Oral Chemotherapeutic Agent Research Articles

O-01 Case report: Temozolomide treatment of refractory prolactinoma

Abstract Introduction Treatment of refractory prolactinoma is challenging. Temozolomide (TMZ), an oral chemotherapeutic agent, has been recommended as an effective drug for refractory pituitary adenomas or carcinomas. Clinical Case We report a 53-year-old male who presented with diplopia, left eye proptosis, conjunctival congestion, and headache. Magnetic resonance imaging (MRI) showed a macroadenoma 20×17 mm in diameter with compression of the optic chiasm and invasion of both cavernous sinuses. Hormonal evaluation revealed hyperprolactinemia of 2382 ug/L, 120x above the upper limit of normal (ULN), with central hypothyroidism and hypogonadism. Cabergoline was recommended as an initial treatment. Despite the maximum cabergoline dose of 1.5 g daily, tumor volume increased with visual disturbances and headaches. Prolactin (PRL) remained 60x above ULN so the patient underwent transsphenoidal surgery. Tumor histology was consistent with an atypical pituitary adenoma, positively stained for prolactin and sporadically for growth hormone, Ki-67 of 6.4%, no mitosis and negative p53. Postoperatively, the PRL level was still high (25x above ULN) with tumor remnants in both cavernous sinuses. Due to the tumor resistance to dopamine agonist treatment and uncomplete surgical resection, patient underwent stereotactic gamma knife radiosurgery (GK prescription dose 22 Gy, isodose 49%) simultaneously with TMZ treatment. After 2 cycles of TMZ (1. cycle TMZ 300mg/5days, 2. cycle TMZ 400 mg/5days), the PRL level decreased significantly (126 ug/L). The plan is to apply a total of 6 cycles of temozolomide. Conclusion Clinical evidence for the efficacy of TMZ in refractory prolactinoma remains limited, but early use of this agent may be helpful in some cases.

SAT581 Parathyroid Hormone Related Protein-induced Hypercalcemia In Medullary Thyroid Carcinoma In Pediatric Patient With MEN2A

Abstract Disclosure: S.A. Ackah: None. L.A. DiMeglio: None. J.C. Sanchez: None. G.C. Geddes: None. Background: PTHrp is a well-known cause of hypercalcemia of malignancy. Although PTHrp can often be detected in papillary, follicular and anaplastic thyroid cancers it does not always lead to hypercalcemia. Okotur 2007 described PTHrp in an adult medullary thyroid carcinoma (MTC). No pediatric cases have been described. Case: 8 year old female presented on transfer from hospital in Kenya where she had been admitted for three months with diarrhea and malnourishment (weight Z-score -6.5). She had been initially treated for aspiration pneumonia with negative testing for HIV, tuberculosis, stool cultures and parasites. At our facility, chest, abdomen and pelvis imaging were interpreted as an abscess from perforated appendicitis, bilateral hydroureteronephrosis, bilateral multifocal pneumonia and coronary artery ectasia. She experienced respiratory status decline requiring intubation. Further work up included consults and testing by infectious disease, genetics, immunology, cardiology, gastroenterology, pulmonology, and urology. In Kenya, the patient was initially normocalcemic and the calcium then slowly increased, so that on admission to our facility was found to have calcium 18.3 mg/dL (8.5-10.5), phosphorous 3.3 mg/dL (3.4-5.5), Creatinine 0.3 mg/dL (0.3-0.8), albumin 3.5 g/dL (3.5-4.7), PTH 5 pg/mL(10-65), TSH 1.9 mIU/ml (0.4-4.2), Free T4 0.8 ng/dL(0.6-1.5). IV hydration and pamidronate 0.5 mg/kg x 3 days administration resolved the hypercalemia. Rapid whole genome testing revealed a de novo pathogenic variant in RET (RET NM_020975.6 c.2753T>C; p.M918T) previously reported in individuals with MEN type 2A and 2B phenotypes. Thyroid ultrasound showed 2 nodules. FNA of both showed MTC; MTC was also present on lung biopsy. Screening labs obtained then showed PTHrp 301 pmol/L(adult range 0.0-3.4), Calcitonin 1433 pg/mL(0.0-5.1), VIP <13 pg/mL(0-60), Gastrin 45 pg/mL(0-100), Chromogranin A 4049 ng/mL(0-103), CEA123.7 ng/mL(0.0-2.5), metanephrine 0.91 nmol/L(0.00-0.49), normetanephrine 0.48 nmol/L(0.00-0.89). Bone scan showed diffusely diminished physiological uptake in the growth plates and diffuse bilateral lung uptake. Due to concern about ability to tolerate thyroidectomy, the patient was begun on selpercatinib, an oral chemotherapeutic agent specifically for tumors with disruption of RET gene. On day 11 of treatment, she was extubated to noninvasive respiratory support. Now, 3 months out from pamidronate and her hypercalcemia has not recurred. Conclusions: Hypercalcemia in pediatric patients with low PTH should prompt further workup including PTHrP measurement. In this case, we report a case of a child with MEN 2A and metastasized MTC with hypercalcemia attributable to PTHrp secretion.

