Adverse Events Criteria Research Articles

Patient-reported fatigue and risk of treatment-related adverse events (AEs) in patients receiving systemic therapy in cancer clinical trials.

11015 Background: Fatigue in patients with cancer is common and negatively impacts quality of life. Patient-reported outcomes (PROs) assess a patient’s direct report of their symptoms and well-being; research has highlighted their potential to predict cancer outcomes. We examined whether fatigue prior to treatment was associated with AEs. Methods: We analyzed 18 phase II and III cancer treatment clinical trials with baseline fatigue data conducted by SWOG between 1988-2018. The Common Terminology Criteria for Adverse Events was used. Symptomatic AEs were defined as those aligned with the NCI’s PRO-CTCAE; laboratory-based or measurable AEs were designated as objective (hematologic v nonhematologic). Thirteen symptomatic and 14 objective AE categories were examined. Fatigue was derived from multiple scales (e.g., FACT, EORTC QLQ-C30 and PROMIS-Fatigue 7a). Each measure was mapped to a 5-point Likert scale. Binary categories were compared (e.g., < some vs. > = some fatigue). Generalized estimating equations were used with a binomial distribution and logit link, adjusting for age, sex, race, and BMI, with clustering by study. Results: We examined N = 8,040 patients receiving systemic therapy. Among 18 trials (prostate, 5; lung, 3; colorectal, 2; lymphoma, 2; breast, 2; bladder, 1; melanoma, 1; ovarian, 1, pancreas, 1), n = 108,059 AEs were examined. Patient fatigue was present at levels of “a little” or greater in 75.8%, “some” or greater in 42.8%, and “quite a lot” or “very much” in 17.7%. Patients with some or greater fatigue were nearly twice as likely to have severe or worse toxicity (OR = 1.92, 95% CI, 1.53-2.40, p < .001) or life-threatening toxicity (OR = 1.93, 95% CI, 1.44-2.59, p < .001) and nearly threefold more likely to have fatal toxicity (OR = 2.76, 95% CI, 1.37-5.53, p = .004). Similar patterns were seen at a threshold of “quite a lot”. A dose response pattern was evident; patients reporting quite a lot/very much compared to no fatigue were > 5 times more likely to experience fatal toxicity (OR = 5.63, p = .002). These patterns were consistent in symptomatic, objective hematologic, and objective non-hematologic AEs. Conclusions: Baseline fatigue was highly predictive of subsequent risk of AEs. These findings suggest that in an era of precision medicine, patient-reported fatigue may be an important component of determining toxicity risk and could aid in treatment decision making.[Table: see text]

Association between heavy metal concentrations and chemotherapy-related acute adverse events in the patients with nasopharyngeal carcinoma: A prospective, longitudinal, observational study.

e18045 Background: Chronic exposure to heavy metals may cause chronic burden on liver, kidney, bone marrow and other organs. To determine whether the accumulation of heavy metals prior to treatment was related to the occurrence of acute adverse events in patients with nasopharyngeal carcinoma (NPC) receiving platinum-based chemotherapy, we conducted a single-center, prospective, longitudinal study. Methods: The heavy metal concentrations of pretreatment whole blood samples and the pretreatment and posttreatment morning urine samples for 140 NPC patients were measured, which were classified into low and high levels based on the 75% quartile. The highest grades of acute adverse events for every cycle of platinum-based chemotherapy were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03). Wilcoxon rank-sum test was used to compare the difference in the distribution of acute adverse events between two levels. To illustrate the potential relationship of metal between in blood and urine, the spearman’s correlation coefficient of metal concentration in blood and urine adjusted by creatinine was calculated. The kendal's correlation coefficients were calculated to characterize the correlation between heavy metal levels and acute adverse events. Finally, the study developed multivariable adjusted logistic regression models to calculate odds ratios (OR) and 95% CIs of the association between various heavy metals and risk of chemotherapy-related acute adverse events, respectively. Results: The study enrolled 140 patients with stage II (n=2, 1.4%), III (n=76, 54.3%), and IVa (n=62, 44.3%) NPC. A total of 13 heavy metals of both blood and urine samples were measured, with Cd, Pb, Hg, As, Pt, Mg, Ca, Cr, Co, Ni, Cu, Zn, and Se included. The concentrations of the same metals in blood and urine (including Cd, Pb, Hg, As, Pt, Co and Se) had a moderate correlation (0.2 < correlation coefficient < 0.7). High level patients were prone to experiencing acute adverse events ( p<0.05). In multivariable adjusted logistic regression, patients with impaired liver function had higher BCd (Cd in blood) level (OR, 3.65; 95% CI, 1.38–9.64; p=0.009). Patients with thrombocytopenia had higher UCr (Cr in urine) level (OR, 5.63; 95% CI, 1.60–19.87; p=0.007). And UPb (OR, 3.16; 95% CI, 1.26–7.92; p=0. 014) and UZn (OR, 2.69; 95% CI, 1.10–6.59; p=0. 030) were found significantly higher in patients with abnormal blood glucose. Conclusions: NPC patients with chronic accumulation of BCd had tendency to have impaired liver function when receiving platinum-based chemotherapy. Similar correlations were also observed in the thrombocytopenia with UCr, and the abnormal blood glucose with UPb and UZn.

