Advanced Solid Malignancies Research Articles

6MO Subcutaneous amivantamab administered every 4 weeks (Q4W) in patients with advanced solid malignancies: The phase Ib PALOMA study

6MO Subcutaneous amivantamab administered every 4 weeks (Q4W) in patients with advanced solid malignancies: The phase Ib PALOMA study

Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPα That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies.

Increasing the phagocytotic capabilities of tumor-associated macrophages by modulating macrophage-tumor cell surface signaling via the CD47-SIRPα axis is a novel strategy. Molecules targeting CD47 have potential but its ubiquitous expression necessitates higher therapeutic doses to overcome potential antigen sink effects. The restricted expression pattern of SIRPα may limit toxicities and lower doses of the SIRPα antibody BMS-986351 may overcome target mediated drug disposition while maintaining the desired pharmacology.

A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma.

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .

Beyond traditional therapies: clinical significance of complex molecular profiling in patients with advanced solid tumours-results from a Turkish multi-centre study.

The objective of this multi-centre, real-world study was to examine the potential influence of comprehensive molecular profiling on the development of treatment decisions or adjustments for patients with advanced solid malignancies. We then evaluated the impact of these informed choices on patient treatment outcomes. The study encompassed 234 adult patients (mean age: 52.7±14.3years, 54.7% women) who were diagnosed with solid tumours at 21 different medical centres in Turkey. Remarkably, 67.9% of the patients exhibited metastasis at the time of diagnosis. We utilized an OncoDNA (Gosselies, Belgium) platform (OncoDEEP) integrating next-generation sequencing with additional tests to harvest complex molecular profiling data. The results were analyzed in relation with two specific outcomes: (i) the impact on therapeutic decisions, including formulation or modifications, and (ii) associated treatment response. Out of the 228 patients with final molecular profiling results, 118 (50.4%) had their treatment modified, whilst the remaining 110 (47.0%) did not. The response rates were comparable, with 3.9 versus 3.4% for complete response, 13.6 versus 29.3% for partial response, 66.9 versus 51.7% for progressive disease and 15.5 versus 15.5% for stable disease for treatments informed and not informed by complex molecular profiling, respectively (P=0.16). Our real-world findings highlight the significant impact of complex molecular profiling on the treatment decisions made by oncologists for a substantial portion of patients with advanced solid tumours. Regrettably, no significant advantage was detected in terms of treatment response or disease control rates.

A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers.

129 Background: Myristoylation catalyzed by N-myristoyltransferases (NMT) 1 and 2 regulates membrane-bound signaling important in cancer, including Src and Src-family tyrosine kinases. Zelenirstat is a potent oral small molecule pan-NMT inhibitor. Transcriptomic analysis of zelenirstat treated cell lines identified an expression signature that predicts cancers most likely to be responsive to NMT inhibition; high sensitivity scores were seen in colorectal carcinomas and diffuse large B-cell lymphoma. The objectives of this phase I study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of zelenirstat monotherapy in patients (pts) with refractory cancers. Methods: Pts with advanced solid malignancies or relapsed/refractory B-cell lymphomas were dose escalated with daily oral zelenirstat in 28-day cycles until progressive disease or dose-limiting toxicity (DLT). Results: Between September 2021 and July 2023, pts received 28-day cycles of zelenirstat ranging from 20 mg/d to 280 mg/d. In 21 evaluable patients, DLT was not observed up to and including the 210 mg/d cohort. Gastrointestinal DLTs were seen in the 280 mg/d cohort, establishing 210 mg/d to be the MTD. In doses up to and including 210 mg/d, gastrointestinal adverse events were the most common, reported in 29% of pts; these were primarily Gr 1 or 2 diarrhea, nausea or vomiting. Transient Gr 2 thrombocytopenia was seen in 3 pts. Zelenirstat did not induce neuropathy, alopecia, or prolong QT intervals. Plasma concentrations peaked between 1h and 4 h, terminal half-lives were 6.7 to 12 h, and steady state was achieved by day 8. Proton pump inhibitors lowered exposure and were prohibited in the higher dose cohorts. At 100 mg/d and higher, trough plasma concentrations exceeded the levels predicted to be therapeutic. Stable disease as best response was seen in 5 (30%) of 17 evaluable pts, including 1 patient with advanced refractory colon cancer who received 6 cycles of therapy at 140 mg daily dosing prior to PD. Another colon cancer patient with 5 prior lines of therapy continues 210 mg/d dosing after > 5 cycles of therapy, with non-RECIST criteria reductions of approximately 50% in CEA and tumor volumes. Conclusions: Zelenirstat was well-tolerated on a continuous daily oral schedule at doses as high as 210 mg/d, establishing the MTD to be 210 mg. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of clinical benefit in patients with refractory colon cancer warrant further trials. Updated data will be presented. Clinical trial information: NCT04836195 .

