Experimental Arm Research Articles

Evaluation of a complex survivorship intervention incorporating electronic patient-reported outcomes in early stage breast and gynecologic cancer: Results from the Linking You to Support and Advice (LYSA) randomized controlled trial.

1505 Background: Expert consensus supports a multidisciplinary strategy in cancer survivorship care to enhance patient outcomes and quality of life. We hypothesized that introducing a women’s survivorship clinic into routine follow up care would be feasible, and associated with improved symptom management and quality of life (QOL). Methods: LYSA was a multisite randomized controlled trial with parallel arms (experimental and active comparator), co-designed with public and patient involvement. Eligibility: early-stage hormone receptor-positive breast or gynaecologic cancer (GYN) within 12 months of completing primary therapy, and internet access (NCT05035173). Experimental arm attended a nurse-led clinic targeting symptom management, and dietetic consultation. Electronic patient-reported outcome (ePRO) assessments were undertaken at baseline, and bimonthly to 12 months. An online trigger alert system facilitated symptom management. Active comparator arm attended the nurse-led clinic at baseline and end of study. Primary endpoint (feasibility): Proportions of participants completing baseline and follow up ePRO surveys, and engaging in healthcare consultations after ePRO triggers. Pilot efficacy endpoints: changes in cancer-related symptom (PROMIS, PRO-CTCAE, Fear of Cancer Recurrence), health-related QOL Questionnaires (EORTC-QLQ, EQ5D5L) . Sample size target (n=200) facilitated feasibility outcomes. Between arm differences were estimated using generalized linear model, adjusted for baseline outcome. Results: 200 women were randomized, March 2021-August 2022 across two sites; 84% breast and 16% GYN. Consent was obtained in clinic (51%), video call (33%) or phone (16%). Median age was 54 (range 23-78). Of the 173 participants completing the study (n = 90 experimental, 83 comparator), all completed both baseline and end of study surveys. Following symptom triggers (experimental arm), there were 322 study nurse visits across 86 participants, and 243 dietician visits across 73 participants. Engagement with healthcare and other supportive resources was approximately twice more than comparator arm, due to referral. There were no notable between-arm differences with respect to EQ5D5L items at study end. However, experimental arm participants had better EORTC Total scores at study end relative to comparator (difference in means -3.87 95%CI -6.58 to -1.16, p=0.005). There were also significant (p < 0.05) differences observed between the arms for 8/12 symptom items reflecting less fatigue, anxiety and depression in experimental arm at study end. Conclusions: The LYSA trial met its primary feasibility endpoint, with high rates of ePRO completion. Secondary endpoint analysis is ongoing including an economic analysis and future studies. Clinical trial information: NCT05035173 .

Randomized controlled, open-label, phase IIb/III study of lurbinectedin in combination with doxorubicin versus doxorubicin alone as first-line treatment in patients with metastatic leiomyosarcoma.

TPS11590 Background: Lurbinectedin (LUR) is a synthetic chemical entity structurally related to trabectedin that inhibits oncogenic transcription and is active in tumors addicted to transcription. Synergistic activity of the combination of LUR with Doxorubicin (DOX) was found in solid tumors. Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at different doses. In a phase 2 trial in soft tissue sarcoma (STS) patients (pts) (mostly with LMS: 12/20 pts), a combination of DOX 50 mg/m2 + LUR 2 mg/m2 Day (D)1 q3wk resulted in a response rate (RR) of 35% (4/7 LMS pts responding) and a disease control rate (DCR) at 24 wks of 40% (1). A phase 1b/2 trial in 10 advanced STS pts found a RR of 60% (5 were LMS, with 3 partial responses) treated at DOX 25 mg/m2 D1 or D1,D8 + LUR 3.2 mg/m2 D1 q3wk, (2). The promising results of these trials provide a rationale for further exploring this combination in a phase 2b/3 trial as first-line therapy for metastatic LMS (SaLuDo - NCT06088290). Methods: SaLuDo is a randomized, open-label study evaluating LUR in combination with DOX compared to DOX alone as first-line treatment of pts with metastatic LMS. The primary endpoint is progression-free survival (PFS) according to Independent Radiological committee (IRC). Secondary endpoints include overall survival, PFS according to Investigator assessment (IA), overall response rate, duration of response, and clinical benefit rate (according to IRC and IA), safety profile, patient-reported outcomes, pharmacokinetics, and exploratory pharmacogenomic analysis. Main inclusion criteria include age ≥ 18 years, confirmed diagnosis of metastatic LMS, and no prior systemic treatment for metastatic disease. Exclusion criteria include prior treatment with anthracyclines, lurbinectedin or trabectedin. The phase 2b part of the study will randomize approximately 120 pts into 3 arms (1:1:1): Control arm (DOX 75 mg/m2 D1 q3wk; experimental ARM A (DOX 50 mg/m2 D1 + LUR 2.2 mg/m2 D1 + 1ry GCSF prophylaxis q3wk), and experimental ARM B (DOX 25 mg/m2 D1 + LUR 3.2mg/m2 D1 + 1ry GCSF prophylaxis q3wk). Stratification will be done according to site of primary tumor (uterine vs. soft tissue), sites of metastatic disease (lung as unique site vs. other) and time from diagnosis to study entry (≤ 12 months vs. >12 months). One of the two experimental arms will be dropped out at the end of phase 2b. The study will then enter the phase 3 part and approximately 120 pts will be randomized 1:1 between the control arm and the selected experimental arm. An Independent Data Monitoring Committee will oversee the conduct of the study. The first patient was randomized in 09/2023. The phase 2b part of the study is ongoing and recruiting patients in Europe and the USA. 1. Cote EJC 2020; 126:21-32. 2. Cote. JCO 2023; 41: Abst 11507. Clinical trial information: NCT06088290 .

