Combination Of Capecitabine Research Articles

Dual effects of DLG5 (disks large homolog 5 gene) modulation on chemotherapy-induced thrombocytopenia and nausea/vomiting via the hippo signalling pathway.

The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy-induced adverse effects (CRAEs). To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole-genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by in vivo and in vitro verifications for selected gene and CRAE pair. Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy-induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the DLG5 gene. We found that DLG5 mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype-Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that DLG5 overexpression affected genes involved in cytoskeleton formation and alpha-granule formation, which could impact the normal generation of proplatelets. We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed DLG5 expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and DLG5 in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions.

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer After Trastuzumab Failure (PROVE): A Prospective Phase 2 Study.

Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. NCT04720131.

Neoadjuvant S-1 plus cisplatin-based chemoradiotherapy compared with surgery alone for locally advanced gastric cancer: Randomized, phase II trial.

4076 Background: Patients with locally advanced gastric cancer (LAGC), are known to have a high risk of recurrence even after surgery. This study was designed to delineate whether neoadjuvant concurrent chemoradiotherapy (CCRT) using the S-1/Cisplatin (SP) regimen can effectively downstage the T stage in patients with clinically T4 stage compared with surgery alone (OP). Methods: This is a randomized phase II open label trial and gastric cancer patients with initial clinical T4 were enrolled. Patients were randomized into neoadjuvant CCRT or OP. For the CCRT group, S-1 (20 mg/m2 twice daily, 2 weeks on and 1 week off) and cisplatin (30 mg/m2/day, first day of week 1, 2, 4, and 5) were administered concurrent with radiotherapy (day 1-5 for 5 weeks, total 45 Gy/25 fractions,). Surgery was performed within 3 to 6 weeks after the completion of CCRT. For the OP group, curative surgery was performed within 3 weeks after randomization. Post-operative adjuvant chemotherapy was chosen as S-1 monotherapy or combination of Capecitabine, and Oxaliplatin according to the physician’s choice. The primary objective of this study was to compare the downstaging rates between the groups (65% and 40% for the CCRT and OP group). Using a type I error rate of 0.10 and a power of 0.80, the planned sample size was 51 patients per group but the study was closed prematurely. Results: Between November 2016 and August 2021, 49 patients with T4 were enrolled. Of those, 26 (CCRT) and 23 (OP) patients were randomized but diagnostic laparoscopy for preoperative screening revealed peritoneal seeding in some patients. Finally, 23 (CCRT) and 17 (OP) patients were evaluable and clinicopathologic characteristics were well balanced between the two groups in per protocol analysis. For CCRT, 19 out of 23 (82.61%) patients satisfied downstage, while among 8 out of 17 (47.06%) patients in OP group satisfied downstage ( P=0.038). The median disease-free survival (DFS) was 27.91 months in CCRT group, and 45.96 months in OP group ( P=0.985). The median overall survival (OS) was not reached in CCRT group, and 51.2 months in OR group ( P=0.335). There were no statistically significant differences between neoadjuvant CCRT and surgery group in the aspect of both hematologic and non-hematologic adverse events. Conclusions: In this study, neoadjuvant SP based CCRT significantly increased downstaging in T stage compared than OP alone. The prespecified genomic analysis with transcriptomic sequencing will be available at the meeting. Clinical trial information: NCT03814759 .

A phase Ia/b trial of ARX788 combined with toripalimab for HER2-low advanced breast cancer (ABC) and other HER2-expressing solid tumors.

