Capecitabine In Patients Research Articles

Phase I/Ib study of afatinib with capecitabine in patients with refractory solid tumors and pancreaticobiliary cancers.

594 Background: The epidermal growth factor receptor (EGFR) and ErbB2/HER2 signaling is overactive in many solid tumors. Afatinib, an irreversible inhibitor of ErbB signaling, downregulates thymidine synthase and synergizes with capecitabine in preclinical models. This phase I trial evaluated the safety, maximum tolerated dose (MTD) and preliminary efficacy of afatinib plus capecitabine in patients (pts) with refractory solid tumors and pancreatic ductal adenocarcinoma (PDA) and biliary tract cancers (BTC). Methods: The phase I study had a 3+3 design with capecitabine 1000 mg/m 2 twice daily (BID) on days 1-14 and afatinib 20 mg, 30 mg or 40 mg daily (QD) in 21-day cycles. In phase Ib, 15 pts each with PDA and BTC were treated at MTD. Results: 41 pts enrolled from November 2016 to October 2021, who received a median of 2 (range 1-5) prior therapies. No dose-limiting toxicities were observed. The MTD was 40 mg afatinib QD plus 1000 mg/m 2 capecitabine BID. Grade 3 treatment related adverse events were diarrhea (12.2%) and nausea (4.9%). Among 36 response evaluable pts, best response was 1 partial response (PR, 3%) in a pt with KRAS wild type (WT)/EGFR amplified BTC, and 8 stable diseases (SD, 22%), with disease control rate (DCR) of 25%. PDA pts (n=20) had DCR of 24%, median progression-free (PFS) and overall survival (OS) of 1.9 months (95% CI 1.05, 2.03) and 3.2 months (95% CI 2.01, 5.82) respectively. BTC pts (n=18) had DCR of 31%, median PFS and OS of 1.9 months (95% CI 1.55, 3.39) and 4.6 months (95% CI 1.88, 6.09), respectively. Eight pts with cancers with EGFR/HER2/HER3 pathway alterations, most KRAS WT (n=6), had DCR of 29%, and median PFS and OS of 2.1 months (95% CI 1.05, 4.14) and 3.5 months (95% CI 1.64, 6.09), respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have significant efficacy in pts with refractory PDA/BTC, including in KRAS WT cancers with EGFR/HER2/HER3 alterations. Clinical trial information: NCT02451553 .

Safety and preliminary efficacy of ivaltinostat, an HDAC inhibitor, plus capecitabine in patients with pretreated metastatic pancreatic adenocarcinoma (mPDAC): Results of a phase Ib study.

742 Background: Front-line chemotherapy for patients (pts) with mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses cell proliferation, and promotes apoptosis. Preclinical data demonstrated synergy with 5-FU/capecitabine (cape) in mouse models. We report here results of the Phase Ib portion of a Ib/2 trial evaluating the safety and recommended phase 2 dose (RP2D) of this combination to use in a randomized study of ival + cape vs cape as maintenance therapy. Methods: Key eligibility criteria for phase 1b included unresectable or metastatic PDAC; ≥18 years old; ≥1 prior therapy; ECOG PS 0-1; and no known germline BRCA1/2 mutation. Three cohorts were enrolled, receiving ivaltinostat at 60, 125, or 250mg/m 2 iv (weekly on days 1 and 8) in combination with cape (1000mg/m 2 po BID on days 1-14) of a 21-day cycle. 1o objectives: safety, tolerability and RP2D; 2o objectives: pharmacokinetics (PK) of ival + cape. Results: A total of 28 patients were enrolled at the 60 (n=6), 125 (n=10) and 250 (n=12) mg/m 2 ival dose levels. Median prior lines of therapy: 2 (range 1-7). Median age: 67 years (range 50-83). Only one DLT (G4 thrombocytopenia) was observed at 250mg/m 2 dose level. Treatment-emergent AE profile was similar across dose levels, with common TEAEs including fatigue (n=15, 53.6%), nausea (n=14, 50.0%), palmar-plantar erythrodysesthesia syndrome (n=12, 42.9%), diarrhea (n=10, 35.7%), and constipation (n=9, 32.1%). G3 AEs included neutropenia (n=6, 21.4%), anemia (n=4, 14.3%), abdominal pain (n=3, 10.7%) and diarrhea (n=3, 10.7%). G4 AEs included 1 (3.6%) event of neutropenia and 1 (3.6%) of thrombocytopenia. No SAEs related to study drugs occurred in any of the 3 dose cohorts. PK analyses indicated dose proportional increases in exposure with increasing doses of ival. Histone H3K27 acetylation for ival showed the similar trend in optical density evaluation. Across all dose levels and prior treatments, median OS and PFS were 9.6 and 3.3 months, respectively. Conclusions: The combination of ival and cape was generally well tolerated in this heavily pretreated patient population. Ival 250 mg/m 2 is the dose selected for the ongoing randomized study of ival + cape vs cape in the maintenance setting for mPDAC pts post-FOLFIRINOX, which is expected to finish accrual in 2025. Clinical trial information: NCT05249101 .