The value of blinded independent central review (BICR) in recent trials in non-small cell lung cancer (NSCLC).

e23000 Background: Progression free survival (PFS) is an endpoint that has been increasingly used to obtain approval of new cancer drugs and strategies. However, there are a number of issues that can complicate assessment of PFS. One of these is the potential for investigator bias. This has been addressed by the use of blinded independent central review (BICR). However, BICR increases costs and complexity. Methods: The current study evaluated the results of BICR versus investigator assessment (IA) for phase III randomized clinical trials in thoracic oncology with initial publication from 1.01.2013-12.31.2023. Trials were included if they involved targeted agents, antibody drug conjugates or immunotherapy. Studies with < 100 pts or comparing only cytotoxic chemotherapy or maintenance strategies were excluded. Studies with cytotoxic chemotherapy as part of therapy or within the control arm were included. A search of clinicaltrials.gov with the terms “phase III”, “non-small cell lung cancer” for completed studies was done, supplemented by a bibliographic search. Publications were then reviewed for whether a BICR was utilized and whether both BICR and IA were reported. Hazard Ratios (HR) for PFS between IA vs BICR were compared. Results: 49 randomized phase III trials were identified of which 34 describe BICR of which 21 reported both IA and BICR results. Six studies evaluated immunotherapy and enrolled 3337 pts, 15 evaluated targeted agents and enrolled 6531 pts. All immunotherapy studies were significantly positive for the experimental arm and 14 of 15 of the targeted therapies were positive. PFS data was reported for 17 of the studies (not reached for experimental arms in 2 and not reported in 2 others). HRs were directionally similar in all studies, though were lower (more favorable) in IA vs BICR in 5 of 6 immunotherapy studies and 11 of 15 targeted therapy studies. The mean % difference for immunotherapy studies was 8.9% and the median 10%, range 2-23.5%. For the positive targeted therapies studies the mean/median differences were 14.6%/15.6%, range 1.5-42%. The largest % differences were seen at the lowest HRs (e.g..19 vs .27; 42%). For immunotherapy studies, the median PFS difference was 0.2 and 0.28 months for the control and experimental arms, respectively. For targeted therapy studies, median PFS differences were 0.4 and 0.95 months for the control and experimental arms, respectively. The studies were performed in multiple countries including the United States, European Union, China and Japan. Conclusions: Despite a wide range of agents and settings, no trial for which information is publicly available comparing BICR to IA has demonstrated any qualitative difference in outcome nor more than a marginal numerical difference.

A phase II study evaluating the effect of IMNN-001 on second-look laparoscopy (SLL) when administered in combination with bevacizumab (BEV) and neoadjuvant chemotherapy (NACT) in patients newly diagnosed with advanced epithelial ovarian cancer (EOC).

TPS5633 Background: IMNN-001, an interleukin-12 (IL-12) DNA plasmid formulated with a DNA carrier, polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has been shown to exhibit a favorable benefit/risk ratio when administered intraperitoneally (IP), in combination with intravenous platinum-taxane chemotherapy, up to doses of 100 mg/m2 in women with advanced EOC in earlier Phase I & II studies. The 201-21-202 study (NCT05739981) is a multi-center, randomized, open-label phase I/II study which hypothesizes the addition of IMNN-001 to neoadjuvant & adjuvant carboplatin-paclitaxel and bevacizumab (chemo + BEV) reduces the risk of histologically documented minimal residual disease (MRD) as determined by SLL by 50%. Methods: Patients with newly diagnosed stage III and IV high grade serous EOC who are candidates for NACT will be enrolled into the trial. Initial safety lead-in will evaluate at least 6 patients randomized to the experimental arm. Upon confirmation of safety by the DSMB, a target of ~50 patients will be randomized 1:1 to receive either chemo + BEV with or without IMNN-001. Patients receive at least 4 cycles of NACT followed by interval cytoreductive surgery (ICS), and 3 additional adjuvant cycles of study treatments will be administered. BEV will be included with each cycle except cycle 1, the last cycle of NACT immediately preceding ICS, and the first cycle of adjuvant chemotherapy. In the experimental arm, IMNN-001 will be administered on C1D15 and continue weekly though the last cycle of adjuvant therapy. Following adjuvant therapy, all patients will undergo SLL with peritoneal washing and multiple biopsies. Pathologic detection of residual tumor in any biopsies or peritoneal cytology constitutes presence of MRD. All patients will receive maintenance therapy with Olaparib + BEV, IMNN-001 + BEV, or BEV alone based on their homologous recombination deficiency status and treatment randomization. Translational:All subjects will undergo biospecimen collection and organoid preparation prior to treatment, at the time of ICS and SLL for comprehensive longitudinal genomic, circulating tumor DNA, immune, and microbiome profiling. Subjects in the experimental arm will also undergo peritoneal lavage and collection of fluid and cells for assessment of the peritoneal tumor environment. Endpoints: The primary endpoint is the rate of MRD at SLL. Secondary endpoints include progression-free survival, overall survival, objective response rate, chemotherapy response score, surgical response, and serologic response. All patients will be evaluated for safety. Status: The study is actively enrolling and is in the safety lead-in portion. We plan to enlist approximately 4 sites in USA. Clinical trial information: NCT05739981 .