e13159 Background: ARX788 has been proved with superior PFS compared with a combination of capecitabine and lapatinib in the randomized phase Ⅱ/Ⅲ study for HER2-positive ABC (Ambrx, 2023). Here we report the preliminary safety and efficacy of ARX788 plus toripalimab in HER2-low ABC and other HER2-expressing solid tumors. Methods: This was a phase Ⅰ study conducted in China. Eligible patients were HER2-low (IHC2+ and FISH- or IHC1+) ABC or HER2-expressing (IHC 2+ or 3+) solid tumors. Dose exploration with ARX788 is 1.3, 1.5mg/kg, IV, Q3W plus toripalimab 240mg, IV, Q3W. Primary endpoint was safety and RP2D of Ⅰa and efficacy of Ⅰb. Results: Totally, 12 patients were enrolled in phase Ⅰa, 10 patients were diagnosed with ABC, 1 was diagnosed with BTC and 1 was CRC. 6 patients each were treated with 1.3 and 1.5mg/kg. No DLTs were observed. 12 patients (100%) experienced ≥1 ADRs. The most common (≥20%) ADRs were AST increased (75%), platelet count decreased (75%), alopecia (41.67%), white blood cell count decreased (25%), ALT increased (25%), dry eye (25%), interstitial lung disease (25%) and neutrophil count decreased (25%). 1.5mg/kg dose level showed a slightly higher incidence in hematologic toxicities, interstitial lung disease and alopecia. Grade 3 ADRs occurred in 8 patients (66.67%) with equal incidence of the 2 dose levels, those were ocular events (41.7%, 2 of each level), interstitial lung disease (8.3%, 1 of 1.5mg/kg), platelet count decreased (8.3%, 1 of 1.5mg/kg), jaundice (8.3%, 1 of 1.3mg/kg) and immune-mediated myocarditis (8.3%, 1 of 1.3mg/kg). No grade 4 or 5 ADRs occurred. All ADRs were manageable and have recovered. ORR was 41.7% in 12 patients, with 33.3% and 50% in 1.3 and 1.5mg/kg dose level. In 10 patients with ABC, ORR was 50%, with 40% and 60% in each level. DCR was 83.33% and 100%, respectively. Thus, 1.5mg/kg was determined as RP2D and phase Ⅰb is ongoing with HER2-low ABC patients. Conclusions: ARX788 with 1.5mg/kg combined with toripalimab was shown acceptable safety profile with promising efficacy, no significant increase in adverse reactions or serious unexpected immune-related adverse reactions compared with ARX788 monotherapy, which supports further evaluation for HER2-low ABC in a larger sample in Ⅰb trial. Clinical trial information: CTR20222247.

Efficacy of systemic treatments in patients with metastatic lung invasive mucinous adenocarcinoma.

e20609 Background: Invasive mucinous adenocarcinoma (IMA) is a relatively rare histological subtype of lung adenocarcinomas that differs in its clinical behavior, radiologic features, histopathological, and genomic characteristics than invasive non-mucinous adenocarcinomas (INMA). Methods: We retrospectively investigated medical records of patients diagnosed with lung IMA at four oncology centers in Turkey. Patients who were ≥18 years of age, pathologically diagnosed with lung IMA, and who received at least one course of treatment for metastatic or inoperable disease were included in the study. Results: Forty-one patients were included in the study. The median follow-up was 16.6 months. Among the included patients, 24 (58.5%) were male, 17 (38.5%) were female, and their average age was 62. Six (14.6%) patients had a targetable mutation. Three (7.3%) patients were epidermal growth factor receptor (EGFR), two (4.8%) anaplastic lymphoma kinase (ALK) mutation, and one (2.4%) neurotrophic tyrosine receptor kinase (NTRK2) fusion. Most patients (83.1%) had received platinum-based chemotherapy as a first-line treatment. Of the patients who received cytotoxic chemotherapy, 9 (25.7%) had a partial response, 14 (40%) had a stable response, and 12 (34.3%) had progression. The median PFS was 8.24 months (95% CI: 5.9-10.5 months), and the median OS was 20.4 months (95% CI: 14.4-26.3 months) in all study populations. In those receiving cytotoxic chemotherapy, median PFS and OS were 8.11 months (95% CI: 5.02-11.2) and 17.5 months (95% CI: 11.7-23.3 months), respectively. While the PFS of two EGFR-positive patients were similar at 18.9 months and 20.6 months, the third patient's PFS was quite prolonged (66.5 months). The ALK-positive patients receiving brigatinib and crizotinib PFS were 15.8 months and 2.73 months, respectively. The PFS of the patient receiving entrectinib was only two months. Among the entire patient population, only one patient used oxaliplatin and capecitabine combination (XELOX) as chemotherapy. In this patient, who progressed after four cycles of gemcitabine and platinum first-line treatment, a partial response and 7.23 months PFS were achieved with second line XELOX. Conclusions: Standard-of-care treatments have the same efficacy in IMA and INMA patients. Targetable mutation is less common in IMA patients compared to INMA. 5-FU-based chemotherapies also appear to be effective in lung IMA patients.