Efficacy and Safety of Low-Dose Oral Etoposide Combined With Capecitabine for Patients With Postoperative Metastatic Breast Cancer Resistant to Anthracycline/Taxanes.

The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes. Metronomic chemotherapy, giving lower, more frequent doses of chemotherapy drugs over an extended period, often without long breaks between cycles. With oral low-dose etoposide + capecitabine was administered to patients who had postoperative MBC resistant to anthracycline/taxanes: etoposide 30 mg/m2/day, qd for 7 days + capecitabine 1400 mg/m2/day, administered in two equal dose for 14 days, with 21 days as a cycle. Patients received treatments if complete response, partial response, or stable disease was obtained until disease progressed or became intolerable. RECIST criteria were used for standard efficacy evaluation and NCI-CTC version 3.0 was used for evaluation of side effects. From June 2008 to May 2020, 85 patients received the aforesaid treatment; 67 of these patients were eligible for efficacy and side effects evaluation. After treatment, 6 (8.96%) patients obtained partial response, 41 (61.19%) patients had stable disease, and 20 (29.85%) patients had disease progression. The overall response rate (complete response + partial response) was 8.96%, and disease control rate (complete response + partial response + stable of disease) was 70.15%. Clinical benefits (complete response + partial response + stable of disease ≥ 24 weeks) were obtained for 50% of the patients. The median and mean treatment to progression time was 5 months and 6.06 months (95% CI: 3.43~8.70), respectively. The most common grade I/II side effects were leukopenia and fatigue (15.8%). For patients with postoperative MBC resistant to anthracycline/taxanes, oral low-dose etoposide + capecitabine was effective with tolerable safety. The patients did not need antiemetics or leukocytic drugs, and the treatment was cost-effective because the patients did not need to be hospitalized for intravenous infusion.

Observational Study of Best Supportive Care With or Without Oral Capecitabine in Patients With Metastatic Gallbladder Carcinoma at a Tertiary Center in India.

To compare overall survival (OS), toxicity, and quality of life (QOL) in patients with metastatic gallbladder cancer receiving oral capecitabine (X) with best supportive care (BSC) and BSC alone. Patients with metastatic gallbladder cancer and Karnofsky Performance Status (KPS) ≥70 were accrued and assigned to either arm A or B. Assignment to these two arms was based on physician/patient discretion. Arm A received oral capecitabine 825 mg/m2 twice a day d1-14, repeated every 3 weeks for six cycles with BSC, and arm B received BSC alone. The Kaplan-Meier method computed OS and comparison was using a log-rank test. QOL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 administered at baseline, 3 months, and 6 months. The linear mixed-effects model was used for the longitudinal analysis of QOL. Between December 2020 and April 2022, 64 patients diagnosed with metastatic gallbladder carcinoma and KPS ≥70 were accrued in the study, and 32 patients were assigned to each arm. In arm A versus B, the median age was 52 versus 55 (P = .21); the median KPS was 80 versus 70 (P = .008). The median OS in arm A versus B was 3.4 versus 2 months (P = .001). Grade 1-2 vomiting and diarrhea were seen in 50% versus 78% (P = .041) and 59% versus 9.3% (P = .01) patients in arm A versus B, respectively. Grade 1-2 hand-foot syndrome was seen in 12 (37.5%) patients in arm A. Dynamic changes showed an improvement in pain in the linear mixed model with a significant difference between the arms (P = .011); arm A experienced a significant improvement in pain over time (arm × time P = .020). Global QOL improved over time (P = .038) with parallel improvement between arms (arm × time P = .490). Compared with BSC alone, patients who receive X + BSC experience an OS improvement of 1.4 months and better pain control without grade 3 toxicities or negative impact on QOL.