Evaluating generalizability of landmark randomized controlled trials in common metastatic cancers using machine learning-based emulated trials.

e13618 Background: Randomized controlled trial (RCT) results often lack generalizability to real-world oncology patients (pts). We present TrialTranslator, a machine learning (ML) framework to evaluate the generalizability of Phase III oncology RCTs by emulating trials across prognostic risk groups. Methods: TrialTranslator was applied to 11 landmark RCTs encompassing the most prevalent advanced cancers – non-small cell lung (aNSCLC), breast (mBC), prostate (mPC), and colorectal (mCRC). Flatiron Health’s EHR-derived de-identified database was used for model development and trial emulation. In Stage I, ML models (gradient boosted [GBM], random forest, support vector machine and penalized Cox) were trained to predict survival from time of metastatic diagnosis. Models used 130 longitudinal demographic, cancer-related, lab, and biomarker features. In Stage II, trial emulation, pts meeting RCT cancer and biomarker eligibility criteria were stratified into low, medium, and high-risk groups based on the top-performing ML model. We used inverse probability of treatment weighted survival analysis for each risk group to compare the median overall survival (mOS) or median progression free survival (mPFS) between experimental and control arms. Results: GBM models achieved the highest time-dependent area under the receiver operating curve (AUC) in the test set in all cancer types. For example, the 1-year AUC for the aNSCLC GBM vs the Lung Cancer Prognostic Index (validated Cox model) was 0.783 vs 0.689. ML-predicted low-risk pts typically had similar mOS or mPFS as RCT populations (Table). In emulated trials for low-risk pts, real-world survival benefit – the absolute difference in mOS or mPFS between experimental and control arms – was similar to RCT results. In contrast, for high-risk pts, survival benefits were not statistically or clinically significant. For example, in the FLAURA trial, RCT mPFS for experimental arm (osimertinib) vs control (gefitinib or erlotinib) was 18.9 mos vs 10.2 months; mPFS was 17.1 vs 10.3 months for low-risk pts and 5.1 vs 4.2 months for high-risk pts. Conclusions: ML frameworks like TrialTranslator may facilitate individual patient-level estimation of real-world treatment benefits of novel oncology agents. TrialTranslator is accessible at trialtranslator.com. [Table: see text]

Use of circulating tumor DNA (ctDNA) to affect the adjuvant or post-adjuvant treatment of patients with stage III and high-risk stage II resected colon cancer: The ERASE-CRC project by GONO.

TPS3644 Background: Three or 6 months of fluoropyrimidines plus oxaliplatin is the standard adjuvant therapy for stage III and high-risk stage II colon cancer, but 20-25% of patients relapse. CtDNA is a promising biomarker of minimal residual disease (MRD) after primary tumor resection and a potential guide in the adjuvant treatment decision-making process. Indeed, ctDNA-positivity after surgery or at the end of adjuvant therapy is associated with higher risk of recurrence. Intensifying the adjuvant and/or the post-adjuvant treatment could be a valuable strategy in these cases. CtDNA clearance has been suggested as a predictor of long-term clinical outcome. Methods: ERASE-CRC is a prospective, open-label, multicentre study, including three phase 2 trials enrolling ctDNA-positive patients with radically resected stage III or high-risk stage II (one major prognostic factor or at least two minor prognostic factors) adenocarcinoma of the colon or intraperitoneal rectum. CtDNA is centrally assessed through a tissue-informed method, F1Tracker. In the phase II ERASE-CRC Part 1 study, patients that are ctDNA-positive after surgery (2-6 weeks) are randomized 1:1 to 6 months of either FOLFOX or CAPOX at investigators’ choice (standard arm) versus FOLFOXIRI (experimental arm). In the phase II single arm ERASE-HER2 study, ctDNA-positive patients with HER2 amplified and RAS wild-type tumors received FOLFOX plus trastuzumab and tucatinib for 12 cycles. In the phase II ERASE-CRC Part 2 study, ctDNA-positive patients after the end of an oxaliplatin-based adjuvant therapy (either in the context or outside ERASE-CRC Part 1 or ERASE-HER2) are randomized 1:2 to observation (standard arm) or trifluridine/tipiracil for 6 cycles (experimental arm). The primary endpoint is the clearance rate of ctDNA after the adjuvant (ERASE-CRC Part 1 and ERASE-HER2) or the post-adjuvant treatment (ERASE-CRC Part 2). 300 patients will be randomized in ERASE-CRC Part 1 to detect a 15% difference in ctDNA clearance rate between the experimental and the standard arm with expected clearance rates of 65% and 50%, respectively, and 1-sided alpha and beta errors of 0.05 and 0.2, respectively. 18 patients will be enrolled in ERASE-HER2 to observe a ctDNA clearance rate of 80% with the targeted treatment ( versus 50% expected), and ctDNA clearance should be observed in 13 cases to consider the strategy promising. Finally, 159 patients will be randomized in ERASE-CRC Part 2 to detect a 15% difference in ctDNA clearance rate between the experimental and the standard arm with 20% and 5% expected clearance rates respectively, and 1-sided alpha and beta errors of 0.05 and 0.2, respectively. Approximately 40 Italian Oncology Units are participating in the study. Currently, 19 and 8 patients have been randomized in ERASE-CRC Part 1 or 2, respectively. NCT05062889. Clinical trial information: NCT05062889 .