Pyrotinib plus taxanes or vinorelbine for human epidermal growth factor receptor 2-positive metastatic breast cancer: A prospective study.

e13004 Background: Pyrotinib in combination with capecitabine is recommended as the second-line treatment for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) in China. The efficacy and safety of pyrotinib combined with non-capecitabine chemotherapy regimens remain unclear. Thus, we conducted this study to evaluate the efficacy and safety of pyrotinib combined with taxanes or vinorelbine in HER2-positive MBC. Methods: Patients with HER2-positive MBC were included to receive pyrotinib combined with taxanes or vinorelbine in Jiangsu Cancer Hospital. Patients received pyrotinib 400mg orally once daily plus taxanes (docetaxel 75-100 mg/m2 on day1, or nab-paclitaxel 125 mg/m2 on days 1 and 8, paclitaxel 80 mg/m2 on days 1 and 8, every 3 week) or vinorelbine 25 mg/m2 on days 1 and 8, every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and safety. Results: Between Nov 20, 2018, and Jan 11, 2023, a total of 101 patients were assigned to pyrotinib plus taxanes group (n=83) and pyrotinib plus vinorelbine group (n=18). The median number of pyrotinib therapy lines was 2 (IQR 1-7), the first line accounted for 23.8%, the second line, and third line and above was 34.6%, 41.6%, respectively. As of May 24, 2023, the median PFS in the total was 11.5 months (95% confidence interval [CI], 8.8-15.7). The median PFS was significantly longer in the pyrotinib plus taxanes group than in the pyrotinib plus vinorelbine group, with median PFS being 12.2 months (95% CI, 9.2-18.6) and 8.4 months (95% CI, 5.5-13.7) (HR=2.2 [95% CI, 1.2-3.9]; P=0.005), respectively. The median PFS in the first-line, second-line, and third-line and above treatment was 28.6 (95% CI, 10.6-NA), 12.2 (95% CI, 8.5-16.3), and 8.3 months (95% CI, 6.3-14.5), respectively. The most common grade 3 or 4 adverse events were diarrhea (22.8%), leukopenia (19.5%), and neutropenia (18.2%). Conclusions: The median PFS of pyrotinib plus taxanes or vinorelbine, especially taxanes, was not inferior even superior to that of pyrotinib combined capecitabine. No increase treatment-related side effects was reported. Thus, the combination of pyrotinib and taxanes or vinorelbine regimen can be an option for HER2-positive MBC. Clinical trial information: ChiCTR2000041217.

Efficacy of Systemic Treatments in Patients With Metastatic Lung Invasive Mucinous Adenocarcinoma

BackgroundInvasive mucinous adenocarcinoma (IMA) is a rare histological subtype of lung invasive adenocarcinoma with unique clinical, radiological, histopathological, and genomic characteristics. There have been limited studies on the effectiveness of systemic therapy for lung IMA, with conflicting results reported. MethodsWe retrospectively investigated the medical records of patients diagnosed with lung IMA. Patients who were ≥ 18 years of age and received at least 1 course of treatment for metastatic or locally advanced inoperable disease were included in the study. Archive records of 113 patients diagnosed with IMA were screened for the study. ResultsA total of 41 patients with lung IMA were included. The targetable mutation rate was 20.6% (in 6 of 29 patients). Most patients (83.1%) had received platinum-based chemotherapy as a first-line treatment. The objective response rate (ORR) was 25.7%, and median progression-free survival (PFS) and overall survival (OS) were 8.1 months (95% CI, 5.02-11.2) and 17.5 months (95% CI, 11.7-23.3 months), respectively, in the patients who received chemotherapy. The median PFS and ORR were 20.6 (95% CI, 18.9-66.5) and 66.6%, respectively, in epidermal growth factor receptor (EGFR) mutation-positive patients (n = 3) with relevant targeted therapy. Only 1 patient used oxaliplatin and capecitabine combination (XELOX) as chemotherapy in the second-line treatment and achieved a partial response (PR) at 7.2 months. ConclusionPlatinum-based chemotherapies moderately enhance IMA patients’ survival rates. Anti-EGFR-targeted drugs are seen as potentially effective in patients with EGFR driver mutation positive. Large, prospective studies are needed to confirm our findings.

