key findings from correlative analyses included diversity, taxonomic and functional metagenomic gut microbiome signals associated with distant metastasis-free survival at 2 years. Notably, we observed a strong correlation between low microbial arginine biosynthesis (required for T-cell activation and effector function) and early distant recurrence (p=0.0005), which correlated with taxonomic differential abundance findings. Peripheral blood immune monitoring revealed increased double-positive (CD4+CD8+) T cells in patients with early recurrence. Conclusions Neoadjuvant treatment with cobimetinib and atezolizumab±vemurafenib was associated with a low rate of distant metastasis in patients with high-risk stage III melanoma. Freedom from early distant metastasis was highly associated with taxonomic differences in gut microbiome structure and with functional pathway alterations known to modulate T cell immunity. Identification of predictive biomarkers will permit optimization of neoadjuvant therapy regimens for individual patients. Trial registration number NCT03554083.

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Importance Patient withdrawal of consent from a cancer clinical trial is defined as a patient’s volitional cessation of participation in all matters related to a trial. It can undermine the trial’s purpose, make the original sample size and power calculations irrelevant, introduce bias between trial arms, and prolong the time to trial completion. Objective To report rates of and baseline factors associated with withdrawal of consent among patients in cancer clinical trials. Design, Setting, and Participants This multisite observational cohort study was conducted through the Alliance for Clinical Trials in Oncology. Patient withdrawal was defined as a patient’s voluntary termination of consent to participate anytime during trial conduct. Baseline patient- and trial-based factors were investigated for their associations with patient withdrawal within the first 2 years using logistic regression models. All patients who participated in cancer therapeutic clinical trials conducted within the Alliance for Clinical Trials in Oncology from 2013 through 2019 were included. The data lock date was January 23, 2022. Main Outcomes and Measures The percentage of patients who withdrew consent in 2 years and factors associated with withdrawal of consent. Results A total of 11 993 patients (median age, 62 years; 67% female) from 58 trials were included. Within 2 years, 1060 patients (9%) withdrew from their respective trials. Two-year rates of withdrawal were 5.7%, 7.6%, 8.5%, 7.8%, 8.4%, 9.5%, and 9.8% for each of the respective years from 2013 through 2019. In multivariable analyses, Hispanic ethnicity (odds ratio [OR], 1.67; 95% CI, 1.30-2.15; P < .001), randomized design with placebo (OR, 1.64; 95% CI, 1.38-1.94; P < .001), and patient age 75 years and older (OR, 1.39; 95% CI, 1.12-1.72; P = .003) were associated with higher likelihood of withdrawal by 2 years. Use of radiation was associated with patient retention (OR, 0.68; 95% CI, 0.54-0.86; P = .001). Conclusions and Relevance In this cohort study, rates of withdrawal of consent were less than 10% and appeared consistent over time. Factors that are associated with withdrawal of consent should be considered when designing trials and should be further studied to learn how they can be favorably modified.