Capecitabine and the Bowel Battle: Addressing Diarrhea in Gastrointestinal Cancers - A Pakistan Perspective

Cancer continues to be a global health challenge, and gastrointestinal malignancies significantly burden healthcare systems worldwide, including in Pakistan. Among the various treatment options available for gastrointestinal cancers, capecitabine, an oral chemotherapeutic agent, has shown promising results. However, its effectiveness comes with a potential side effect that poses a considerable challenge to both patients and healthcare providers – capecitabine-induced diarrhea. In the context of Pakistan’s healthcare landscape, where access to specialized cancer care can be limited, addressing this issue becomes a critical aspect of ensuring better patient outcomes.

Capecitabine and the Bowel Battle: Addressing Diarrhea in Gastrointestinal Cancers - A Pakistan Perspective

Cancer continues to be a global health challenge, and gastrointestinal malignancies significantly burden healthcare systems worldwide, including in Pakistan. Among the various treatment options available for gastrointestinal cancers, capecitabine, an oral chemotherapeutic agent, has shown promising results. However, its effectiveness comes with a potential side effect that poses a considerable challenge to both patients and healthcare providers – capecitabine-induced diarrhea. In the context of Pakistan’s healthcare landscape, where access to specialized cancer care can be limited, addressing this issue becomes a critical aspect of ensuring better patient outcomes.

Capecitabine and the Bowel Battle: Addressing Diarrhea in Gastrointestinal Cancers - A Pakistan Perspective

Cancer continues to be a global health challenge, and gastrointestinal malignancies significantly burden healthcare systems worldwide, including in Pakistan. Among the various treatment options available for gastrointestinal cancers, capecitabine, an oral chemotherapeutic agent, has shown promising results. However, its effectiveness comes with a potential side effect that poses a considerable challenge to both patients and healthcare providers - capecitabine-induced diarrhea. In the context of Pakistan's healthcare landscape, where access to specialized cancer care can be limited, addressing this issue becomes a critical aspect of ensuring better patient outcomes.

Oral chemotherapeutic agents in metastatic hormone-sensitive prostate cancer: A network meta-analysis of randomized controlled trials.

Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents. We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate. We identified 18 RCTs (n=13,509). Concerning OS, ADT+abiraterone, ADT+abiraterone+docetaxel, ADT+apalutamide, ADT+bicalutamide, ADT+darolutamide+docetaxel, ADT+enzalutamide, ADT+orteronel, and ADT+rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT+bicalutamide, nilutamide, flutamide, ADT+bicalutamide+palbociclib, and ADT+nilutamide. ADT+docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis. Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT+docetaxel SOC. Even so, ADT+docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.

Capecitabine-induced Gastrointestinal Injury Shows a Graft-Versus-Host Disease (GVHD)-like Pattern.

Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5y, range: 61 to 76y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.

Oral Chemotherapeutic Ingestions Reported to a Poison Control Center Treated in a Health Care Facility.