PRE-ISPY phase I/Ib oncology platform program (PRE-I-SPY-P1).

e12641 Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .

Patient-reported treatment-related symptoms and use of the PRO-CTCAE for multiple myeloma clinical trials: A qualitative interview study.

e19516 Background: Therapeutic regimens for multiple myeloma (MM) involve multiple pharmacological agents, including steroids. Many cause treatment-related symptoms that add to patient burden or may trigger treatment cessation. This study gathered qualitative data about the patient experience with MM treatments, including regimens with steroids. Findings were summarized and compared to the Patient Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), to assess its comprehensiveness and relevance in MM clinical trials. Methods: Individual, semi-structured interviews were conducted virtually with a diverse sample of 16 US-based, English-speaking adults (38% male, 25% Black, 13% Hispanic) to explore their experiences with MM and treatments, including perspectives on steroids and potential benefits of steroid-sparing regimens. Content analysis was used to summarize and compare terminology participants used to describe their experiences with treatments. Results: Participants reported a diverse set of treatment-related symptoms impacting their overall experience, indicating the importance of assessing regimen tolerability in clinical trials. Steroids were linked to increased energy that interfered with sleep or functioning, irritability, taste changes, weight gain, increased appetite, and cognitive symptoms like brain fog. Participants reported that most symptoms were tolerable, but they would prefer to avoid steroids if treatment benefits did not diminish. Many reported symptoms were included in the PRO-CTCAE items (see Table), but several symptoms related to regimens with steroids are not covered: excess energy, bitter/metallic taste, taste sensitivity, brittle nails, irritability, hunger/increased appetite, and muscle weakness. Conclusions: MM patients experience a range of treatment-related symptoms, many of which impact their quality of life. If given the option, patients would prefer a steroid-free regimen if there was proven clinical benefit. While the PRO-CTCAE covers most of the treatment-related symptoms, proving to be an option for multiple myeloma clinical trials, additional PRO instruments may be needed to cover specific gaps in the PRO-CTCAE item library content coverage. [Table: see text]

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .

Analysis of glycemia during olaparib therapy in patients with ovarian cancer.

e17559 Background: Olaparib (poly(ADP-ribose) polymerase inhibitor) is a relatively new anticancer drug and some of its metabolic side effects, such as its effect on blood glucose, are not yet well defined. The aim of the study was a retrospective analysis to investigate olaparib-induced changes in glucose levels in patients with ovarian cancer (OC). Methods: The study was conducted on 32 OC patients with normoglycemia (3.9–5.5 mmol/l) confirmed before olaparib treatment. The fasting glucose (FG) levels were estimated after I (one month), II (two months), and III (three months) courses of olaparib treatment. The severity of hyperglycemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Results: During treatment with olaparib, grade 1 hyperglycemia was found in 18 patients (56.2%), therefore hemoglobin A1C level measurement was recommended. The number of patients with impaired fasting glucose (5.6–6.9 mmol/l), characteristic of a pre-diabetic state, was 17 (53.1%), while glycemia indicative of diabetes (≥7.0 mmol/l) were found in 1 patient (3.1%). The statistically significant increase in glycemia was observed after I course of treatment (p< 0.0001), then after the second (p=0.0003), and III course (p=0.0025). Conclusions: During olaparib therapy, hyperglycemia was observed in 56.2% of the analyzed OC patients, implying the need for glycemic monitoring during monthly routine check-ups to implement effective behavioral and therapeutic management.

Pilot evaluation of portable scalp cooling for chemotherapy-associated alopecia in early-stage breast cancer.