Role of celecoxib in reducing cognitive impairment in patients receiving definitive chemoradiation for head and neck carcinoma: A phase II randomized placebo controlled trial (CELCI-HN study).

TPS12150 Background: Head and neck squamous cell carcinoma (HNSCC) is common in the Indian subcontinent and majority (65%) patients present in an advanced stage. Chemotherapy related cognitive impairment (CRCI) is a poorly defined and underestimated phenomenon in the HNSCC population. Through this study, we are attempting to establish evidence of activity of agents targeting neuro-inflammation in reducing or halting cognitive decline associated with definitive chemoradiotherapy for head and neck malignancies without adding to treatment-associated toxicity. This study can potentially aid in developing a cost effective approach with a readily available and cheap agent like celecoxib in improving the quality of life in this cohort of patients. Methods: This is a single center, double blinded placebo controlled phase 2 randomized trial. We intend to randomize 92 non metastatic HNSCC patients registered at a large tertiary cancer center of North India {Department of Medical Oncology (Head and Neck Cancer Clinic, All India Institute of Medical Sciences-National Cancer Institute, India)} planned for definitive chemoradiation (CTRT) with or without induction chemotherapy. Patients in the experimental arm will receive celecoxib 100 mg or matched placebo tablet orally twice a day starting with day 1 of initiation of definitive chemoradiotherapy/induction chemotherapy for a duration of 6 months or until unacceptable toxicity. Our primary objective is to determine the activity of celecoxib versus placebo in reducing cognitive decline in patients undergoing definitive CTRT with or without induction chemotherapy in HNSCC through patient reported outcome tools (FACT cog questionnaire). Secondary objectives include assessment of adverse event profile (measured using CTCAE v5.0), objective assessment of neurocognitive decline using neuropsychological battery of tests, to identify predictors of cognitive decline on the basis of site of malignancy, radiation dose to the base of skull and brainstem, age, comorbidities and educational status. Tertiary objective include evaluation of inflammatory biomarkers e.g serum COX-2, serum Interleukin and tumor necrosis factors-alpha levels at the end of therapy and on follow up. Clinical trial information: CTRI/2022/09/045579.

Statistical fragility of findings from randomized phase 3 trials in pediatric oncology.

e23003 Background: The fragility index (FI) and survival-inferred fragility index (SIFI) have been proposed as adjunctive metrics to facilitate interpretation of p-values in clinical trials. FI/SIFI is the number of patients on a positive (p < 0.05) trial’s experimental arm who would need to switch from “responder/non-event” to “non-responder/event” to cause p > 0.05. Fragility indices have been reported previously in medical oncology, with median values < 10 often seen in the literature. This metric has not been studied in pediatric oncology trials. Methods: PubMed was used to identify randomized phase 3 pediatric oncology trials published between 1980-2020. We report trial characteristics and calculate FI for trials with a binary outcome and SIFI for trials with a time-to-event outcome. We also report the fragility quotients (FQ and SFQ) to normalize FI and SIFI relative to trial size. Results: 113 trials included sufficient data for analysis. The median FI for trials with a binary outcome (n = 40) was 4.5 (range: 1-33). The median SIFI for trials with a time-to-event outcome (n = 73) was 13 (range: 0-61). The FI or SIFI was less than the number of patients lost to follow-up in 25% of 36 trials. Median FQ = 0.026 and SFQ = 0.03, indicating that revised outcome in 2.6% or 3% of trial participants would be sufficient to alter the trial conclusion. FQ and SFQ did not significantly vary according to trial characteristics. While sample sizes increased over time (mean 187, 1980s; mean 437, 2010s), FQ and SFQ remained stable between 2-3%. Conclusions: The statistical conclusions of pediatric oncology phase 3 trials hinge on a relatively small number and proportion of patients. Despite sample size limitations of low prevalence diseases, pediatric cancer trials appear similarly or less fragile than adult oncology trials. Fragility was similar for large versus small trials and remained constant over four decades. [Table: see text]

Characterizing the authorship of phase 3 randomized clinical trials in oncology, 1960-2023.

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

Phase 2 randomized study of rintatolimod following FOLFIRINOX in patients with locally advanced pancreatic adenocarcinoma.