Fisetin and/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines

Capecitabine is recommended as one of the first-line chemotherapy treatments for advanced or metastatic colorectal cancer. Researches have been conducted on capecitabine’s impact on the viability of human colon cancer cells and its potential to induce apoptosis. However, even in cases initially responsive to treatment, the development of acquired resistance significantly limits its efficacy. Challenges still exist in effectively treating patients with chemotherapy, and developing new cytotoxic drugs is hindered by drug resistance. Fisetin alters the cell cycle, inducing apoptosis, inhibiting cancer cell proliferation, and enhancing the therapeutic effectiveness of chemotherapy drugs. This work aims to create a plan for reversing capecitabine resistance. For this purpose, the role of capecitabine and/or fisetin combinations in cell proliferation and apoptosis has been determined in both wild-type and capecitabine-resistant HT29 cells (CR/HT29). We developed capecitabine-resistant cell line from wild-type HT29 cells. This study demonstrated the effects of capecitabine, fisetin, and their combinations on both resistant and wild-type cells through experiments including cell survival skills, cell proliferation, wound healing, colony formation, hoechst staining, and western blot analysis. We established capecitabine-resistant cell lines. P-gp expression increased in CR/HT29 cells. Capecitabine effects on a CR/HT29 cells less than wild-type HT29 cells. The combination of fisetin and capecitabine in cell proliferation caused greater reductions in wild-type HT29 cells than in capecitabine-resistant cells. Fisetin has also additive effects on the apoptotic pathway in CR/HT29 cells. This study provides new perspectives on the combination of capecitabine and/or flavonoid treatment in resistant cells.Graphical abstract

A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. NCT02393755.

Combination of metronomic capecitabine and letrozole in metastatic hormone receptor positive, HER2 negative breast cancer: a randomized phase II trial

First line endocrine therapy is the gold standard for advanced estrogen receptor positive, human epidermal growth factor receptor 2 negative breast cancer. Adding CDK4/6 inhibitors has improved progression free survival. Metronomic Capecitabine has proven to be safe to combine with endocrine therapy with promising efficacy. We conducted a phase II randomized, open label, single centre clinical trial on patients with metastatic ER positive and HER 2 negative breast cancer. Eligible patients were randomized (1:1) to arm A: metronomic dose of capecitabine (500 mg/m2 BID) combined with letrozole (2.5 mg OD) or arm B: letrozole single agent. The primary endpoint was progression free survival. The study was terminated early due to poor accrual and 60 eligible patients out of the planned 204 were randomized. This clinical trial is registered on ClinicalTrials.gov (MD-127-2019, NCT04571437). Between February 2019 and April 2022, 60 patients were randomized. This is the first report of the study, after a median follow-up of 18.6 months. The median age at diagnosis was 47 years with only 41.7% of patients post-menopausal. Half of our patients had bone-only disease, 45% had visceral metastasis (liver and lung) and 63% presented with endocrine sensitive disease. The estimated median PFS for the whole population was 16.2 months. Median PFS for capecitabine arm was 17.7 months versus 14.6 months for letrozole alone (p = 0.078). Overall response rate was 70% for capecitabine/letrozole arm and 56.6% for letrozole only. Clinical benefit rate was 90% in the capecitabine/letrozole arm versus 73.3% in the letrozole arm. Overall survival data is still immature after this short follow up duration. Adverse event assessment showed acceptable all grade and high grade toxicity profile consistent with the established adverse events of both capecitabine and letrozole. Anaemia (28.3%) and hand & foot syndrome (43.8%) were significantly more common in the capecitabine/letrozole arm. Capecitabine combined with letrozole have showed a trend towards improvement in progression free survival with potential more benefit to certain sub-groups and the combination showed acceptable safety profile consistent with the established known safety profile of both letrozole and capecitabine.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that treatment with immunotherapy containing arms (nivolumab or a combination of nivolumab plus capecitabine) leads to an increase in PIS from baseline to week 6 compared with capecitabine alone, meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Abstract 1196: Peripheral immune analyses correlate with clinical outcome: A phase II trial of nivolumab, capecitabine, or the combination in patients with triple negative breast cancer