12141 Background: Chemotherapy-induced alopecia significantly impacts quality of life (QOL). First-generation scalp cooling systems PAXMAN and Dignicap, while effective in reducing alopecia, are not universally adopted due to their lack of portability. Amma is a second-generation, portable and battery-powered scalp cooling system that offers the opportunity for widespread clinical usage by allowing self-administration and mobility. Here, we report first-in-human outcomes of Amma in a preliminary cohort receiving curative-intent taxane-based chemotherapy for early-stage breast cancer. Methods: We conducted a pilot clinical trial (NCT05508984) of the Amma system at Providence Cancer Institute in Oregon. Key inclusion criteria included: no baseline alopecia [Dean’s scale 0], intent to receive 4-6 cycles of taxane-based, anthracycline-sparing therapy, willingness to participate in quality-of-life questionnaires, and serial scalp photography. The primary outcome was the feasibility of Amma devices for adoption within the clinic ascertained by patient reported outcomes (PRO) and provider feedback. The secondary outcome was efficacy defined as the proportion of subjects achieving < 50% hair loss [Dean’s scale 0-2] at 30 days post-treatment, and tolerability assessed by common terminology criteria for adverse events (CTCAE). Results: 14 participants were enrolled and evaluable from 9/2022-1/2024. Participants received docetaxel/cyclophosphamide (TC x 4, n=10) or weekly paclitaxel/trastuzumab+/- pertuzumab (TH(P), n=4). 93% of participants (n=13/14) successfully completed treatment. One participant discontinued scalp cooling prematurely. Primary efficacy endpoint of <50% hair loss was achieved in 64% participants (n=9/14, [95% CI: 0.39, 0.89]) (TC: n=5/10; TH(P): n=4/4). On the validated “Was it Worth It?” questionnaire, 92% reported the treatment “worthwhile”, 85% would repeat participation, and 100% would recommend it to others. After treatment, 93% reported a similar or increased QOL with participation and 71% deemed the experience “better than expected”, paralleling PRO outcomes from previously published trials using first-generation cooling devices. Provider feedback was favorable regarding feasibility of treatment. Conclusions: Scalp cooling with the portable Amma system was both feasible and effective in this pilot study. Point estimates of efficacy were like those reported for PAXMAN (Dean’s 0-2: 50%) and DigniCap (66%). A follow-up clinical trial is planned with a primary outcome of efficacy in patients receiving taxane-based chemotherapy (NCT06215469, PI: Rugo). Clinical trial information: NCT05508984 .

A phase IIA clinical trial to evaluate a reversible Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

e19042 Background: This clinical study is to evaluate HBW-3220, a novel BTKi with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (approved) and nemtabrutinib (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (enriched in pirtobrutinib resistance), and hematopoietic cell kinase (HCK, a key contributor to BTKi resistance due to kinase-defective BTK). Methods: This phase IIA clinical study is conducted in R/R B-NHL patients who had received two or more prior lines of treatment. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determine whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) are assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment is based on iwCLL 2018 guidelines for chronic lymphocytic leukemia (CLL), IWWM-7 consensus for Waldenstrom macroglobulinemia (WM), and Lugano 2014 guidelines for all other lymphomas, including small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL). Results: 29 patients have been enrolled, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (36%), diarrhea (32%), headache (18%), anemia (39%), infectious pneumonia (18%), decreased neutrophils count (39%), decreased platelet count (29%), increased alanine aminotransferase (21%), etc. Drug-related Grade 3 AEs included decreased neutrophil count (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 23 patients underwent at least 1 response assessment. The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 4 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 83% (5/6), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR, 90% (9/10) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated with no DLT occurred at daily doses up to 150 mg, displaying most promising efficacy in patients with CLL/SLL, MZL, and MCL. Clinical trial information: ChiCTR2200062537.

Preventing chemotherapy-induced peripheral neuropathy with acupuncture, a multinational parallel randomized controlled trials project (PACT).

TPS12156 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant challenge for patients (pts) with breast cancer treated with taxanes and platinum compounds. CIPN severely affects quality of life, leading to paresthesia and pain, and often results in dose modifications and discontinuation of treatment. Although preliminary trials suggest the effectiveness of acupuncture in managing existing symptoms of CIPN, the use of acupuncture to prevent CIPN is not well studied. Prior studies provide inconclusive results, underscoring the need for more rigorous investigation. We designed an international study, PACT, to evaluate the impact of acupuncture on the prevention of CIPN in breast cancer pts who undergo adjuvant or neoadjuvant taxane-based chemotherapy. Methods: PACT is a coordinated multi-national study consisting of three parallel randomized trials in USA, China, and South Korea, using the same inclusion/exclusion criteria, randomization, interventions, and validated measures. PACT is designed to evaluate the effectiveness of acupuncture in preventing CIPN in pts undergoing taxane-based chemotherapy for early-stage breast cancer. Participants include pts with newly diagnosed stage I-III breast cancer without preexisting neuropathy, scheduled for adjuvant or neoadjuvant taxane-based chemotherapy. Target enrollment is 140 pts from three sites: Dana-Farber Cancer Institute (USA) (n=100), Jiangsu Province Hospital of Chinese Medicine (China) (n = 20) and the Daegu Catholic University Medical Center (South Korea) (n=20), randomized (1:1) to the acupuncture arm or a control. The acupuncture arm receives a standardized protocol of 1-2 sessions per week for 12 weeks (total of 14 sessions). The control arm receives relaxation exercises with nature scenery videos for 14 sessions. The follow-up period for both arms is 12 weeks. Main measures include The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20, QLQ-30 and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) CIPN items. The primary outcome measure is the change in CIPN severity, assessed using the EORTC QLQ-CIPN20 sensory subscale, between baseline and week 12, with secondary outcomes including occurrence of CIPN and maximum CIPN scores, pain, sleep quality, and overall quality of life. A planned pooled analysis of individual patient data will be performed. The ethics review committee of each site has approved the study. Today, 89 (64%) of the planned 140 participants have been enrolled. Clinical trial information: NCT05528263 , ChiCTR2200066714, KCT0008470.

