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Unconditional (upfront) incentives are proposed to improve acceptance of cancer research among underrepresented, racial/ethnic minority populations, but few studies have tested incentive strategies among rural cancer survivors. Descriptive statistics summarized demographic characteristics of survey respondents, and response rates by arm were compared using Chi-square tests. We compared upfront ($2) and response-based ($10 conditional) incentives in a mailed survey of adult post-treatment rural survivors. Individuals meeting eligibility criteria from the electronic medical record (n = 2,830) were randomized into two incentive arms (n = 1,414 for the upfront arm and n = 1,416 for the contingent arm). Of the total delivered, presumed eligible participants (n = 1,304 upfront arm; n = 1,317 contingent arm), 67.8% were aged 65y+, 49.8% were female, and 95.1% were non-Hispanic white. The response rate for all participants was 18.5%. We received eligible surveys from 281 rural survivors in the first arm (response rate: 21.5%); and 205 surveys in the second arm (response rate: 15.6%). Participants who received the upfront incentive had a higher response rate than those receiving a response-based incentive, X

e14013 Background: Patient portals support self-management, including symptom reporting and control, patient engagement, care coordination, and patient-provider communication, yet not all patients may be deriving the benefits of such digital health tools. Prior studies have not considered how enrollment or use may vary by cancer site, particularly among patients with rare and/or complex diagnoses like malignant brain tumors. Methods: We retrospectively examined portal enrollment and use at an NCI-designated comprehensive cancer center from January 2015 - February 2022 among patients 18+ years old diagnosed with cancer during this time period. We used multivariable logistic regression to generate odds ratios (ORs) for portal enrollment, and Poisson regression to determine incidence rate ratios (IRRs) for number of logins and number of healthcare team interactions (portal messages or appointment requests) by cancer site. Cancer site was categorized using ICD-10-CM codes C00-C96 as brain, breast, colorectal, endocrine, gynecologic, head/neck, leukemia, liver, lung, lymphoma, male genitourinary, melanoma, multiple myeloma, non-melanoma skin, pancreas, soft tissue, upper gastrointestinal (GI), urinary, and other. Regression models controlled for gender, race/ethnicity, relationship status, age, rurality, residential distance from the cancer center, and time since diagnosis. We conducted a subset analysis among patients with a malignant brain tumor diagnosis. Results: We identified 10,365 cancer patients, with 39% enrolled in the patient portal. Enrolled patients had a median of 203.5 total logins and 20 total healthcare team interactions. Enrollment and use significantly varied by cancer type. Patients with lung (OR: 0.24 [0.19 - 0.29]) and liver (OR: 0.27 [0.18 - 0.40]) cancers were the least likely to enroll in the portal. Patients with malignant brain tumors (IRR: 0.74 [0.73 - 0.76]; IRR: 0.57 [0.54 - 0.60]) and upper GI cancer (IRR: 0.64 [0.62 - 0.66]; IRR: 0.46 [0.41 - 0.51]) had the lowest login and interaction rates, respectively. In malignant brain tumors subset analyses, being single (OR: 0.14 [0.04 - 0.53]) or older (OR: 0.94 [0.90 - 0.97]) was significantly associated with lower portal enrollment. Rural residents (IRR: 0.90 [0.86 - 0.94]), divorced (IRR: 0.18 [0.16 - 0.21]) or single patients (IRR: 0.50 [0.47 - 0.52]), and older patients (IRR: 0.98 [0.97 - 0.98]) had lower login rates, while men had higher login rates (IRR: 1.95 [1.88 - 2.01]). Divorced, widowed, and single patients had lower portal interaction rates (IRR: 0.15 [0.08 - 0.26], IRR: 0.47 [0.29 - 0.76], IRR: 0.84 [0.73 - 0.96], respectively), while men had a higher interaction rate (IRR: 2.71 [2.39 - 3.10]). Conclusions: Interventions to support portal enrollment and use among patients with lung, liver, and upper GI cancers and subsets of patients with malignant brain tumors may enhance care quality among these patients with complex diagnoses at high risk for poor outcomes.