A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies

ABSTRACT Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study

ObjectivesCurrently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. Materials and MethodsThis phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1–5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. ResultsBetween February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8–8.3). The clinical benefit rate was 57% (95% CI: 43–70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. ConclusionIn this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition

Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound’s interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.

Challenges and Future Directions in the Management of Tumor Mutational Burden-High (TMB-H) Advanced Solid Malignancies.

A standardized assessment of Tumor Mutational Burden (TMB) poses challenges across diverse tumor histologies, treatment modalities, and testing platforms, requiring careful consideration to ensure consistency and reproducibility. Despite clinical trials demonstrating favorable responses to immune checkpoint inhibitors (ICIs), not all patients with elevated TMB exhibit benefits, and certain tumors with a normal TMB may respond to ICIs. Therefore, a comprehensive understanding of the intricate interplay between TMB and the tumor microenvironment, as well as genomic features, is crucial to refine its predictive value. Bioinformatics advancements hold potential to improve the precision and cost-effectiveness of TMB assessments, addressing existing challenges. Similarly, integrating TMB with other biomarkers and employing comprehensive, multiomics approaches could further enhance its predictive value. Ongoing collaborative endeavors in research, standardization, and clinical validation are pivotal in harnessing the full potential of TMB as a biomarker in the clinic settings.

Safety and pharmacokinetics of imaradenant (AZD4635) in Japanese patients with advanced solid malignancies: a phase I, open-label study

PurposeImaradenant is a novel potent and selective adenosine A2A receptor antagonist that is hypothesized to reduce immune suppression in the tumor microenvironment. This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and anti-tumor activity of imaradenant.MethodsJapanese patients with advanced solid malignancies received imaradenant 50 mg (n = 3) or 75 mg (n = 7) once daily (QD). The primary objective was safety and tolerability, and the secondary objectives were pharmacokinetics and anti-tumor activity.ResultsThe median treatment duration was 2.10 months and 2.14 months for the 50- and 75-mg QD cohorts, respectively. The most common adverse events were nausea, malaise, decreased appetite, and vomiting. Five patients (50%) reported adverse events that were considered causally related to imaradenant; three patients had Grade 2 adverse events of malaise, nausea, and diarrhea. No deaths or serious adverse events occurred. The median times of maximum observed concentrations sampled after a single dose in the 50- and 75-mg QD cohorts were 1.08 h (range, 0.95–1.95) and 2.00 h (range, 0.92–5.52), respectively. There was little accumulation after multiple dosing, with geometric mean accumulation ratios of maximum concentration of 1.3 (50-mg QD) to 1.4 (75-mg QD) and area under the concentration–time curve 0–24 of 1.4 (50-mg QD) to 1.5 (75-mg QD). The best objective response was stable disease (3/10).ConclusionNo new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD.ClinicalTrials.gov identifier NCT03980821 (June 10, 2019).

Bexmarilimab Activates Human Tumor-Associated Macrophages to Support Adaptive Immune Responses in Interferon-Poor Immune Microenvironments.

Immune checkpoint inhibitors (ICI) show substantially greater efficacy in inflamed tumors characterized by preexisting T-cell infiltration and IFN signaling than in noninflamed "cold" tumors, which often remain immunotherapy resistant. The cancer immunotherapy bexmarilimab, which inhibits the scavenger receptor Clever-1 to release macrophage immunosuppression and activate adaptive immunity, has shown treatment benefit in subsets of patients with advanced solid malignancies. However, the mechanisms that determine bexmarilimab therapy outcome in individual patients are unknown. Here we characterized bexmarilimab response in ovarian cancer ascites macrophages ex vivo using single-cell RNA sequencing and demonstrated increased IFN signaling and CXCL10 secretion following bexmarilimab treatment. We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to ICIs.