Prostate-specific membrane antigen PET/CT-guided, metastasis-directed radiotherapy for oligometastatic castration-resistant prostate cancer.

e17057 Background: Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), chemotherapy, and radiopharmaceutical therapy, all of which have associated toxicity. We hypothesized that prostate-specific membrane antigen (PSMA) PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastatic sites. Methods: We retrospectively screened 7 prospective databases of PSMA PET/CT scans conducted between 1/2016-2/2023 for patients with mCRPC who had ≤5 sites of oligorecurrent or oligoprogressive disease and received metastasis-directed radiotherapy to all sites of disease. Castration resistance was defined as either radiographic progression or biochemical progression (two consecutive prostate-specific antigen [PSA] increases ≥3 weeks apart) while on ADT with serum testosterone <50 ng/dL. Progression-free survival (PFS), freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Progression was defined as the first instance of biochemical progression (PSA increase of 25% and 2 ng/mL above nadir, confirmed by repeat measurement ≥3 weeks later), radiographic progression, biopsy-proven recurrence, new systemic or local therapy, or death. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 5. Results: Twenty-six patients met inclusion criteria with a median follow-up of 34.6 months (interquartile range, 28.1-47.2 months). All patients previously received ADT, 20 (77%) received ARPIs, and 3 (12%) had prior chemotherapy. Median PSA was 1.2 ng/mL, median time from initial diagnosis was 6.2 years, and median time from castration resistance was 1.8 years. Between 10/2017-4/2023, 12 patients (46.2%) had one treated metastatic site, 11 patients (42.3%) had two, and 3 patients (11.5%) had three. Twenty-four patients (92.3%) received concurrent systemic therapy. Median PFS was 16.4 months (95% confidence interval [CI], 11.4-21.4 months). Four-year PFS was 26.7% (95% CI, 8.9-44.5%). Median time to initiation of a new line of systemic therapy was 18.0 months (95% CI, 0-36.2 months). Four-year freedom from new lines of systemic therapy was 36.1% (95% CI, 15.5-56.7%). Median OS was not reached. Four-year OS was 72.5% (95% CI, 51.1-93.9%). Grade 2 and ≥3 toxicity rates were 3.8% and 0%, respectively. Conclusions: For patients with oligometastatic CRPC, PSMA PET/CT-guided metastasis-directed radiotherapy appears to offer durable disease control with low toxicity. Further prospective studies are needed to compare PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Initial results from phase I trial of a novel oncolytic adenovirus Ad-TD-nsIL12 in recurrent glioblastoma connecting to ventricular system.

2057 Background: Glioma is the most common primary central nervous system malignancy in adults, of which glioblastoma (GBM) accounts for more than 50% of the incidence and is the most aggressive subtype of glioma, with a median survival of about 15 months. Oncolytic virus emerges as a promising therapy for recurrent GBM (rGBM), but its safety and efficacy are not evaluated in patients with rGBM connecting to ventricular system. Methods: This is a dose-escalating trial to study the safety and efficacy of Ad-TD-nsIL12, a novel oncolytic adenovirus, in patients with rGBM connecting to the ventricular system. The assigned dose levels of Ad-TD-nsIL12 were 5x109vp, 1x1010vp, and 5x1010vp. Adverse events (AEs) associated with the virus were graded using the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0), and Grade ≥ 3 AEs identified the dose-limiting toxicity (DLT). Tumor response was evaluated based on the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Eight patients, aged from 45 to 71 years, were enrolled between December 2019 and September 2022, with treatment doses ranging from 5x109 to 5x1010vp. Grade 3 seizure according to CTCAE occurred in two patients from Cohort 3 (5x1010vp) after AD-TD-nsIL12 injection. Minimal adverse events were observed at a treatment dose of 1x1010 vp, even after multiple injections. Complete response (CR) was demonstrated in one patient, partial response (PR) in one patient, stable disease (SD) in four patients and progressive disease (PD) in two patients. Immunohistochemical staining showed higher infiltrations of CD3+, CD4+ and CD8+ T cells and positivity of E1A and Hexon in virus post-treated tissues. Inflammation associated cytokines in the blood were not significantly elevated by Ad-TD-nsIL12. Conclusions: AD-TD-nsIL12 treatment was safe and effective in patients with rGBM and warrants examination in a phase II clinical study. Clinical trial information: ChiCTR2000032402.

Patient-reported symptom interference with activity- and mood-related functioning prior to start of an early-phase oncology combination trial including immune checkpoint blockade.