FDA Approval Summary: Capecitabine Labeling Update under Project Renewal.

On December 14, 2022, the FDA approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

524P A phase II study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with metastatic colorectal cancer who failed two prior standard chemotherapies

524P A phase II study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with metastatic colorectal cancer who failed two prior standard chemotherapies

A Phase I Trial of Alpelisib Combined With Capecitabine in Patients With HER2-Negative Metastatic Breast Cancer

BackgroundAlpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown. Patients and MethodsThis phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status. ResultsEighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation. ConclusionThis study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.

Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

Adjuvant tislelizumab combined with capecitabine for patients with biliary tract cancer with high risk of postoperative relapse (ACTIVE): Primary analysis from a prospective cohort study.

e16248 Background: Only 20% of biliary tract cancer (BTC) patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. This rate is even lower in patients with high-risk features. Capecitabine as an adjuvant therapy in biliary tract cancer has been verified to improve overall survival, however, the efficacy still remains limited. PD-1/L1 antibody combined with chemotherapy have been demonstrated to improve survival in advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of adjuvant tislelizumab and capecitabine following surgery for biliary tract cancer with high risk of recurrence. Methods: This was a single-center, prospective cohort phase II study. BTC patients (pts) underwent R0/R1 resection with high postoperative recurrence risk were eligible. The high-risk factors included positive resection margins, positive lymph nodes, positive perineural invasion, and tumor > 5cm in diameter. The patients were divided into two groups, the tislelizumab (TIS 200 mg Q3W for 1 year )+capecitabine (CAP D1-14, 1500mg/m2 for eight 3-weekly cycles) group and the capecitabine group. The primary endpoint was DFS (disease free survival). The second endpoints was OS (overall survival) and adverse event (AE). Results: A total of 37 pts were enrolled into the study, while 22 pts in the TIS+CAP group and 15 in CAP group, 23 males and 14 females with a median age of 66 years. According to the location of the tumor, 37.8% pts were intrahepatic cholangiocarcinoma, 21.6% were gallbladder cancer, 5.4% were distal cholangiocarcinoma and 35.1% were hilar cholangiocarcinoma. The median DFS was 16.2 months (95% CI, 8.1-26.2) in the TIS+CAP group, which was longer than CAP group (11.4 months, 95% CI 4.2-27.1). 12-month RFS rates were 56.5% and 36.6% , respectively. The most common adverse events (AEs, any grade) were rash (18.2%), vomiting (13.6%), neutropenia (13.6%) and anorexia (13.6%) in the TIS+CAP group. Conclusions: Tislelizumab in combination with capecitabine were effective and safe as adjuvant therapy, which can prolong the DFS of BTC patients with high recurrence risk after resection. Clinical trial information: NCT04782804 .