The approach to cancer chemotherapy has changed in recent years, and there are several new oral chemotherapeutics that offer convenience to patients. These medications have toxicity, which may be particularly amplified in an overdose. This was a retrospective review of all oral chemotherapy overdoses reported to the California Poison Control System between January 2009 and December 2019. Inclusion criteria were all ingestions coded as "antineoplastic, monoclonal antibody, or thalidomide" that were evaluated at a health care facility. We evaluated outcomes per AAPCC criteria (stratified as death, major, moderate, mild, or no effect) as well as symptoms and interventions. There were 314 total cases reported; 169 single-substance ingestions (54%) and 145 cases with coingestant(s) (46%). One hundred eighty cases were female (57%) and 134 male (43%). Age ranges were as follows: ages 1-10 years old (87 cases); ages 11-19 years old (26 cases); 20-59 years old (103 cases); ages 60 and older (98 cases). The majority of cases were unintentional ingestions (199, 63%). The most common medication reported was methotrexate with 140 cases (45%), followed by anastrozole (32 cases) and azathioprine (25 cases). One hundred thirty-eight cases were admitted to the hospital for further care (ICU 63 cases; non-ICU 75 cases). Eighty-four of the methotrexate cases received the antidote leucovorin (60%). Five of the capecitabine ingestions received uridine (36%). Outcomes included 124 cases with no effect, 87 cases with minor effect, 73 case with moderate effect, 26 cases with major effect, and 4 deaths. Although methotrexate is the most common oral chemotherapeutic agent involved in overdoses reported to the California Poison Control System, there are many other oral chemotherapeutics from various drug classes, which can lead to toxicity. Although deaths are rare, further studies are needed to determine if particular drugs or drug classes warrant more scrutiny.

Erdafitinib-associated Central Serous Chorioretinopathy: A Case Report

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor approved to treat patients with metastatic or advanced urothelial carcinoma and is being developed for the treatment of other cancer types. This oral chemotherapeutic agent carries a warning for potential ocular adverse reactions including central serous chorioretinopathy and dry eyes. This case report describes an 88-year-old Caucasian male co-managed in the eye clinic over the course of treatment with erdafitinib for metastatic urothelial carcinoma. The patient developed asymptomatic episodes of recurring and remitting bilateral central serous chorioretinopathy correlating to erdafitinib dose modifications and interruptions. It is crucial for eye care providers to recognize the potential ocular adverse events related to erdafitinib, its drug class, and medications which target similar pathways. Effective communication and careful co-management with oncology is essential in providing quality care to this subset of patients. With the care coordination, an effective yet tolerable dosing may provide the patient with increased survival rate and improved quality of life.

Standardization of informed consent for oral chemotherapeutic agents.

e18665 Background: Informed consent is an essential prerequisite to the administration of any oral or parenteral chemotherapeutic agent. Obtaining informed consent for treatment is the oncologist’s responsibility and all the information the oncologist and patient share and agree to in this process should be documented in the patient’s medical record. Informed consents at Inova Schar Cancer Institute are created through an electronic consent, a web-based solution that creates procedure-specific consent forms that can be used for treatments and procedures for patients and is integrated in our electronic medical record system. While the oncology nurse administering parenteral chemotherapy ensures that the consent is signed before infusion starts, no clear plan existed at our institution for patients starting oral chemotherapeutic agents. In addition, with the transition to telemedicine visits during covid-19 pandemic, patients are often not in clinic at time of discussion of the new treatment plan with the oncologist or for chemotherapy teaching session therefore creating a barrier to obtain consent on the computer pad. The aim of this study is to standardize methods to obtain written informed consent for oral chemotherapy agents with 100% compliance. Methods: Our first Plan-Do-Study-Act (PDSA) cycle conducted in the breast medical oncology clinic included the following steps: 1) the oncologist or the registered pharmacist (RPH) creates the electronic consent 2) after completion of chemotherapy teaching session, the RPH ensures that the patient and the physician have signed the consent and also signs as witness. In this first cycle we also tested the “mobile sign” modality that allows to text the informed consent to the patients so they can sign directly on their mobile phone if the teaching is conducted remotely. Results: Baseline chart audit of seven patients who were started on oral chemotherapy regimen during the month of December 2021 revealed that all the patients received chemotherapy teaching, but none provided written informed consent. After implementation of above steps for two weeks, chart audit of five patients showed that all signed informed consent that was also completed by physician’s and witness’s signature. Two patients were successfully consented through the “mobile sign” modality. Conclusions: Our study identified failure to obtain written informed consent for oral chemotherapeutic agents with some barriers created by increasing use of telemedicine. As all our patients receive chemotherapy teaching sessions, we identified this as best timing to obtain informed consent as patients have received comprehensive education on the chemotherapy agent. We also explore the option of “mobile sign” if the teaching session is conducted virtually. Our preliminary results showed 100% compliance in obtaining informed consent and feasible use of “mobile sign” option. We plan for long term chart audits to confirm above results.