12084 Background: We examined symptom interference with activity- and mood-related functioning at baseline in early-stage trials of combination treatments that included at least one immune checkpoint inhibitor, and its association with quality of life (QOL)-, clinical-, and trial-related factors. Methods: Patients scheduled to begin an early-phase trial of a combination treatment with immune checkpoint blockade, and who had not received trial-related treatment were recruited into a prospective longitudinal study design (NCI R01CA242565), and completed the following validated patient-reported outcome (PRO) measures prior to trial start: MD Anderson Symptom Inventory- Immunotherapy (score range: 0-10, higher scores = worse symptom interference); NCI’s PRO Common Terminology Criteria for Adverse Events (0-4, higher = worse severity); EuroQoL-5 dimensions assessing health status (0-100, higher = better health) and problems with self-care, and the Sloan Global QOL scale (0-10, higher = better QOL). Statistical tests included Spearman’s correlation rho (r) and multivariable linear regression. Results: 977 baseline PRO measures were completed by 247 patients (median age = 59 y; 46% female). Worst symptom-related interference was with activity (3.0 on a 0-10 scale), work (2.9), and enjoyment of life (2.4). Composite score means were 2.8 for symptom interference with walking, activity, and work (WAW; activity-related functioning), and 2.1 for interference with relationships, enjoyment of life, and mood (REM; mood-related functioning). Symptoms most associated with worse WAW were fatigue (P<0.001) and appetite loss (P=0.001). Worse WAW was linked to worse REM (r=0.78, P<0.001). Diminished sexual interest/mood (DSI) was associated with worse WAW (r=0.35, P<0.001) and REM (r=0.33, P<0.001). Worse WAW was linked to shorter trial duration (P=0.003) and worse response (progression of disease/immune-related progression) on the clinical trial (P=0.05). Conclusions: This first, comprehensive and prospective examination of symptom interference with functioning at trial baseline found that worse symptom interference was linked to worse QOL, poorer clinical outcomes, and shorter trial duration. These findings suggest that baseline patient-reported symptom interference with functioning can serve as a potential biomarker of poor prognosis in investigational trials, and that trial patients may benefit from initiation of supportive care prior to trial start. [Table: see text]

COPD comorbidity and checkpoint inhibitor pneumonitis in a case-control study of patients with lung cancer.

e14700 Background: Checkpoint inhibitor pneumonitis (CIP) is the most common high-grade immune-related adverse event among patients with lung cancer. Risk factors for CIP include interstitial lung disease, fibrosis on pre-treatment CT imaging, and likely COPD. This study aims to compare COPD variables and CIP outcomes between cases of high and low-grade CIP, and controls without CIP. We hypothesized that the presence and severity of COPD would affect the evaluation, management, and outcomes of CIP. Methods: From a database of patients with lung cancer who received at least one dose of an immune checkpoint inhibitor between 2/1/11 and 4/7/22 at a comprehensive cancer center, we identified all CIP cases and randomly selected a larger number of controls without CIP. The study team reviewed routine clinical documentation and collected data on pre-treatment respiratory function (e.g., comorbidities, spirometry) and CIP outcomes (e.g., diagnostic testing, interventions, severity). Low-grade (grades 1-2) versus high-grade (grades 3-5) CIP were defined by the Common Terminology Criteria for Adverse Events. We tested categorical variables using Chi-squared or Fisher’s exact test depending on assumptions. We compared continuous variables using the Wilcoxon rank sum or the Kruskall-Wallis test. The database was maintained on a secure, cloud-based REDCap database, validated with data quality rules, and with IRB approval. Results: This study compared 84 cases of CIP (including high-grade CIP in 48/84 cases, 57%) with 252 controls. COPD was a commonly documented comorbidity in both groups (60% cases, 53% controls, p 0.28), although not all patients had spirometry (44% cases, 40% controls). Among the cases, CIP diagnosis occurred at a median of 3 months; at that time, 29% of cases were using a scheduled daily inhaled corticosteroid, and 18% continued to smoke tobacco. Between high-grade and low-grade CIP, there was similar COPD prevalence (64% vs. 56%, p 0.51), severity by forced expiratory volume in one second (FEV1) as a predicted percentage (64 ± 21% vs. 62 ± 16%, p 0.81), and diffusing capacity of the lungs for carbon monoxide as a predicted percentage (62 ± 19% vs. 61 ± 18%, p 0.82). In terms of CIP outcomes, COPD was not associated with the incidence of hospitalization (26/46, 57%, p 0.76), length of hospitalization (8.4 vs. 7.8 days, p=0.33), intensive care unit utilization (10/21, 48%, p 0.52), or death (5/9, 56%, p 0.94). Cardiac evaluation appeared slightly different among patients with COPD (e.g., more often ordered echo; less often ordered BNP or diuresis), although CIP management was overall similar. Conclusions: The presence or severity of pre-treatment COPD was not associated with differences in the management or outcomes of CIP when it occurred. The cardiac evaluation of CIP may have been different because COPD can decrease the specificity of BNP and be less responsive to diuretics.

Effects of pre-treatment on odds of immune-related adverse events.