Abstract B047: Phase I trial of αvβ3 integrin cytotoxin ProAgio in patients with previously treated advanced pancreatic cancer and other solid tumor malignancies

Abstract Background: ProAgio is a pegylated peptide drug that targets and kills cells that express integrin αvβ3 including cancer associated fibroblasts (CAFs) and endothelial cells within the tumor microenvironment. ProAgio utilizes a novel binding site to directly trigger apoptosis of target cells in pre-clinical models. Here we describe the interim results of a first-in-human phase 1 trial of ProAgio in patients with advanced solid malignancies, including pancreatic cancer. Methods: The trial is enrolling adults with previously treated and histologically confirmed advanced solid malignancy for which no curative therapy exists. The dose escalation cohort uses a modified 3+3 design to determine the recommended phase 2 dose (RP2D) of ProAgio. This will be followed by a dose expansion cohort which will enroll only participants with non-neuroendocrine advanced pancreatic cancer. The primary objective of the trial is to determine the RP2D of ProAgio. Secondary objectives assess the safety (CTCAE v. 4.03), pharmacokinetics and objective response rate (ORR) of Proagio. Ascending doses of ProAgio were administered as an intravenous infusion every 1-2 weeks depending on dose level. Response is determined by serial imaging (CT or MRI) and tumor marker assessment (CA 19-9 or appropriate tumor-specific marker). Exploratory objectives include assessing biologic effect of ProAgio on pre- and on-therapy tumor biopsy specimens (apoptosis of tumor cells, integrin αvβ3 expression, CAF population, tumor vasculature and architecture), as well as identifying putative surrogate circulating biomarkers (circulating αvβ3 expressing cells among others). Results: Sixteen participants (14 with pancreatic adenocarcinoma and 2 with other gastrointestinal malignancies) have been treated on the dose escalation as of June 30, 2023. Preliminary pharmacokinetic measurements demonstrate a plasma half-life of 17.35 hours, distribution volume of 17.62 L, and clearance of 0.522 L/hr. ProAgio has been exceptionally well tolerated with only transient grade 1 or 2 treatment-related adverse events observed in most participants. Two participants had grade 2 infusion related reaction but were able to continue treatment with increased dose of diphenhydramine pre-medication. A serious adverse event of grade 3 hyperglycemia was observed in 1 participant with insulin-dependent diabetes within 24 hours of ProAgio infusion. No other treatment-associated hyperglycemia has been observed. Two participants with pancreatic cancer receiving weekly dosing of ProAgio had stable disease for >4 months and interval stabilization in CA 19-9 tumor marker. Conclusions: ProAgio is safe and well-tolerated. Upon completion of the dose escalation, a dose expansion phase of 15 participants treated at the RP2D will begin enrolling. NCT05085548 Citation Format: Nebojsa Skorupan, Cody J. Peer, Eve Koehler, Seth Steinberg, Jane B Trepel, William D Figg, Zhi-Ren Liu, Christine Alewine. Phase I trial of αvβ3 integrin cytotoxin ProAgio in patients with previously treated advanced pancreatic cancer and other solid tumor malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B047.