6557 Background: Patient portals support patient access, engagement, and care coordination, yet could also widen the digital divide and exacerbate disparities among vulnerable populations. There is emerging evidence that racial/ethnic minority patients are less likely to use portals, yet prior research has not examined potential rural differences. We identified sociodemographic factors associated with portal enrollment and use among a racially and geographically diverse population of cancer patients. Methods: We retrospectively examined portal enrollment and use at an NCI-designated comprehensive cancer center from January 2015 until February 2022 among patients 18+ years old with a neoplastic disease diagnosis (ICD-10-CM C00-D49). Potential predictors included gender, race/ethnicity, marital status, age, rural (Rural-Urban Continuum Codes [RUCC] 4-9) vs nonrural (RUCC 1-3) residence, residential distance from the cancer center, and time since diagnosis. We used multivariable logistic regression to generate odds ratios (ORs) for portal enrollment and having ever sent a portal message, and Poisson regression to determine incidence rate ratios (IRRs) for number of logins and number of healthcare team interactions (portal messages or appointment requests), controlling for ICD-10 diagnosis (SAS 9.4). Results: We identified 11,333 patients (average age 67 years, 59% female, 24% rural, 10% Non-Hispanic Black, 1% Hispanic, 20% non-melanoma skin cancer, 14% breast cancer, 9% lung cancer). 36% of patients had enrolled in the portal, and of these, 80% had sent at least one message. Patients logged in a median of 203.5 times and had a median of 19 portal interactions. Rural residents were less likely to enroll in the portal than urban patients (28% vs 38%, p < 0.0001). Non-Hispanic Black patients and Hispanic/Latinx patients were less likely to enroll in the portal compared with non-Hispanic White patients (22% and 27%, respectively, vs 38.5%, p < 0.0001). Women, younger patients, more recently diagnosed cancer patients, and patients who were married/ partnered were significantly more likely to enroll. In multivariable analysis controlling for cancer type, rural patients were half as likely to enroll in the portal (OR: 0.48 [0.43-0.54]). Among those enrolled, rural residents were 25% less likely to have ever sent a portal message (OR: 0.75 [(0.62-0.92]), and had nearly half the login and interaction rates (IRR: 0.66 [0.66-0.67]; IRR: 0.58 [0.58-0.59], respectively). Patients who were Non-Hispanic Black, Hispanic, or unmarried were also significantly less likely to enroll or engage in the portal. Conclusions: Patient portals remain underutilized among cancer patients, despite an increased reliance on virtual communications in the COVID era. Interventions to support portal engagement among rural residents and racial/ethnic minority patients are needed to avoid potentially exacerbating health disparities.

Summary Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

Background Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (CRS+HIPEC) is a formidable procedure, often affecting the quality of life (QOL) of the caregiver as well as the patient. We explored the impact of quality of life and depressive symptom burdens of CRS+HIPEC caregivers prospectively. Study design Patient and caregiver dyads were both consented per IRB-approved protocol; CRS ± HIPEC was performed. The impact on QOL and depressive symptom burdens was assessed on patient-caregiver dyads via the Caregiver Quality of Life (CG QOL-C), CES-D (Center for Epidemiological Studies – Depression) instruments; pre-CS+HIPEC (T1), postoperative (T2), 6 (T3), and 12 (T4) months. Results Seventy-seven dyads were approached, with 73 participating. Both caregiver and patient depressive symptom trajectories changed significantly. CES-D means for caregivers were (T1-4): 15.1 (SE [standard error] 1.7), 15.0 (1.4), 10.3 (1.4), 13.1 (2.1), p = 0.0008; for patients were: 10.3 (SE 1.1), 13.7 (1.4), 9.0 (1.2), and 10.3 (1.5), p = 0.0002. Preoperatively, caregivers scored 4.8 points (SD 13.4) (p = 0.026) higher than patients. Patients experienced an increase in depression scores at the postoperative visit. At T3, both groups dropped to less concerning levels; yet caregiver CES-D scores increased again at T4 4.7 points (SD 12.5) higher than the patients, and financial well-being became worse from T1 to T3. Possible, probable, and “cases” of depression were higher for caregivers were at all measured time points. Conclusions Significant numbers of caregivers endured high depressive symptom burdens and financial concerns. Different caregiver-patient trajectories reflect the need for differential timing of supportive interventions. Evaluation of quality of life and impact of CRS+HIPEC procedures must move beyond assessment of only the patient.