TPS4214 Background: The immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC) is a driver of its lethality and resistance to immunotherapy. Strategies which modulate the immunosuppressive milieu have the potential to improve the anti-tumor response and improve outcomes in patients with PDAC. Rintatolimod is a synthetic double-stranded RNA molecule that activates the toll-like receptor 3 (TLR3) present on dendritic cells, B-cells, natural killer cells and pancreatic epithelial cells. TLR3 stimulation may increase cytotoxic T-cell activity in PDAC through dendritic cell maturation, antigen priming and downstream proliferation of cytotoxic T-cells. Twenty-seven patients were treated with rintatolimod in a single center Named Patient Program at Erasmus University Medical Center in Rotterdam between January 2017 and February 2019. All had locally advanced or metastatic PDAC which had not progressed on FOLFIRINOX (median 8 cycles). Maintenance rintatolimod, administered intravenously twice weekly for up to 18 weeks, was generally well tolerated. The most common toxicities were grade 1-2 myalgia (30%), chills (52%) and fatigue (30%); no toxicities ≥ grade 3 were observed. Progression-free and overall survival (from cycle 1 FOLFIRINOX) were 13 and 19 months. Methods: This is a phase 2 randomized, open-label, multicenter clinical trial. The primary objective is to assess the efficacy of rintatolimod compared to observation in subjects with locally advanced PDAC which has not progressed after FOLFIRINOX. Eligible patients have completed at least 4 months of FOLFIRINOX, have no evidence of progressive disease, have measurable disease by RECIST v1.1, Karnofsky Performance Status ≥80 and have adequate organ function. Subjects with resected PDAC or metastatic disease are not eligible. Subjects are randomized 2:1 to rintatolimod vs. observation. Rintatolimod is administered intravenously twice weekly until disease progression in the experimental arm. Cross-sectional imaging is performed every 8 weeks in both arms. The primary endpoint is progression-free survival, as assessed by the investigator. Secondary endpoints include overall survival, objective response rate, duration of response and safety, as assessed by CTCAE v5.0. Exploratory endpoints include quality of life and changes in immune cell composition and T-cell response in the peripheral blood to characterize the immunomodulatory effects of rintatolimod. The planned sample size is 90 subjects. The final analysis will be performed after 64 events (disease progression or death) have been observed. The study is powered to detect a hazard ratio of 0.47 for median PFS with 80% power and significance level of 5%. Clinical trial information: NCT05494697 .

Adjuvant chemotherapy with mFOLFOXIRI versus mFOLFOX6 in MRD-positive stage II-III colorectal cancer.

TPS3642 Background: About 25% to 30% of resectable high-risk stage II and stage III colon cancers might relapse after radical resection and adjuvant chemotherapy with FOLFOX regimen. Recent studies have underscored the significance of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), representing a residual presence of cancer cells, as a prognostic factor for postoperative recurrence in CRC. Patients exhibiting positive MRD predicted a considerable high risk of recurrence and metastasis, even after adjuvant chemotherapy. In the realm of postoperative adjuvant chemotherapy, Comparing with FOLFOX, whether the early introduction of intensified chemotherapy, mFOLFOXIRI, could further eradicate MRD and improve the long-term prognosis remains unclear. Methods: This multicenter phase III study (NCT05427669) plans to enroll 340 colorectal cancer patients with MRD positive after curative-intent R0 surgical resection, age 18 to 70 years, ECOG performance status 0-1. Patients were randomized (1:1) to receive mFOLFOXIRI (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², and 5-FU 2.4 g/m²over 46 h) or mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU bolus 400 mg/m2 then 2.4 g/m² over 46 h) every two weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. The primary endpoint was 3-year DFS. A gain of 14% in 3-yr DFS is expected (74% in the experimental arm vs. 60% in the control arm; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints included overall survival, 3-year distant metastasis-free survival, QoL and toxicity. Clinical trial information: NCT05427669 .

Metabolic changes due to dexamethasone premedication in patients with breast cancer.

e24127 Background: The treatment for patients diagnosed with breast cancer is based, in the curative intent scenario, on chemotherapy (CT) such as anthracyclines and taxanes. We are aware that some drugs are widely used and necessary before CT administration to avoid unwanted side effects. Dexamethasone is part of the arsenal of these medications, however, pathological conditions resulting from high doses of administration of this corticosteroid are clinically evident in these patients. In this study we aim to evaluate whether omitting a dose of corticosteroid therapy as a premedication after the second week of treatment with taxane can prevent or reduce the incidence of metabolic changes, and its impact on a patient's quality of life (QoL). Methods: A prospective, randomized, open label study. Breast cancer patients with indication for adjuvant or neoadjuvant treatment with doxorubicin, cyclophosphamide and paclitaxel + trastuzumab (AC-T+ TTZ) chemotherapy were randomized to standard arm, with dexamethasone 10 mg IV administered pre-paclitaxel in all cycles and experimental arm, where dexamethasone was omitted from the premedication from the third to the last taxane application. Results: 86 patients were included, 43 patients in each arm. Premedication was administered every cycle and/ or week before the administration of chemotherapy drugs. Patients had lab analysis and QoL EORTC QLQ-C30 before the beginning of the CT, before the third application of Paclitaxel and 24 hours after the last administration. We observed an increase in ACTH in the experimental group, which is predictable since high doses of corticosteroids suppress the hormone pathway; a drop of insulin levels in its levels in the experimental group and stability in its serum levels in the control group; a stability of GH and IGF-1 in the control group and a more pronounced drop in circulating levels of this hormone in the experimental group. The control group had a greater increase in the excretion of aldosterone, probably due water retention caused by the use of dexamethasone. There were no adverse events reported in the experimental group and also hypersensitivity or anaphylactic reactions were not observed. The EORTC-QLQ-C30 scores related to diarrhea, constipation, inappetence and insomnia were better in the experimental group, as well the average score for global health. Conclusions: The omission of dexamethasone in patients in the experimental group improved QOL scores related to common AEs during CT, mainly GI and also insomnia. Insulin levels were also lower in this group. The potential reduction of the incidence of metabolic syndrome seems palusible but would require larger sample size. The short term safety and tolerability of this regimen warrants its use in larger populations. Clinical trial information: NCT04350229 .

Assessment of endocrine therapy adherence in a nurse-led cancer survivorship clinic: Results from the Linking You to Support and Advice (LYSA) trial.