Self-reported financial difficulties among patients with multiple myeloma and chronic lymphocytic leukemia: An Alliance for Clinical Trials in Oncology study.

6602 Background: Treatment advances have greatly improved survival and quality of life among blood cancer patients, yet significant financial costs are a growing concern. Methods: We conducted an observational, prospective survey in 2019-2020 to estimate the self-reported prevalence of financial difficulty among multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients and identify sociodemographic correlates of financial difficulty. Patients with an MM or CLL diagnosis >/= 18 years of age were recruited from NCI NCORP sites of care. Financial difficulty was measured in a previously validated single question from the EORTC QLQ C30 and a composite measure of five questions from the EORTC QLQ C30. Results: 521 MM and CLL patients were registered to the study, 416 patients were administered all or part of the patient survey, for an overall response rate of 79.8%. 16.8% of respondents reported experiencing financial difficulty in response to the single item question and 58.6% reported experiencing financial difficulty in response to the composite measure. Respondents reporting financial difficulty to both measures had reported household incomes of less than $60,000, identified their highest education levels as a high school diploma or GED, had more than one medical comorbidity and used an expensive oral chemotherapeutic agent to treat their blood cancer. Conclusions: Blood cancer patients treated at NCI NCORP sites are experiencing financial difficulties. Results of this study aim to inform physician, site of care and policy efforts to improve access among cancer patients. Clinical trial information: NCT03870633. [Table: see text]

Febrifugine dihydrochloride as a new oral chemotherapeutic agent against visceral leishmaniasis infection

Visceral leishmaniasis (VL) is the deadliest form of leishmaniasis without a safer treatment option. This study implies drug repurposing to find a novel antileishmanial compound, namely febrifugine dihydrochloride (FFG) targeting Leishmania antioxidant system. Starting with virtual screening revealed the high binding affinity and lead likeness of FFG against the trypanothione reductase (TR) enzyme of Leishmania donovani, followed by experimental validation. The promastigotes inhibition assay gave the IC50 concentration of FFG and Miltefosine (positive control) as 7.16 ± 1.39 nM and 11.41 ± 0.29 μM, respectively. Their CC50 was found as 451 ± 12.73 nM and 135.9 ± 5.94 μM, respectively. FFG has been shown to increase the reactive oxygen species (ROS), leading to apoptosis-like cell death among L. donovani promastigotes. Spleen touch biopsy resulted in 62% and 55% decreased parasite load with FFG and miltefosine treatment, respectively. Cytokine profiling has shown an increased proinflammatory cytokine response post-FFG treatment. Moreover, FFG is safe on the liver toxicity parameter in mice post-treatment.

Conventional Therapies Do Not Prolong the Prognosis of Hepatocellular Carcinoma Patients with Extrahepatic Metastases under Receiving of Tyrosine Kinase Inhibitors.

Simple SummaryTyrosine kinase inhibitors (TKIs), including sorafenib and lenvatinib, have been the current standard treatment for advanced hepatocellular carcinoma (HCC) in cases where an immune checkpoint inhibitor cannot be used. The SHARP study showed that sorafenib tended to be less effective for extrahepatic metastases than for vascular invasion. Moreover, lenvatinib showed a response similar to that of sorafenib in such patients. The aforementioned data suggested that the addition of conventional therapies, including chemoembolization and radiation therapy, may improve the prognosis of such patients. Our retrospective study found that TKI promoted a longer overall survival in patients with extrahepatic metastases compared to conventional therapies. TKI plus conventional therapies did not promote a better prognosis compared to TKI alone. Thus, conventional therapies can be an option when events that worsen the quality of life occur in HCC patients with extrahepatic metastases.Background: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase inhibitor (TKI) treatment. Methods: We retrospectively investigated 127 HCC patients with extrahepatic metastases, who were divided into the non-TKI (conventional therapies) and TKI groups and further subdivided into the TKI alone and TKI plus conventional therapies groups. Conventional therapies included transcatheter arterial chemoembolization, cisplatin-based chemotherapy, radiation, surgery, and UFT, an oral chemotherapeutic agent. Results: The median of the overall survival (OS) of the 127 patients with extrahepatic metastases was 7.0 months. Meanwhile, the median OS of the TKI and non-TKI groups was 12.1 and 4.1 months, respectively. Imitating TKI after diagnosing metastases promoted a favorable increase in OS. Among the TKI group, the median OS in the TKI alone group was 8.9 months. TKI plus conventional therapies promoted no improvement in OS after adjusting for the patients’ background data. Conclusion: TKI promoted a better OS in HCC patients with extrahepatic metastases compared to conventional therapies. However, TKI plus conventional therapies promoted no improvement in the prognosis of such patients.

Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields.

BackgroundThe genomic and overall biologic landscape of glioblastoma (GB) has become clearer over the past 2 decades, as predictive and prognostic biomarkers of both de novo and transformed forms of GB have been identified. The oral chemotherapeutic agent temozolomide (TMZ) has been integral to standard-of-care treatment for nearly 2 decades. More recently, the use of non-pharmacologic interventions, such as application of alternating electric fields, called Tumor-Treating Fields (TTFields), has emerged as a complementary treatment option that increases overall survival (OS) in patients with newly diagnosed GB. The genomic factors associated with improved or lack of response to TTFields are unknown.MethodsWe performed comprehensive genomic analysis of GB tumors resected from 55 patients who went on to receive treatment using TTFields, and compared results to 57 patients who received standard treatment without TTFields.ResultsWe found that molecular driver alterations in NF1, and wild-type PIK3CA and epidermal growth factor receptor (EGFR), were associated with increased benefit from TTFields as measured by progression-free survival (PFS) and OS. There were no differences when stratified by TP53 status. When NF1, PIK3CA, and EGFR status were combined as a Molecular Survival Score, the combination of the 3 factors significantly correlated with improved OS and PFS in TTFields-treated patients compared to patients not treated with TTFields.ConclusionsThese results shed light on potential driver and passenger mutations in GB that can be validated as predictive biomarkers of response to TTFields treatment, and provide an objective and testable genomic-based approach to assessing response.

Efficacy of a Novel Oral Chemotherapeutic Agent, TAS-102, Against Human Oral Squamous Cell Carcinoma Cells.

TAS-102 is effective against unresectable advanced or recurrent colorectal and gastric cancer. However, its effect on oral squamous cell carcinoma (OSCC) is still unknown. Here, we tried to clarify the possible effect of TAS-102 against angiogenesis and proliferation of human OSCC cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration assay and mice xenograft models were used to determine the effect of TAS-102 on growth and migration of OSCC. The activity of phosphorylated nuclear factor kappa light-chain-enhancer of activated B-cells (NF-κB) (p-p65) in cells was detected by immunocytochemistry. The expression of p-AKT serine/threonine kinase 1 (p-AKT), p-p65, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2) and CD31 in mouse tumors were detected by immunohistochemistry. TAS-102 significantly inhibited growth and migration of OSCC both in vitro and in vivo. It suppressed the activity of NF-κB in cells. TAS-102 down-regulated the expression of p-AKT, VEGF, FGF2 and CD31, which was associated with reduced vascularization of HSC2 tumor lesions. These findings suggest that TAS-102 might inhibit angiogenesis and proliferation of OSCC cells.

Abstract PO-058: Anti-cancer activity of NTAX-44 (bioprocessed arsenic trioxide) on pancreatic cancer cell line