Abstract B160: A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors

Abstract Introduction: CDK4/6 mediate cell cycle progression and are important for cancer initiation, growth, and survival. CDK4/6 inhibitors are approved for patients with advanced HR+/HER2– breast cancer but are ineffective against primary or metastatic brain tumors. PRT3645 is an investigational, highly selective, and potent CDK4/6 inhibitor, designed to achieve high tissue and brain penetration. This phase 1 dose-escalation study (NCT05538572) aims to evaluate safety, preliminary efficacy, and pharmacokinetic/pharmacodynamic profile of PRT3645. Methods: Patient eligibility criteria include: age ≥18 years; Eastern Cooperative Oncology Group/Karnofsky performance status ≤1/≥80; adequate organ function; histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy: breast cancer (HR+/HER2– or HR+/HER2+), glioblastoma (isocitrate dehydrogenase [IDH] wild type), CDKN2A/B homozygous deleted IDH–mutant astrocytoma, non-small cell lung cancer (KRAS mutant), or select solid tumors with CDK pathway alterations; and progression on, ineligibility for, or refusal of standard therapy. Patients with treated and untreated brain metastases (lesion <1.5 cm) could enroll if they had no neurological symptoms and did not require immediate local treatment. PRT3645 was taken orally once daily for 28 days (1 cycle) with dose escalation employing a Bayesian optimal interval design to evaluate the safety, tolerability, incidence of dose-limiting toxicities, and pharmacokinetic/pharmacodynamic profile. Results: At data cutoff (May 18, 2023), 8 patients received 20 and 40 mg once daily (first 2 dose levels of dose escalation). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. Median age was 62 (range, 53-76) years; 50% of patients were male; in these early dose cohorts 75% of patients discontinued therapy (all due to progressive disease; median duration of therapy: 8 [range, 4-16] weeks); 5 patients had glioblastoma, 2 had breast cancer, and 1 had sarcoma. All-cause, any-grade adverse events (AEs) reported in ≥1 patients were anemia and dizziness. One grade 1 AE (fatigue) was considered related to PRT3645. No patients had grade ≥3 AEs, serious AEs, diarrhea, QTcF prolongation, or hepatotoxicity. No patients had dose reductions, interruptions, withdrawals, or deaths due to AEs. Between pre-dose and 2 weeks post first dose, a reduction in phosphorylated Rb (>70% in 3/4 patients) and Ki67 (>60% in 2/4 patients) expression was seen at 40 mg; both markers showed a correlation between histochemical score and drug exposure. Conclusions: Treatment with the next-generation CDK4/6 inhibitor PRT3645 was associated with a substantial decrease in phosphorylated Rb and Ki67 expression, indicating a high level of target engagement at a low dose. PRT3645 exhibited tolerable dose escalation in the initial 2 cohorts of patients with no significant gastrointestinal or hematologic events reported to date, leveraging its enhanced selectivity profile. Dose escalation is ongoing. Citation Format: Amita Patnaik, Mohamad A. Salkeni, Manish R. Patel, Atrayee Basu-Mallick, Dale Shepard, Christine Lihou, William Sun, Jennifer Xavier, Sri Sahasranaman, Neelesh Sharma, Erika Hamilton. A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B160.

BE-A-PAL: Behavioral economics and automated analytics to improve palliative care among patients with advanced cancer.

268 Background: Patients with advanced solid malignancies often experience high symptom burden and aggressive end-of-life care. Early specialist palliative care (PC) can improve symptom management, mood, and quality of life. However, many patients do not receive PC before they die, with clinician inertia and difficulty identifying high-risk patients being barriers to initiating PC referrals. Methods: In a 2-arm pragmatic randomized clinical trial among patients with stage 3 or 4 lung or non-colorectal gastrointestinal malignancies, oncology clinics were randomly assigned to intervention or usual practice. In the intervention arm, oncologists received automated algorithm-based default notifications prompting specialty PC referral. The control arm received usual care, in which oncologists could refer to PC at their discretion. The algorithm was adapted from NCCN guidelines, identified high-risk patients based on prognosis or symptom/psychosocial burden, and was integrated into the EHR. Oncologists were alerted weekly about eligible patients and had the option to opt-out of PC referral. If there was no response or agreement, a PC coordinator introduced and offered a PC visit to the patient. The primary outcome was a completed PC visit within three months of identification among high-risk patients. We report descriptive results from an interim analysis of the trial. Results: 15 practices (7 clinics and 32 physicians in intervention; 8 clinics and 31 physicians in control) and 567 patients (299 intervention; 268 control) were randomized. Rates of completed early PC visits were 46.4% (139/299) the intervention arm and 11.2% (30/268) in the control arm. The opt-out rate in the intervention arm was 10.7%. Among clinicians who did not opt-out, 79% of their patients agreed to an initial PC visit. Adjusted analyses and demographic data will be completed and available by September 2023. Conclusions: Algorithm-based default PC referrals meaningfully increased utilization of specialty PC within a community oncology practice. Targeting high-risk patients using guideline-based risk stratification prevented overwhelming PC capacity. Further analyses will assess the impact of the intervention on end-of-life care, acute care utilization, patient-reported outcomes, and explore clinician perspectives. Clinical trial information: NCT05590962 .