Abstract Introduction: Patients with triple negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy have a higher risk of recurrence and worse outcomes than patients achieving pathologic complete response. Here, we report on immune correlates from the OXEL study (NCT03487666), an open label randomized phase II trial in TNBC patients with residual disease following neoadjuvant chemotherapy, who were treated with post-neoadjuvant nivolumab (360 mg intravenously every 3 weeks, Arm A), capecitabine (1,250 mg/m2 orally twice daily on days 1-14 of each 3-week cycle, Arm B), or the combination of nivolumab and capecitabine (Arm C). The primary endpoint was to assess the immunologic effects of nivolumab, capecitabine, or the combination. Methods: Peripheral blood mononuclear cells were evaluated at baseline and after 6 and 12 weeks of therapy in patients from Arm A (n=15), B (n=14), and C (n=13) by flow cytometry to identify 158 immune cell subsets. Peripheral immunoscores reflective of enhanced immune cell function were calculated to evaluate changes in the immune profile induced by each therapy, and the association between the immune profile at baseline and disease recurrence. Results: At 6 weeks versus baseline, an increase in immune cell function was seen in patients on Arms A+C compared to Arm B. Additional distinct immune subsets showed statistical changes after 6 and 12 weeks of therapy that were specific to each arm. At baseline, a higher peripheral immunoscore was associated with a lack of eventual disease recurrence in patients on Arm A or Arms A+C, but not for patients on Arm B. Patients on Arm A (p=0.0003) or Arms A+C (p=0.0085) with a peripheral immunoscore above the median also had a longer interval of disease-free survival than patients at or below the median; this association was not seen in Arm B. Distinct immune subsets at baseline also associated with development of recurrence in each arm; higher levels of naïve CD8+ T cells and HLA-DR+ Tregs and lower levels of NKp30+ NK and PD1+ NKT cells associated with recurrence in Arm A, while in Arm B, greater levels of intermediate and nonclassical monocytes associated with recurrence. In Arm C, higher frequencies of multiple Treg subsets were associated with recurrence. Conclusions: Patients receiving nivolumab, with or without capecitabine, showed enhanced immune cell function. A peripheral immunoscore based on the immune profile at baseline was associated with disease recurrence only in patients receiving immunotherapy. These data highlight the importance of assessing peripheral blood to reveal important immunologic phenomenon and potential associations with clinical outcome. Citation Format: Nicole J. Toney, Filipa Lynce, Candace Mainor, Claudine Isaacs, Jeffrey Schlom, Renee N. Donahue. Peripheral immune analyses correlate with clinical outcome: A phase II trial of nivolumab, capecitabine, or the combination in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1196.