2540 Background: For many tumor types, there is an option to start an immune checkpoint inhibitor (ICI) at the time of diagnosis or to sequence ICI after chemotherapies or targeted therapies. The risk of immune-related adverse events (irAE) may vary by the line of therapy. Prior systemic therapies might release cancer epitopes and increase the risk of an irAE through awakened subclinical autoimmunity. Conversely, prior systemic therapies may lead to residual immunosuppression and reduce the risk of irAEs. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. Study personnel reviewed the electronic medical record and defined irAEs according to Common Terminology Criteria for Adverse Events. Research specialists at Vasta Global captured most clinical outcomes. Line of therapy was defined ordinal manner, with four or more combined into a single group due to data sparsity. A multivariable logistic regression model was built to assess effect of line of therapy on any irAE while controlling for confounders identified either a priori or in univariate analysis. Given potential for heterogeneity, interaction between tumor primary and line of therapy was tested. SAS v9.4 was used for all analyses. Results: Among the final cohort of 3,101 patients, 1,169 (38%) were noted to have an irAE of any grade. ICI were used as first-line therapy in 1,432 patients and second-, third-, or at least fourth-line in 1,119, 328, and 222 patients, respectively. The most common tumor type was non-small cell lung cancer (36%), followed by melanoma (14%). At baseline, any-grade irAE were more common among first-line ICI with 618 (43.2%) than for second-line (395, 35.3%), third-line (102, 31.1%), or at least fourth-line (54, 24.3%; p<0.01). After adjusting for age (over 65), sex, smoking history, and body mass index, the model revealed significant heterogeneity, indicated by a significant interaction between the ICI line and the primary tumor type (p=0.01). The impact of the ICI line on the odds ratio (OR) of irAE for each primary calculated: melanoma (OR) 0.54 (95% confidence interval [CI] 0.32-0.93), non-small cell lung cancer OR 1.14 (CI 0.96-1.35), head-neck cancer OR 0.82 (CI 0.58-1.14), and renal cell carcinoma OR 0.78 (CI 0.57-1.06). Conclusions: The effect of pre-treatment with prior systemic therapy was significantly associated with the odds of developing an irAE, though this effect was significantly heterogeneous between tumor primaries. Melanoma was significantly less likely to develop irAE when heavily pre-treated. In contrast, NSCLC suggested a trend of increased odds of irAE with more pre-treatment however it was not statistically significant. Further study is indicated to clarify the types of prior systemic therapy that may modulate the risk of irAE and better clarify the optimal sequencing of ICI.

Correlation between irAEs and treatment efficacy of anti-PD-1 single agent in patients with recurrent/metastatic head and neck squamous cell carcinoma: A monocentric real-world observational study.

6029 Background: Immune-related adverse events (irAEs) are associated with efficacy of ICIs-based treatment in various cancer types. The aim of this retrospective study was to assess the relationship between irAEs and outcomes in patients with recurrent/metastatic Head and Neck squamous cell carcinoma (R/M-HNSCC) treated with immune checkpoint inhibitors (ICIs) monotherapy. Methods: We retrospectively reviewed data from patients with R/M HNSCC treated with ICIs single-agent between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Common Terminology Criteria for Adverse Events v.5.0 was used to assess irAEs evaluation. Patients were stratified into irAEs (any grade) and non-irAEs groups. Overall survival (OS) and progression free survival (PFS) were assessed using the Kaplan-Meier method. Univariate and multivariate Cox-regression were used to compare survival outcomes. The chi-square test was used to assess the association between irAEs and objective responses (ORR). Results: A total of 89 patients were eligible for the analysis. Patients with platinum-refractory disease received nivolumab (64 patients, 72%). All the 25 patients (28%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab as first line treatment for R/M disease. Median follow-up was 8.7 months. IrAEs (any grade) were observed in 60 patients (67%), including 9 patients (10%) with grade ≥3 AEs. The most common irAEs were endocrinopathies (35%), skin events (15%), hepatic events (13%), diarrhea/colitis (10%) and lipase/amylase elevation (10%). The ORR was higher in the irAEs group than in the non-irAEs group (19.5% vs 2%, p=0.017). PFS and OS were also significantly longer in the irAEs group: median PFS was 3.9 months vs 2.1 months (HR 0.48 95% CI 0.30-0.77; p=0.003) and median OS was 12.5 months vs 4.3 months (HR 0.36 95% CI 0.21-0.60; p=0.000). The statistically significant benefit for both PFS and OS was confirmed at the multivariate analysis (Table1). Patients who experienced endocrine-related irAEs (p=0.004), diarrhea/colitis (p=0.040) and lipase/amylase increase (p=0.005) had significantly longer OS than those without the corresponding toxicity. A positive trend was observed for skin toxicity (p=0.051). Conclusions: The occurrence of irAEs was a predictor of response and survival outcomes in patients with R/M HNSCC treated with ICIs single-agent.[Table: see text]

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.

e15132 Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.