4635 Background: Glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species, such as nab-paclitaxel. CPI- 613 is a novel antimitochondrial agent developed by Rafael Pharmaceuticals that showed promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggested possible synergy of CPI-613 with nab-paclitaxel. Methods: Single arm, open-label, phase I study of CPI-613 with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer to determine MTD, safety, and preliminary efficacy of CPI-613 in combination with chemotherapy. Key eligibility criteria included: histologically documented and measurable locally-advanced or metastatic, PDAC. ECOG performance status 0-2; and first line systemic treatment. CPI-613 was infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel (100mg/m2) and gemcitabine ( 800 mg/m2) on Days 1, 8, and 15 of a 28-day cycle. The the primary endpoint, the MTD of CPI-613 was determined by a two-stage, dose-escalation schema, with 6-month treatment duration for patients exhibiting treatment response. Secondary endpoints were treatment-related adverse events, complete response (CR) and partial response (PR). Results: From February 2018 to 2020, 26 patients were screened, (23 metastatic and 3 locally advanced), 22 patients enrolled and 18 patients underwent a restaging scan. As of the time of submission 3 patients are still on active treatment. Patient demographics were: median age of 65, ECOG was 0-1, The MTD of CPI- 613 was determined to be 1500 mg/m2. The dose limiting toxicities were not achieved. Overall the treatment was well tolerated with toxicities mainly related to chemotherapy; most common grade 3 and 4 toxicities were hematologic toxicity and neuropathy. 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results demonstrate that CPI 613 can be safely administered with gemcitabine and nab-paclitaxel at doses up to 1,500 m/g2. Efficacy data suggest synergy with chemotherapy. Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Clinical trial information: NCT03435289 .

e15661 Background: Biliary duct carcinoma is a rare but highly fatal malignancy. The five-year survival rate for advanced bile duct cancer is 2%, per SEER data. As such, new treatment options are desperately needed. CPI-613, a novel anticancer agent that selectively inhibits mitochondrial metabolism in cancer cells, was employed in this study. Methods: This phase 1 study utilized a two-stage dose-escalation schema to determine the maximum-tolerated dose (MTD) and safety of single agent CPI-613 in patients with locally advanced or metastatic bile duct cancers. The 1st cohort enrolled 4 patients at 2300 mg/m2, with no dose-limiting toxicities (DLT) observed. The 2nd cohort enrolled patients at 1200 mg/m2/day for pre-cycle (days 1-5) and 3000 mg/m2 on days 1 and 4 weekly for 3 weeks (28 day cycle). The 5th and 6th patient experienced a DLT. The 3rd cohort was initiated at 600 mg/m2 pre-cycle and 3000 mg/m2 weekly with no other DLTs observed. Results: To-date, 14 patients have been enrolled in the study. The MTD was determined at 600 mg/m2/day pre-cycle and 3000 mg/m2 as per schedule. Once the MTD was determined, the cohort was expanded and, 8 patients have been treated at the MTD with no DLTs observed. Two additional patients are planned to be enrolled at this dose prior to trial completion. Of these 8 patients, 3 are still alive with 1 having prolonged survival (15 months) and the other 2 still on treatment. The most commonly observed toxicities were mild, such as anemia, anorexia, dehydration, fatigue, nausea and thrombocytopenia. Conclusions: Treatment with CPI-613 was well tolerated by patients with heavy tumor burden and refractory disease. CPI-613 has recently been shown to be well tolerated in combination with FOLFIRINOX in pancreatic cancer patients. Due to the low toxicity of CPI-613 in this study, even among highly symptomatic patients, it is anticipated that combination with other active agents is feasible in patients with advanced bile duct cancer. CPI-613 represents a novel treatment that could prove to be an exciting therapeutic alternative for patients with previously limited options and poor survival. Clinical trial information: NCT01766219.