<i>Tarantula cubensisalcohol</i> extract enhances the tumoricidal effect of capecitabine via multiple pathways in azoxymethane-induced colorectal cancer in rats

Purpose: To evaluate the effect of a combination of Tarantula cubensis alcohol extract (TCAE) and capecitabine (CAP) in the treatment of azoxymethane (AOM)-induced colorectal cancer (CRC). 
 Methods: Forty-two Wistar albino rats were divided into 7 groups with 6 rats in each group. The groups consisted of Control (C), Control+TCAE (C-TCAE), Control+CAP (C-CAP), Cancer control (CC), Cancer+TCAE (CC-TCAE), Cancer+CAP (CC-CAP) and Cancer+CAP+TCAE (CC-CAP+TCAE). To induce CRC, AOM (15 mg/kg) was administered to rats subcutaneously (sc) twice at a one-week interval to all the groups except control. From the 15th week, TCAE (0.2 mL/rat sc) was administered to CC-TCAE group every 3 days for 4 weeks, and CAP (40 mg/kg/day) was administered by gavage to CC-CAP group for 4 weeks. In CC-CAP+TCAE group, TCAE (0.2 mL/rat sc) was administered every 3 days for 4 weeks, and CAP (40 mg/kg/day) was administered gavage for 4 weeks. Animals were treated for 18 weeks. Aberrant crypt foci (ACF) were evaluated histopathologically among CC, CC-TCAE, CC-CAP, and CC-CAP+TCAE groups. β-catenin, CD15, Proliferating Cell Nuclear Antigen (PCNA), and Nuclear Factor kappa B (NF-κB) expression levels were immunohistochemically compared among all groups. 
 Results: Histopathologically, ACF scores were significantly increased in CC group, while a significant decrease in the relevant scores (p < 0.001) was observed in CC-CAP and CC-CAP+TCAE treatment groups, and the lowest scores were in CC-CAP+TCAE group. Immunohistochemically, in CC group, β-catenin, Nuclear Factor kappa B (NF-κB), Proliferating Cell Nuclear Antigen (PCNA) and CD15 expressions were highly irregular. CC-CAP and CC-CAP+TCAE groups had significantly reduced expressions (p < 0.001), and the lowest expressions were in CC-CAP+TCAE group. 
 Conclusion: The combined use of TCAE and CAP in treatment of CRC has a synergistic effect and increases the anticancer efficacy of TCAE, and CAP. More studies at the molecular level are needed in the future to demonstrate the clinical benefit of TCAE supplementation during the treatment of CRC with CAP.

Intracranial Efficacy of Pyrotinib and Capecitabine Combination Therapy in HER2-Positive Breast Cancer with Brain Metastases.

Approximately 50% of patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (BC) are estimated to develop brain metastases (BMs). This study was aimed to assess the intracranial efficacy and survival benefits of pyrotinib and capecitabine combination therapy in the treatment of BMs in patients with HER2-positive BC. A total of 56 HER2-positive BC patients with BMs were treated with 400 mg pyrotinib once daily along with 1000 mg/m2 capecitabine twice daily for 14 days in 21-day cycles. The patients were allocated into three cohorts: (1) Cohort A composed of patients with newly diagnosed BMs without prior local radiotherapy, (2) Cohort B included patients with stable post-local radiotherapy, and (3) Cohort C composed of patients with progression following local radiotherapy. The primary endpoint was the intracranial objective response rate (CNS-ORR), while secondary endpoints included intracranial disease control rate (CNS-DCR), progression-free survival (PFS), overall survival (OS), safety, as well as QoL. The observed CNS-ORR CNS-ORR of 72.73% (95% CI 51.85-86.85%) in cohort A, 55% (95% CI 34.21-74.18%) in cohort B, and 42.86% (95% CI 21.38-67.41%) in cohort C. The mPFS was 11 months, 8.4 months, and 5.2 months in cohorts A, B, and C, respectively. Diarrhea, accounting for 23.21% of all the patients, was the most common grade 3/4 adverse event related with treatments (6/22 [27.3%] in cohort A, 4/20 [20.0%] in cohort B, and 3/14 [21.4%] in cohort C). However, there were no deaths related with treatments observed. Importantly, the QoL was efficiently maintained throughout the treatment duration. Pyrotinib and capecitabine combination therapy proved significant effectiveness as well as tolerability in treating HER2-positive BC with BMs, yielding satisfactory results, especially in radiotherapy-naive population.

A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer.

Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Real-world assessment of capecitabine and oxaliplatin (CAPOX) tolerability in patients with localized colorectal cancer undergoing curative-intent therapy: A comprehensive single institution analysis.

90 Background: The combination of capecitabine and oxaliplatin (CAPOX) is commonly used in patients with localized colorectal cancer (CRC) receiving curative-intent treatment. However, real-world data on the tolerability of CAPOX in this patient population are limited. This study aimed to assess the tolerability of CAPOX in a single-institution cohort of patients with localized CRC. Methods: A retrospective analysis was conducted using our institutional pharmacy database to identify patients with localized CRC who received neoadjuvant or adjuvant CAPOX. Demographic information, clinical characteristics, and treatment details were extracted from electronic health records. The primary endpoint was the rate of treatment completion, defined as the receipt of all planned chemotherapy cycles at full dosage, for both the overall cohort and patients aged 65 and above. Secondary outcome measures included the rate of grade 3 or higher adverse events, the frequency of hospital admissions due to CAPOX-related toxicities, and dose reductions. Results: A total of 153 patients were included in the analysis, with a median age of 61 years (range 32-84). Among them, 49% were female, 78.4% had stage III CRC, and the remaining had stage II disease. The racial distribution was 81% White and 15.7% Black. The proportion of patients who completed all planned CAPOX doses was 55.5% (85/153) in the entire cohort and 38% (23/60) in patients aged 65 and above (p = 0.22). Among patients intended to receive 4 cycles of CAPOX, only 57% (37/65) completed all 4 cycles. Female patients were less likely to complete treatment than male patients (p = 0.01). Dose reductions for oxaliplatin and capecitabine were observed in 37% (57/153) and 39% (59/153) of patients, respectively. Hospitalizations related to CAPOX-induced toxicities occurred in 18% (27/153) of patients, and 31% (47/153) experienced grade 3 or higher adverse events. A switch to FOLFOX was observed in 5% (8/153) of patients. Conclusions: This study highlights that a substantial number of patients with localized CRC undergoing curative-intent treatment with CAPOX do not complete the planned courses, potentially impacting their overall survival. Moreover, a significant proportion of patients experience grade 3 or higher toxicities with CAPOX, necessitating hospital admissions. These findings underscore the need for careful patient selection and management strategies to optimize the therapeutic benefits of CAPOX in this setting.

Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors.

This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3+3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.

Cost-effectiveness of utidelone and capecitabine versus monotherapy in anthracycline- and taxane-refractory metastatic breast cancer.

This study aimed to assess the cost-effectiveness of combining utidelone with capecitabine, compared to capecitabine monotherapy, for the treatment of anthracycline- and taxane-refractory metastatic breast cancer within the Chinese healthcare system. A partitioned survival model was formulated based on patient characteristics from the NCT02253459 trial. Efficacy, safety, and health economics data were sourced from the trial and real-world clinical practices. We derived estimates for costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) for the two treatment strategies. Sensitivity and subgroup analyses were conducted to rigorously evaluate uncertainties' impact. Over a 5-year span, the combination therapy manifested substantially higher costs than capecitabine monotherapy, with a differential of US$ 26,370.63. This combined approach conferred an additional 0.49 QALYs, resulting in an ICER of US$ 53,874.17/QALY. Utilizing the established willingness-to-pay threshold, the combination might not consistently be deemed cost-effective when juxtaposed against monotherapy. However, at an ICER of US$ 53,874.4/QALY, the probability of the combination being cost-effective increased to 48.97%. Subgroup analysis revealed that the combination was more cost-effective than capecitabine alone in specific patient groups, including those <60 years, patients with more than two chemotherapy rounds, patients lacking certain metastases, patients having limited metastatic sites, patients with an Eastern Cooperative Oncology Group status of 0, and patients with particular hormone receptor profiles. Although the combination of utidelone and capecitabine may not be an economically viable universal choice for anthracycline- and taxane-refractory metastatic breast cancer, it could be more cost-effective in specific patient subgroups than capecitabine monotherapy.

CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease. METHODS This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.