Talquetamab (Tal) therapy in relapsed/refractory (R/R) multiple myeloma (MM): Assessing weight loss and dysgeusia.

e19514 Background: Tal, a bispecific antibody targeting CD3 and GPRC5D receptors, has shown high response rates in heavily pretreated R/R MM patients. This study aimed to evaluate adverse events (AEs), specifically dysgeusia and weight loss in MM patients treated with tal. Methods: Patients treated at the University of Arkansas for Medical Sciences who received at least one dose of tal were included. Common Terminology Criteria for Adverse Events (CTCAE) was used to grade AEs. The body mass index (BMI)-adjusted weight loss grading system (WLGS) was used to capture weight loss trends over duration of treatment. Weight loss based on BMI was graded based on the BMI-WLGS. Results: 17 patients were included in our analysis. Nine patients (53%) were male. Ten patients (59%) were African American. Median age at diagnosis was 62 (range: 51-75years). Six patients (35%) had Eastern Cooperative Oncology Group (ECOG) performance status ≥2. The median number of prior lines of therapy was seven (range: 3-12). Fourteen patients (82%) received at least one prior autologous hematopoietic stem cell transplant. The median number of tal doses received was 14.8 (range: 2-29). Median time on treatment (ranging from 1.15 to 15.84) was 4.36 months (range: 1.2-15.8 months). Overall response rate (ORR) for was 76%. Cytokine release syndrome occurred in 12 patients (70.6%), with 5 patients (29.4%) in grade 2 or higher CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) in four patients (23.6%), and 2 patients (11.8%) had grade 2 ICANS. Fourteen patients (82%) developed significant weight loss during treatment with tal. The median weight loss was 11.6 lbs., and median decrease in BMI was 1.85. Median percentage of weight loss was 6.1% from weight prior to tal ranging from 0% to 14.3%. Two patients had grade I, five patients had grade II, six patients had grade III, and one patient had grade IV weight loss per the BMI-WLGS grading system. Fourteen patients (82%) reported dysgeusia during tal treatment. Eight of these patients had grade I dysgeusia, and six patients had grade II dysgeusia. Two patients had persistent dysgeusia even after discontinuation of tal treatment at time of last follow up. Eight patients had weight gain after tal discontinuation (n = 8/14, 57%), with 5 returning to their baseline weight or higher. Six of these patients had dysgeusia during tal, and all six had resolution of dysgeusia after tal discontinuation. Conclusions: In this study, tal resulted in weight loss and dysgeusia in the majority of patients with most cases of dysgeusia resolving after tal discontinuation. Patients, on average, lost 6% of their initial weight during tal treatment. More than two-thirds of patients treated with tal developed BMI-adjusted WLGS grade ≥II. Weight loss persisted in approximately half of the patients after discontinuation of tal. Such AEs need to be discussed with patients and monitored during treatment.

Predictive markers of complete pathological response to neoadjuvant chemo-immunotherapy in triple negative breast cancer.

e12650 Background: Results from the Keynote 522 clinical trial, which played a pivotal role in evaluating the efficacy of neoadjuvant pembrolizumab in combination with chemotherapy (NAICT), showed a significant improvement in pathological complete response (pCR) rates compared with chemotherapy alone. To date, no significant markers have been identified to predict pathological complete response to NAICT. The primary objective was to identify markers, both molecular and clinical, predictive of pCR to NAICT in a real-world clinical setting. Methods: The retrospective analysis included 38 consecutively treated pts with early stage TNBC who received NAICT including pembrolizumab at the Institute of Oncology, Ljubljana (OIL) between 4 January 2022 and 17 October 2023. Data collected from electronic medical records included tumour size, nodal status, UICC stage, BRCA status, systemic immune-inflammation index (SII) before NAICT and before surgery, and frequency and grade of immune-related adverse events (iAEs) (according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5). In pts who completed surgical treatment, response to treatment was assessed by pathological examination of post-treatment surgical specimens. Descriptive statistical methods were used to summarise and describe the main characteristics. Pearson chi-squared test was used to analyse categorical variables and t-test to evaluate associations between continuous variables. Results: Of the 38 pts, 28 completed surgical treatment and were further analysed. Pathohistological examination of post-treatment surgical specimens revealed pCR in 11 pts (39.3%), with residual disease in 17 pts (60.7%). Of the 17 pts without pCR, 11 pts had RCB score 2 (64.7%) and 5 pts had score 3 (29.4%). The distribution of size, nodal status, UICC stage at diagnosis, BRCA status, frequency of iAEs in correlation with pCR is shown in the Table. A borderline correlation was found between pCR and SII at the start of pembrolizumab treatment (p=0.05). Age, tumour size, nodal status, UICC stage, BRCA status, AEs, SII before surgery were not found to be predictive of pCR. Conclusions: SII at the start of pembrolizumab was found to be a borderline significant marker predictive of pCR. Other characteristics evaluated did not correlate with pCR. [Table: see text]