Meaning-centered pain coping skills training for patients with metastatic cancer: Protocol for a randomized controlled efficacy trial

BackgroundMany patients with advanced cancer describe pain as a debilitating symptom that greatly interferes with daily activities and enjoyment of life. Psychosocial interventions can improve cancer-related pain but rarely address spiritual concerns (e.g., loss of meaning, peace), which can influence the pain experience for those facing life-threatening illness. To address these needs, we systematically developed and pilot tested a novel psychosocial intervention called Meaning-Centered Pain Coping Skills Training (MCPC). In this randomized controlled trial, we aim to determine MCPC's efficacy for reducing pain interference (primary outcome) and improving secondary outcomes. We will also estimate MCPC's cost-effectiveness. Method/DesignPatients (target N = 210) with advanced solid tumor malignancies (Stage IV) and clinically-elevated pain interference will be enrolled and block randomized with equal allocation to MCPC + enhanced usual care or enhanced usual care alone. MCPC's four, videoconferenced, 45–60 min weekly sessions will be individually delivered by trained study therapists. Primary (pain interference) and secondary (pain severity, anxiety and depressive symptoms, pain self-efficacy, social support, spiritual well-being) patient-reported outcomes will be assessed at baseline, and 8-weeks (primary endpoint) and 12-weeks after baseline. ConclusionOur MCPC intervention is the first to systematically address the biopsychosocial-spiritual aspects of pain in patients with advanced cancer. If MCPC demonstrates efficacy, next steps will involve hybrid efficacy-effectiveness and implementation work to broaden access to this brief, manualized, remotely-delivered intervention, with the goal of reducing suffering in patients with life-threatening illness.

Percutaneous Transhepatic Biliary Drainage for Malignant Biliary Obstruction in Advanced Solid Organ Malignancy: Clinical Outcomes and a Perspective on Quality of Life

Background: Malignant obstructive jaundice is associated with a poor prognosis. Patients can undergo percutaneous transhepatic biliary drainage (PTBD), but the impact it has on quality of life is not well understood.Objective: To assess the potential impact of PTBD on quality of life in patients with obstructive jaundice from advanced malignancy using surrogate markers including complications, hospital length of stay, readmission, reintervention, and mortality. Methods: A retrospective analysis of a single-centre cohort of all patients with advanced solid organ malignancy undergoing PTBD between April 2020 and February 2022. Data was collected from electronic medical records.Results: Among the sixteen patients, abdominal pain and cholangitis were observed in 62.5% and 37.5% patients, respectively. Peritonitis, biliary leak, perihepatic abscess, and haemobilia occurred in individual cases. The median hospital length of stay post PTBD was nine days. The 30-day readmission rate for PTBD-related complications was 31.3% with a median of three total readmissions per patient. The 30-day reintervention rate was 62.5%. The 30-day all-cause mortality was 25% (95% CI:8.9-53.3), which included one procedure-related death. Conclusions: Quality of life in patients with obstructive jaundice from advanced solid organ malignancy undergoing PTBD can be adversely impacted due to the high risk of complications, reintervention, hospitalisation, and mortality. Thorough patient assessments are crucial in selecting appropriate candidates for PTBD.

1079TiP A phase I first-in-human study of PRTH-101, an IgG1 monoclonal antibody targeting DDR1, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

1079TiP A phase I first-in-human study of PRTH-101, an IgG1 monoclonal antibody targeting DDR1, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

Dissemination and Implementation of a Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC): a study protocol for a hybrid type 1 randomized controlled trial

BackgroundThere are persistent racial and ethnic health disparities in end-of-life health outcomes in the United States. African American patients are less likely than White patients to access palliative care, enroll in hospice care, have documented goals of care discussions with their healthcare providers, receive adequate symptom control, or die at home. We developed Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC) to address these disparities. DeCIDE PC is an integrated community health worker (CHW) palliative care intervention that uses community health workers (CHWs) as care team members to enhance the receipt of palliative care for African Americans with advanced cancer. The overall objectives of this study are to (1) assess the effectiveness of the DeCIDE PC intervention in improving palliative care outcomes amongst African American patients with advanced solid organ malignancy and their informal caregivers, and (2) develop generalizable knowledge on how contextual factors influence implementation to facilitate dissemination, uptake, and sustainability of the intervention.MethodsWe will conduct a multicenter, randomized, assessor-blind, parallel-group, pragmatic, hybrid type 1 effectiveness-implementation trial at three cancer centers across the United States. The DeCIDE PC intervention will be delivered over 6 months with CHW support tailored to the individual needs of the patient and caregiver. The primary outcome will be advance care planning. The treatment effect will be modeled using logistic regression. The secondary outcomes are quality of life, quality of communication, hospice care utilization, and patient symptoms.DiscussionWe expect the DeCIDE PC intervention to improve integration of palliative care, reduce multilevel barriers to care, enhance clinic and patient linkage to resources, and ultimately improve palliative care outcomes for African American patients with advanced cancer. If found to be effective, the DeCIDE PC intervention may be a transformative model with the potential to guide large-scale adoption of promising strategies to improve palliative care use and decrease disparities in end-of-life care for African American patients with advanced cancer in the United States.Trial registrationRegistered on ClinicalTrials.gov (NCT05407844). First posted on June 7, 2022.