1627 Background: The care of those living with and beyond a cancer diagnosis requires dedicated cancer survivorship services to ensure optimal symptom control and quality of life. Supporting adherence to adjuvant endocrine therapy is also an essential component of care. We examined endocrine therapy adherence rates, and factors associated with non-adherence, in patients with early-stage breast cancer enrolling in a survivorship trial (LYSA). Methods: Women with early-stage hormone positive breast (n=168) cancers within 12 months of completing primary therapy, were enrolled in a randomized control trial with parallel arms (PMID 36357934). Experimental arm had access to nurse-led symptom management, dietetic consultation, and undertook bimonthly electronic patient reported outcome (ePRO). Active comparator group had access to conventional care and ePRO was completed at beginning and end of study. Endocrine therapy adherence was reported as the ability to take medication as prescribed over prior 4 weeks (Michigan Oncology Quality Consortium Adherence Tool), with response quantified as Excellent (adherence close to 100%), Very Good (80%), Good (60%), Fair (40%) and Poor (20%). Adherence Objective (Secondary) was adherence rate at 12 months after study entry in both arms, and factors associated with non-adherence. Results: A total of 148/168 women with breast cancer who completed the LYSA study reported adjuvant endocrine therapy use (74 experimental arm, 74 active comparator) during study conduct. Therapies included aromatase inhibitors (53%), tamoxifen (39%) and ovarian suppression combinations (8%). At study entry ≥ 80% adherence was reported in 74% of overall cohort (75% experimental, 72% comparator, p=0.7), with 1.6% reporting not taking any medication. By end of study (12 months), ≥ 80% adherence was reported in 74% overall (77% experimental, 71% comparator, p=0.4), while non-adherence rates were 2.9%. Among the pre-specified reasons for non-adherence at study end, “simply missing it” ranked highest (10%), and 5% “experienced side effects”. Post-menopausal patients were more likely than pre-menopausal to report excellent (versus sub-excellent) adherence at study end (OR 4.60, 95%CI 1.45 – 16.13, p = 0.012, adjusted for arm, age, and ECOG). Additional exploration of reasons for non-adherence will be presented. Conclusions: Adjuvant endocrine therapy adherence rates in both arms at 12 months after study entry collected via ePRO were good (≥ 90% reporting excellent or very good adherence). Additional factors potentially associated with non-adherence are being analyzed including self-care agency, symptom burden and quality of life. Clinical trial information: NCT05035173 .

Impact of date-based energy bar intake on postprandial appetite, metabolism and thermogenesis

Research studies suggest that date-palm (Phoenix dactylifera L.) fruits provide a superior nutritional and health benefits, compared to other fruits (1). They are rich source of many essential nutrients including carbohydrates, dietary fibre, vitamins, minerals, phytochemicals, and antioxidants. The date palm fruits are produced in many countries around the world and about 10-15% of the total production is lost or sold extremely at low prices (2, 3). Despite these, date fruits have been rarely used as an ingredient in commercially available energy bars. The aim of this study is to investigate the impact of newly formulated date-based energy bar (DBEB) (4) intake on subjective appetite, postprandial metabolism, energy substrate oxidation and diet-induced thermogenesis (DIT).Twenty-seven healthy male adults (mean ± SD, aged 20.8 ± 3.5 years with body weight of 66 ± 8 kg) participated in a randomised crossover design study. Each participant conducted two experimental arms and was investigated prior to (baseline) and for three-hours after consumption of either a date- based energy bar (DBEB) or an isocaloric and macronutrient matched mixed fruit-based energy bar (FBEB) as control arm. The DBEB contained significantly less fructose and glucose, but more sucrose and fibre than FBEB. Both experimental arms involved blood sampling, subjective appetite, and indirect calorimetry measurements. At the end of each experiment, an ad libitum buffet meal was provided. Data analysis used descriptive statistics, paired t-test, and two-way ANOVA.Time-averaged composite appetite and satiety scores were not significantly different between control (FBEB) and DBEB arms. Energy intake during ad libitum buffet was also not different between arms. Metabolic rate measured at baseline and during post-ingestion of the bars were not significantly different between FBEB and DBEB arms (arm effect, P>0.05). Thermic effect of bars calculated as percentage increase in metabolic rate above RMR during whole postprandial duration was (mean ± SE) 9.5 ± 1.6 % in DBEB arm and 8.7 ± 1.3 % in the FBEB arm (arm effect, P>0.05). Rates of carbohydrate and fat oxidation were also not different between the two arms (arm effect, P>0.05) Time-averaged concentrations of blood glucose, insulin and triglycerides were similar between the study arms.The obtained results suggest that energy bars based on dates or mixed fruits produce similar effects on postprandial appetite, fat and carbohydrate oxidation, thermic effect and cardiometabolic risk factors. Date fruits can be used as rich source for carbohydrate and energy. However, future research should investigate the impact of date-based energy bars on antioxidant capacity and other health related markers.

A randomized, multicenter, open-label phase III trial of hyperthermic intraperitoneal chemotherapy in platinum-resistant recurrent ovarian cancer (KOV-HIPEC-02).