A randomized trial of topical cannabis balms for the treatment of aromatase inhibitor–associated musculoskeletal syndrome (AIMSS).

e24129 Background: Aromatase inhibitors (AIs) are commonly used for postmenopausal women with hormone receptor positive breast cancer. Nearly 2 of 3 women on AIs complain of AIMSS leading to poor adherence. Preclinical and clinical pilot data suggest topical cannabinoids can reduce inflammation in arthritis. Methods: We conducted a randomized controlled trial assessing the feasibility and acceptability of two different topical medical cannabis balms for AIMSS. Women with stage 1-3 breast cancer with AIMSS [scoring 4 or higher on at least one of the four screening Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affectations of the Hands (M-SACRAH) questions] were eligible. Patients with skin lesions, use of any cannabis in prior 4 weeks, acupuncture, or plans to increase doses of other analgesics were excluded. Women were randomized 1:1 to cannabidiol (CBD) (2210mg CBD/ < 0.3% THC) vs delta-9-tetrahydrocannabinol (THC) (375mg THC/ < 20mg CBD) predominant balm. Participants enrolled in the Minnesota Medical Cannabis Program and were dispensed balms at state-registered dispensaries. 125cc of balm was applied 3 times daily to hands for 2 weeks. M-SACRAH, brief pain inventory (BPI), and NCI Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) measures were captured weekly. Results: 20 women were enrolled from one academic and one community oncology practice in Minnesota over a 10-month period. Reasons patients with AIMSS did not enroll included patient/clinician not interested, AIMSS not meeting M-SACRAH severity, and patient already using cannabis. Adherence to study protocol through week 2 was 85%. Mean age was 54 years, 85% White/15% Asian, 45% received adjuvant chemotherapy, and 50% reported no lifetime cannabis use. Participants reported improvement in M-SACRAH, BPI, and PRO-CTCAE pain scores from baseline to week 2 (Table 1). No skin toxicity was reported by patients. One patient discontinued balm due to greasy texture. Conclusions: Conducting a randomized trial of topical cannabis using state approved dispensaries is feasible. Both THC and CBD predominant topical balms are well tolerated and appear to reduce AIMSS severity in this pilot study of breast cancer survivors. Further confirmatory studies are warranted. Clinical trial information: NCT05935891 . [Table: see text]

A phase 2 trial of IO102-IO103 and nivolumab-relatlimab fixed-dose combination in previously untreated, unresectable melanoma.

TPS9605 Background: One emerging strategy to augment immune checkpoint inhibitor efficacy is to eliminate immunosuppressive cell populations in the tumor microenvironment (TME) through vaccination. IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the TME. IO102-IO103 treatment promotes inflammation and potentiates anti-tumor activity via activation and expansion of T cells against IDO1 and/or PD-L1 positive cells. IO102-IO103 plus nivolumab demonstrated an impressive objective response rate (ORR) of 80% in the phase 1/2 MM1636 trial of 30 patients with previously untreated, unresectable melanoma, and a randomized phase 3 trial of pembrolizumab with or without IO102-IO103 (NCT05155254) is ongoing. No prior studies have evaluated IO102-IO103 in combination with dual PD-1 and LAG-3 blockade with nivolumab-relatlimab (nivo-rela), and to our knowledge there are no existing clinical data for other investigational agents in combination with nivo-rela. Methods: NCT05912244 is a single-arm, investigator-initiated trial testing IO102-IO103 in combination with nivo-rela in patients with previously untreated, unresectable melanoma. Twelve of forty-three planned patients have been enrolled. All patients will be treated with nivo-rela every four weeks for up to two years. IO102-IO103 will be administered subcutaneously every two weeks for the initial eight weeks, and then every four weeks for up to two years. An interim efficacy analysis for futility will be performed after response data are available for 21 patients. Eligible patients must have histologically confirmed, unresectable stage III or stage IV non-uveal melanoma, measurable disease by RECIST v1.1, an ECOG performance status of 0 or 1, and definitive treatment of any brain metastases. Prior systemic treatment in the neoadjuvant or adjuvant setting is allowed if completed at least six months prior to trial enrollment. Available pre-treatment melanoma tissue is required, and all patients will undergo an on-treatment study biopsy between the second and third dose of nivo-rela. Peripheral blood mononuclear cells will be collected prior to the first three doses of nivo-rela. The primary endpoint is ORR by RECIST v1.1, weighted by PD-L1 expression. Secondary endpoints include safety assessed by Common Terminology Criteria for Adverse Events v 5.0, progression-free survival (PFS) by RECIST v1.1, duration of disease response, and disease control rate. Exploratory correlative endpoints include assessment of changes in PD-L1 and IDO-expressing cells in the TME on paired tumor biopsies, identification of peripheral PD-L1 and IDO-reactive cells in the peripheral blood by ELISpot, and assessment of peripheral pre-treatment and on-treatment T cell clonality by TCR sequencing. Clinical trial information: NCT05912244 .