Immune Checkpoint Inhibitors in Metastatic Bladder and Other Solid Malignancies: How Long is Enough?

The introduction of T-cell targeted immunomodulators blocking the PD-1 and PD-L1 axis is unquestionably one of the most notable advancements in the treatment of advanced or metastatic solid malignancies, including bladder cancer. Immune checkpoint antibodies are now widely utilized as monotherapies or in combination with other systemic therapies in the first or subsequent lines of treatment in approximately 50 cancer types. Deep and durable responses and long tails of survival curves are hallmarks of patients treated with immune checkpoint inhibitors. However, treatment can have negative impacts, including serious treatment-related side effects as well as a high financial burden to individual patients and the healthcare system. There is increasing data that the benefit of immune checkpoint treatment may persist after treatment is discontinued for reasons other than progressive disease, particularly in patients who have achieved a durable complete response. However, the optimal treatment duration and activity after treatment reinitiation remains undefined and will likely be influenced by disease biology (histology and genomics), treatment (monotherapy or combination therapy), and disease context (depth and duration of response). Well-designed prospective clinical trials and the development and validation of biomarkers that predict outcomes after treatment cessation are needed to move the field forward.

Phase 3 randomized controlled trial comparing the effectiveness of dexamethasone in reducing cancer-associated fatigue in patients on palliative chemotherapy.

134 Background: Short-term steroids (< 2 weeks) have been used to alleviate fatigue in patients with advanced cancer. However, the efficacy and safety of long-term steroids (12 weeks) in patients with advanced cancer receiving palliative chemotherapy have not been studied. Methods: The study was an open-label, placebo-controlled, phase 3 RCT to evaluate the efficacy and safety of low dose dexamethasone (DEX) in reducing chemotherapy and cancer associated fatigue. Patients aged 18-60 years with performance status ≤2, undergoing palliative chemotherapy for advanced solid malignancies were randomized 1:1 to receive either DEX (4mg/day) or a placebo for 12 weeks. Fatigue was measured using the Symbolic Assessment of Fatigue Extent (SAFE) scale and EORTC FA12 scale, and QOL was assessed using the EORTC QLQ c30 at baseline, 6 weeks, and 12 weeks.The primary endpoint was to compare fatigue between the study arms at 6 weeks. Secondary endpoints were to compare fatigue at 12 weeks, QOL and toxicities. With a power of 80%, α of 5%, 126 patients (including 25% drop-outs) were required to show the superiority of DEX in reducing SAFE fatigue extent score by 50% at 6 weeks. Results: A total of 126 patients were randomized (64 in the placebo arm and 62 in the DEX arm) between Oct 2018-Sep 2022. The median age was 46.5 years and 67% were females. Metastatic breast (28%) and lung (16%) cancer were the common diagnosis. Twelve and 23 patients in the placebo arm and 13 and 22 patients in the DEX arm did not undergo week 6 and 12 assessment respectively due to disease progression. The results showed no significant differences in mean SAFE scores, FA12 scores, or QOL between the study arms at 6 and 12 weeks, except for higher FA12 social sequelae in the DEX arm at 12 weeks (P = 0.048) (Table). There were no significant differences in toxicities between the arms. Conclusions: The results of this study suggest that low-dose DEX is not effective in reducing chemotherapy associated fatigue or improving QOL in patients with advanced cancer. Clinical trial information: CTRI/2018/08/015222 .[Table: see text]