TPS5635 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreductive surgery has emerged to achieve a higher concentration of chemotherapeutic agents and treat micro-metastases on peritoneal surfaces. At advanced staged ovarian cancer treated with neoadjuvant chemotherapy, HIPEC during interval cytoreductive surgery with cisplatin 75-100mg/m2 increases progression-free survival and overall survival (OV-HIPEC-01 and KOV-HIPEC-01). In chemotherapy-naïve ovarian cancer patients, survival benefit is not identified with HIPEC (KOV-HIPEC-01). And the meta-analysis revealed the survival benefit after recent exposure of chemotherapy. In ovarian cancer, HIPEC is thought to overcome chemotherapy resistance. Methods: This trial (KOV-02) is currently actively enrolling, a multicenter, open-label, 1:1 randomized, phase III trial that will enroll 140 patients in platinum-resistant recurrent epithelial ovarian cancer. The trial is registered on ClinicalTrials.gov (NCT05316181). Institutional review board approval was obtained. The first patient was enrolled on April 07, 2022. The experimental arm will receive cytoreductive surgery and HIPEC (Doxorubicin 35mg/m2 and mitomycin 15mg/m2, 41.5-42.0°C) followed by physician-choice chemotherapy, and the control arm will receive physician-choice chemotherapy until disease progression or intolerable toxicity. The primary objective of the trial is to evaluate progression-free survival (PFS) between the HIPEC group and the control group. Secondary objectives are overall survival (OS), cancer-specific survival, safety, and quality of life. Assuming that the enrollment period is three years and the follow-up period is two years, the total number of events required is 121. Based on the log-rank test, the total number of subjects required to prove HR 0.6 with a two-sided alpha of 0.05 and 80% power is 126. Considering 10% drop-out, 140 patients are finally studied. Clinical trial information: NCT05316181 .

Beta-glucan intake with energy and carbohydrate restricted meals: impact on subjective appetite and gastrointestinal appetite hormones in overweight adults

Energy restriction is commonly used as body weight-loss interventions (1). However, it modifies secretion of gastrointestinal appetite hormones, which might be expected to upregulate appetite and thus impair the ability to comply with prescribed intervention(1). Supplementation with soluble fibre may potentially counteract this matter (2). This study aimed to investigate whether addition of β- glucan to energy and carbohydrate-restricted meals impacts postprandial responses of gastrointestinal appetite hormones and subjective appetite in overweight adults.Twenty-three sedentary individuals living with overweight or obesity (age: 36 ± 8.5 years, BMI: 31.12 ± 4.04 kg/m2) participated in a double-blind randomised crossover study with two experimental arms, each lasting over two days. On day 1, participants consumed Counterweight PRO800 meal replacement shakes/soups for breakfast and dinner at home, each providing ~200 kcal and a carbohydrate-restricted lunch providing 35% of their habitual energy intake. On day 2, participants attended the metabolic investigation room where they consumed the same breakfast and lunch as on day 1. On both days, each meal was taken with either 3g β-glucan (Oat Well) or cellulose (Comprecel) as placebo. On Day 2, fasting and postprandial appetite scores were recorded, and fasting and postprandial blood samples were obtained for the measurements of plasma concentration of acylated ghrelin, PYY, and GLP-1. The study is registered at www.clinicaltrials.gov as NCT05981404.Two-way ANOVA showed that the postprandial concentrations of acylated ghrelin (β-glucan arm, 383 ± 23 pg/ml; placebo arm, 428 ± 23 pg/ml, P=0.02, treatment effect) and composite appetite scores (P=0.003, treatment effect) were significantly lower and PYY concentrations (β-glucan arm, 132 ± 5 pg/ml; Placebo arm, 110 ± 4 pg/ml, P= 0.003, treatment effect) significantly higher in the β- glucan arm than in the Placebo arm. The concentrations of GLP-1 were not different between arms (β-glucan arm, 29 ± 1 pM; placebo arm, 28 ± 0.9 pM, P=0.36, treatment effect).The obtained data suggests that consuming β -glucan with energy and carbohydrate-restricted meals can be expected to attenuate reduction in satiety and diminish increase in hunger. Therefore, supplementation with β-glucan during energy restriction intervention applied to body weight loss might lead to improve compliance and reduce discomfort of negative energy balance.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .

Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in patients (Pts) with relapsed small cell lung cancer (SCLC): Results from a phase 2 expansion cohort.

8094 Background: LUR has been approved in the US and elsewhere for treatment of adult pts with metastatic SCLC and disease progression on or after platinum-based chemotherapy. Preclinical studies found synergy for LUR with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The phase 1b part defined the recommended dose at LUR 2.0 mg/m2 on Day (D)1 + IRI 75 mg/m2 on D1,D8 every three weeks with primary G-CSF prophylaxis, and found promising results for the combination in SCLC pts after first-line therapy (Ponce Aix S. Ann Oncol 2019; 30: Abst 471P). Methods: Eligibility criteria for this cohort of the phase 2 part of this study included: confirmed SCLC, progression after one platinum-containing regimen, controlled brain metastases and ECOG PS ≤ 1. The primary endpoint was overall response rate (ORR). Results: 101 evaluable pts were enrolled. Baseline characteristics included: median age 63 (range, 45-77 y), 60.4% males, 76.2% ECOG PS 1, 28.7% CNS involvement, 39.6% bulky disease and 41.6% pretreated with immunotherapy. Chemotherapy-free interval (CTFI) was <90 d in 51.4% of pts (26.7% had CTFI<30 d. Median CTFI was 85 d (range, 0-323 d). Median number of cycles per pt was 6 (range, 1-34); 25.7% received >10 cycles. Efficacy results by independent review committee are summarized in the table. Treatment-related adverse events (AEs) were observed in 99.0% of pts (grade ≥3 in 69.3%). Most relevant grade ≥3 events/abnormalities were neutropenia (52.5%), anemia (27.7%), diarrhea (19.8%), fatigue (18.8%), and febrile neutropenia (9.9%). Treatment-related SAEs occurred in 25.0% of pts and 5.0% discontinued due to treatment-related AEs. No treatment-related deaths occurred. Conclusions: The LUR/IRI combination showed promising antitumor activity and a manageable safety profile in these pts with poor prognosis, particularly those with CTFI>30 d. These encouraging results reinforce the rationale for including this combination as an experimental arm in the ongoing pivotal phase 3 LAGOON trial (NCT05153239) in relapsed SCLC with CTFI>30 d. Clinical trial information: NCT02611024 . [Table: see text]

A randomized phase II trial of atezolizumab with or without tiragolumab before and after definitive chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC; AFT-57).