Abstract Purpose: Pancreatic Cancer remains to be highly lethal malignancy mainly because of a high incidence of drug resistance. Because of this, there is a great need for new therapies which can improve overall therapeutic outcomes in pancreatic cancer patients. Arsenic trioxide is an approved drug for the treatment of acute promyelocytic leukemia (APML) and is in the experimental stage for use in different malignancies. Earlier in-vitro studies on human pancreatic cell lines have shown that arsenic trioxide has potent anti-proliferative effects with induction of apoptosis. NTAX-44 is a novel orally administrable Arsenic trioxide that is derived using green chemistry based patented technology. This compound is bioavailable when administered orally, and it has demonstrated good safety and tolerability in bioavailability clinical trials. In the present study, we conducted preclinical studies to evaluate the anti-proliferative effect and inhibition of programmed cell death ligand-1 (PD-L1) expression activity by NTAX-44. Method: The effect of NTAX-44 was assessed on the viability of MIA-Pa-Ca-2 cell lines grown as monolayers by MTS assay. We further checked the expression of PD-L1 in MIA-Pa-Ca-2 cell line treated with NTAX-44 by flow cytometry. PD-L1, an immune checkpoint regulator, has been speculated to play a significant role in suppressing the immune system. It also helps tumor cells evade anti-tumor immunity. The expression of PD-L1 was induced by IFN-gamma stimulation. The anti-metastatic capacity of NTAX-44 was evaluated by in ovo chick embryo yolk sac membrane (YSM) angiogenesis assay. The cytocompatibility testing was done by testing the effect of NTAX-44 on the viability of normal human peripheral blood mononuclear cells (PBMC) by MTS assay. Results: NTAX-44 effectively inhibited the viability of MIA-Pa-Ca (IC50 4.63 +/- 1.16μg/ml for 48 hr and 0.50 +/- 0.63 for 72 hr of treatment); demonstrating the anti-proliferative activity of NTAX-44 against MIA-Pa-Ca-2 cell line. Furthermore, NTAX-44 at 25µg/ml concentration significantly inhibited IFN-gamma-induced PD-L1 expression in the MIA-Pa-Ca-2 cell line. Evaluation of the anti-metastatic potential of NTAX-44 exhibited around 40% inhibition in the number of quaternary blood vessels was observed on the treatment of YSM with NTAX-44 compared to vehicle control. It is noteworthy that the anti-angiogenic activity was comparable to that of Bevacizumab (Avastin®). The cytocompatibility testing revealed that it was well tolerated at a concentration up to 200μg/ml in PBMC cells. Conclusions: The preclinical data presented in this study suggests the potential of NTAX-44 to inhibit proliferation and, PD-L1 expression in MIA-Pa-Ca-2 cells and prevent angiogenesis in YSM. These properties along, with their good tolerability as indicated by cytocompatibility testing, are indicative of the potential role of NTAX-44 as an oral chemotherapeutic agent in the treatment of Pancreatic cancer. Though the preclinical studies performed on NTAX-44 are very promising but further clinical evaluation is warranted. Citation Format: Yogesh Bendale, Padma Shastri, Radha Poojari, Nandinee Khot, Surendra Nagare, Avinash Kadam. Anti-cancer activity of NTAX-44 (bioprocessed arsenic trioxide) on pancreatic cancer cell line [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-058.

A review of hydroxyurea-related cutaneous adverse events

ABSTRACT Introduction: Hydroxyurea (HU) is an S-phase specific oral chemotherapeutic agent that inhibits ribonucleotide diphosphate reductase. It is the most common used cytoreductive drug in patients (pts) with BCR-ABL1 negative myeloproliferative neoplasms (MPN) and sickle cell disease (SCD). The World Health Organization lists HU as an „essential drug“. Although most patients tolerate HU well, cutaneous adverse events (CAE) are frequent side effects and may limit its long-term use. This has become increasingly evident in recent years, especially in MPN patients, where CAE were previously underestimated and underdiagnosed. Areas covered: In this review, we present the available literature on HU-related CAE in MPN patients. In particular, data from a recently ? “a recently” published and so far, only prospective non-interventional study investigating CAE in 172 MPN patients will be discussed in detail and compared with previously available data. Finally, we give an overview of the management of HU-related CAE in MPN patients and provide recommendations on the practical clinical approach. Expert opinion: In clinical practice, HU associated CAE are common and have important diagnostic and therapeutic consequences. Therefore, they should be considered in all MPN patients treated with HU in the future.

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.

261 Poster - Treatment efficacy and predictors of durable response to capecitabine monotherapy in advanced breast cancer: Real-world evidence from a large single-centre cohort

Background: Capecitabine, an oral chemotherapeutic agent (fluoropyrimidines), is approved in monotherapy in metastatic breast cancer (MBC) after failure of taxanes and anthracycline. We investigated clinical and pathologic characteristics as possible predictors of durable response, time to progression (TTP) and overall survival (OS) in MBC patients treated with capecitabine monotherapy.

Biopharmaceutics and Pharmacokinetics of Timosaponin A-III by a Sensitive HPLC-MS/MS Method: Low Bioavailability Resulting from Poor Permeability and Solubility.

Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague- Dawley rats by oral (20 mg/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III was 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 × 10-7 cm/s, indicating a difficult absorption. A strikingly high efflux transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10-6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, i.e. 30.58 μg/mL. Timosaponin A-III exhibited low oral bioavailability by oral and intravenous administration, which was probably caused by its low permeability and solubility. This study may provide a reference for its rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.