Abstract PO5-16-12: EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY

Abstract BACKGROUND mChT consists on the administration of repetitive, low doses of chemotherapy drugs and represents an attractive and active therapeutic strategy in cancer patients. Beyond the traditional cytotoxic effect of each drug on tumor cells, mChT seems to play a role in the modulation of angiogenesis and immune-regulation. mChT has demonstrated promising clinical activity and low toxicity in patients with advanced breast cancer (ABC). The aim of this study is to describe the safety and efficacy of CMX in a retrospective cohort of heavily pretreated HER2-negative ABC patients. METHODS This is a multicenter, retrospective study that included patients with HER2-negative ABC who received treatment with CMX (capecitabine 500 mg thrice daily, methotrexate 2.5 mg twice a week, and cyclophosphamide 50 mg daily). Demographic data, tumor characteristics, previous therapies, efficacy, and toxicity of the CMX treatment were collected. Statistical analyses were performed with Stata v.14. For standard summary statistics, mean and range for continuous data and relative and absolute frequencies for categorical data were used while for survival analysis Kaplan Meier approach was employed. RESULTS A total of 25 patients from 4 centers in Spain treated between October 2016 and February 2023 were included in this analysis. Median age was 63 years (range: 37-87), 68% had visceral disease, and 48% had triple-negative tumors. All patients previously received a median of 5 prior lines of systemic therapy in the metastatic setting and 80% of patients had been treated with capecitabine, most of them in the metastatic scenario with a median treatment duration of 6.2 months. Dose reductions were necessary in 5 patients and 1 patient discontinued treatment due to toxicity. No grade 3-4 hand-foot syndrome or diarrhea were reported. Objective response rate was 20.8% and disease control rate was 54.2%. Median progression-free survival was 6.1 months (95% confidence interval [CI] 95%; 4.3 - 12.4) and median overall survival was 12.3 months (95% CI; 6.8 - 24.7). Neither the number of previous lines of treatment nor the prior use of capecitabine showed a negative impact on the efficacy of CMX. CONCLUSIONS CMX is an effective and well-tolerated scheme of mChT and may represent an adequate treatment option for patients with heavily pretreated HER2-negative ABC, including those patients that previously received capecitabine as single agent. These encouraging data warrant further investigation. Citation Format: Cristina Saavedra, María Gion, Alfonso Cortés, Patricia Cortez, Laia Garrigós, José Manuel Pérez-García, Gabriele Antonarelli, Javier Cortés. EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-12.

#31. A Phase I/II trial of ATI-2231 with Phase Ia in advanced soild tumor malignancies followed by Phase Ib/II in combination with capecitabine in patients with hormone receptor-positive (HR+) and HER2-negative metastatic breast cancer

#31. A Phase I/II trial of ATI-2231 with Phase Ia in advanced soild tumor malignancies followed by Phase Ib/II in combination with capecitabine in patients with hormone receptor-positive (HR+) and HER2-negative metastatic breast cancer

Toripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial

Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Clinical management of intrahepatic cholangiocarcinoma: surgical approaches and systemic therapies.

Intrahepatic cholangiocarcinoma (ICCA) is a rare and aggressive malignant tumor that arises from the biliary tracts in the liver. Upfront surgery with adjuvant capecitabine in patients with resectable disease is often the standard treatment. Unfortunately, only 20% of patients present with resectable disease and many individuals will develop recurrence or metastatic disease after curative-intent resection. Patients with advanced or metastatic ICCA often require multidisciplinary care with a combination of cytotoxic chemotherapy, targeted therapy, and/or locoregional therapies. Gemcitabine plus cisplatin is currently first line therapy for advanced or metastatic ICCA. In recent years, efforts have been focused to develop more effective targeted therapy, most commonly with FGFR and IDH inhibitors for ICCA. Despite these efforts, ICCA still carries a poor prognosis. We herein review the current clinical management of ICCA focusing on surgical technique and systemic therapies.

Combination of hSTC810 and capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A single arm, phase 1b/2, multicenter study.

TPS223 Background: hSTC810 is a humanized anti-BTN1A1 monoclonal antibody of the IgG4 isotype that binds to human BTN1A1 and blocks the interaction between BTN1A1 and its ligands. Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1. BTN1A1 has been shown to inhibit anti-CD3-induced cytokine production and T-cell proliferation and also inhibit anti-CD3-induced p38 mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB) and target of rapamycin (TOR) phosphorylation in human T-cells. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. In the first in human phase 1 study, investigating the safety and efficacy of hSTC810 in solid tumors, hSTC810 showed acceptable safety profile and the disease control rate (DCR) was 39.3%, which indicates its potential efficacy. Methods: This multi-center, open label phase 1b/2 study evaluates the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of hSTC810 combined with capecitabine in patients with metastasis/recurrent colorectal cancer. The trial is enrolling adults who are (1) histologically or cytologically confirmed colorectal adenocarcinoma (2) resistant or intolerant to oxaliplatin and irinotecan-based chemotherapy (3) adequate hematologic, hepatic, renal function (4) measurable or non-measurable disease by RECIST 1.1 (5) ECOG PS 0~2 (6) resolved acute effects of any prior therapy. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The primary endpoint of phase 1b is to determine dose-limiting toxicity (DLT), and recommended phase 2 dose (RP2D) of hSTC810 combined with capecitabine, each in 21-day cycles. Phase 1 comprises 3 escalation arms, and if the initial dose is deemed unsafe, 2 deescalation arms will be initiated. Once the RP2D is determined, the Phase 2 will enroll up to 39 patients. The primary endpoint of phase 2 is progression free survival (PFS); secondary endpoints include objective response rate, overall survival, disease control rate, duration of response and quality of life. The study began in Q4 2023 and is recruiting patients. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria. An exploratory study is underway to investigate the impact of hSTC810 on the tumor microenvironment and cytokines, utilizing both tissue biopsies and blood sampling. Clinical trial information: NCT05990543 .

ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.

TPS583 Background: Despite improvements in multidisciplinary healthcare, patients with biliary tract cancer (BTC) have a poor outcome and effective treatment options are limited. Only 20 % of patients are eligible for surgical resection with curative intent, with 5-year overall survival rates < 10 % for all patients. Data on adjuvant chemotherapy alone for BTC are conflicting, and the SOC is treatment with capecitabine according to the UK BILCAP trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ-1 trial in BTC and for the STRIDE regimen in HCC according to the Himalaya trial data, the evaluation of the IO combination in the adjuvant setting seems promising. Also, the MediTreme trial showed promising response rates in BTC. Preclinical studies indicate that the antibody combination leads to stronger and more durable anti-tumour effects than single therapies, as it synergistically modulates the tumour's immunosuppressive microenvironment, which is particularly pronounced in cholangiocarcinoma. The aim of the ADJUBIL trial is to evaluate the clinical activity of the anti-PD-L1 (programmed-death 1 ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant setting. This is a randomized phase II study with a pick-the-winner design. The winner of ADJUBIL could be tested against the current SOC capecitabine in a subsequent phase 2/3 trial. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery (R0/R1) with no previous systemic treatment. Patients are randomized (1:1) to receive either tremelimumab (300 mg, one dose on C1D1) plus durvalumab (1500 mg every 4 weeks; max. 12 months), with or without capecitabine (1250 mg/m2 twice a day on day 1-14 of 3-weekly cycles; max. 8 cycles). 40 evaluable patients will be enrolled in the study to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months. Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints are to identify predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By September 2023, 15 centers in Germany have been activated and 23 out of 40 planned patients have been enrolled. The first 5 patients in each arm were subject to a safety lead-in phase with close monitoring of (serious) adverse events. The safety assessment revealed no concerns. The study is ongoing. Clinical trial information: NCT05239169 .

Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases

The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear. To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases. This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023. Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects. The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function. A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points. The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation. ClinicalTrials.gov Identifier: NCT04582968.

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.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Economic evaluation of third-line neratinib plus capecitabine versus lapatinib plus capecitabine with HER2+ metastatic breast cancer.

Breast cancer (BC) is one of the most common malignant tumors in women. In addition, human epidermal growth factor receptor 2-positive (HER2+) BC is overexpressed in 25% of BC patients, resulting in the predicament of poor prognosis. Although first- and second-line treatments have been established, optimum third-line treatment is still mired in controversies for HER2+ metastatic BC (mBC). Therefore, this study analyzes the cost-effectiveness of neratinib plus capecitabine (N+C) and lapatinib plus capecitabine (L+C) over a 5-year time horizon from a payer perspective. A half-cycle corrected four-state Markov model was established to simulate the course of BC events and deaths in N+C and L+C armed patients. The data of this model were derived from NCT01808573 trail and other published literatures. One-way deterministic sensitivity analysis (DSA) was conducted to investigate the impact of variables and probabilistic sensitivity analysis (PSA) was performed based on second-order Monte Carlo simulation. In addition, subgroup analysis was performed to verify its cost-effectiveness in China. The base-case results found that N+C was in dominant position in 82.70% of the generation scenarios, providing an improvement of 0.17 quality-adjusted life-years (QALYs) and a reduction of $1,861.28 compared with L+C. The ICER was $-1,3294.86/QALY, which did not exceed the willingness to pay (WTP) threshold, while in subgroup, the ICER decreased to $-2,448.17/QALY. This analysis indicated that the combination of neratinib plus capecitabine is likely to be cost-effective in comparison with lapatinib plus capecitabine in patients with HER2+ mBC who continues to progress during or after second-line HER2-targeted therapy. So neratinib plus capecitabine can become a third-line treatment option.