TPS8123 Background: A minority of patients with unresectable stage III non-small cell lung cancer (NSCLC) may be cured by chemoradiotherapy (CRT). Adjuvant checkpoint inhibition through PD-L1 blockade after CRT improved survival compared to placebo in the PACIFIC trial (median progression-free survival (mPFS) 16.9 vs 5.6 months (mo), median overall survival (mOS) 47.5 vs 29.1 mo), but overall survival at 5 years remains below 50% (Spigel D, et al J Clin Oncol 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015199/ . Only patients completing CRT without progression and with good performance status were eligible for this approach. Neoadjuvant checkpoint inhibition would allow more patients the opportunity to benefit from immunotherapy and may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells, thereby improving tumor immunogenicity. Neoadjuvant atezolizumab had favorable outcomes compared to historic PACIFIC data in the phase II single arm trial, AFT-16 (mPFS 30 mo and mOS not reached). Whether combination immunotherapy therapy before CRT will improve outcomes in this setting is the question posed in the AFT-57 trial. Methods: This phase II randomized Alliance Foundation Trials study (AFT-57) will evaluate safety and efficacy of atezolizumab with or without the anti-TIGIT monoclonal antibody, tiragolumab, before and after definitive CRT with concurrent atezolizumab. The primary endpoint is PFS in the two experimental arms with a goal to select the most promising regimen for further study. AFT-57 will randomly assign 158 patients with stage III NSCLC (AJCC v8), Eastern Cooperative Oncology Group performance status 0-1, no active autoimmune disease and no underlying organ dysfunction to 2 cycles of neoadjuvant atezolizumab (1200 mg intravenously [IV] every 21 days) with or without tiragolumab (600 mg IV). Non-progressing patients will receive carboplatin and paclitaxel weekly with atezolizumab 1200 mg IV every 21 days concurrent with 60 Gray involved field thoracic radiation in 30 daily fractions (Monday - Friday) followed by atezolizumab with or without tiragolumab on the same schedule as the neoadjuvant doses, with a plan to complete one year of therapy. A pilot cohort of 20 patients for whom tiragolumab will be combined with atezolizumab during chemoradiotherapy is planned toward the end of accrual. Correlative science includes tissue and blood-based immune-related biomarkers at baseline and during therapy. This trial utilizes the Alliance Participant Engagement Portal, a patient-facing site designed to provide information and resources to Alliance clinical trial participants. The trial was activated on 12/7/23 with the first patient screened 1/19/24. Clinical trial information: NCT05798663 .

Estimating benefit from dose dense adjuvant chemotherapy for early breast cancer in the PANTHER randomized phase 3 trial.

521 Background: Adjuvant dose dense chemotherapy for early breast cancer improves patient outcomes across all subgroups compared with standard interval treatment. However, the effect of dose dense treatment based on individual patient risk and over time, and the performance of the PREDICT model at this setting are not well-studied. Methods: This is an exploratory analysis from the phase 3 PANTHER trial (NCT00798070) that compared adjuvant sequential epirubicin/cyclophosphamide (EC) and docetaxel (D) administered in either tailored dose dense (tDD EC/D, every 2 weeks) or standard interval schedule (FEC/D, every 3 weeks) to patients with high-risk resected early breast cancer. Dose tailoring in the experimental arm was performed according to a predefined algorithm based on hematologic and non-hematologic toxicity. We evaluated the performance of PREDICT in terms of calibration and discrimination in the entire cohort and subgroups of interest, conducted a subpopulation treatment effect pattern plot (STEPP) analysis and observed the relative treatment effect over time. Results: The intention-to-treat population consists of n=2003 randomized patients. Median follow-up was 10.3 years (interquartile range, 9.1 – 10.5 years). PREDICT consistently underestimated 5-year (absolute difference 1.4%) and 10-year overall survival (absolute difference 6.6%) in the entire population and across all subgroups, but mostly so in the highest risk patients where the difference between observed and predicted 10-year survival reached 20.4% for patients with tumors larger than 5 cm. Discriminatory accuracy was lower for 10-year than for 5-year survival (AUC 0.728 and 0.786, respectively), although the difference in model performance between the two treatment groups was small. In STEPP analysis, absolute benefit from tDD EC/D in the primary endpoint of breast cancer relapse free survival was stable across risk-defined overlapping subpopulations and ranged from 3.8% in the lowest risk patients to 3.6% in the highest risk ones. There was no evidence of differential treatment effect through time (pinteraction >0.1 for all time-to-event endpoints). Conclusions: In this largely node-positive population, PREDICT consistently overestimated risk for death in all patient subgroups. We could not reliably identify any subgroup not benefiting from dose dense treatment, which should be the standard of care for primary resected high-risk breast cancer. Clinical trial information: NCT00798070 .