A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.

BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. METHODS: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. RESULTS: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. CONCLUSIONS: P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

Dexamethasone is non-inferior to antihistamine plus dexamethasone premedication in preventing ramucirumab plus nab-paclitaxel infusion-related reactions in gastric cancer: a multicenter retrospective study.

PURPOSE: Ramucirumab (RAM) is recommended as premedication with H1-receptor antagonists (H1RA) to prevent infusion-related reactions (IRRs). However, RAM is a human antibody with a low incidence of IRRs. We evaluated the noninferiority of non-H1RA (dexamethasone [DEX] alone) premedication to H1RA (plus DEX) premedication in terms of IRRs in patients with gastric cancer receiving RAM plus nanoparticle albumin-bound paclitaxel (nab-PTX). METHODS: This was a noninferiority, multicenter, retrospective trial conducted in three Japanese centers to assess the incidence of IRRs in patients receiving RAM plus nab-PTX for gastric cancer between 2018 and 2023. Patients with gastric cancer receiving RAM plus nab-PTX were divided into groups with and without H1RA premedication. The incidence of IRRs was compared between the two groups. RESULTS: Ninety patients were evaluated, with non-H1RA and H1RA premedications in 43 and 47 cases, respectively. After the first dose of RAM, IRRs were not observed in either group. IRRs during the overall doses were 0% for non-H1RA premedication and 2.1% for H1RA premedication (90% confidence interval (CI): -5.6%-1.3% for each comparison). The upper limit of the 90% CI (1.3%) did not exceed the noninferiority margin (Δ) of + 10% and therefore met the noninferiority criteria. CONCLUSION: RAM plus nab-PTX for gastric cancer with DEX premedication may be possible without H1RA premedication.

Real-World Outcomes of First-Line Chemotherapy in Metastatic Pancreatic Cancer: A Nationwide Population-Based Study in Korea.

BACKGROUND/OBJECTIVES: This nationwide population-based study investigated the overall survival (OS) of patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy. METHODS: Data from the National Health Insurance Service linked to the Korea Central Cancer Registry were used. Patients with mPC receiving first-line chemotherapy (2012-2019) were included and followed up until 2020. The gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX groups were matched according to age, sex, and comorbidities. RESULTS: In total, 8652 patients with mPC were treated with chemotherapy. GnP and FOLFIRINOX have been administered since 2016 and 2017, respectively. The median OS increased annually from 6 months in 2012-2013 to 10 months in 2018-2019. The median OSs in the GnP and FOLFIRINOX groups were significantly longer than those in patients receiving gemcitabine ± erlotinib. A total of 1134 patients from both the GnP and FOLFIRINOX groups were selected using propensity score matching. Before matching, the median OS was longer in the FOLFIRINOX group than in the GnP group (p = 0.0029). After matching, however, there was no significant difference in the median OS between the two groups (11 vs. 11 months, respectively, p = 0.2438). CONCLUSIONS: Patients with mPC receiving chemotherapy have shown improved OS since the introduction of GnP and FOLFIRINOX. After matching, OS did not differ between the GnP and FOLFIRINOX groups.

Outcomes After Multimodality Treatment of Pancreatic Cancer in an Unselected Single-Center Cohort.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal and rarely resectable malignancy. Here we explore the outcomes of surgery, as compared to definitive radiotherapy (dRT) or systemic therapy only in PDAC. Methods: Pancreatic surgery and radiotherapy in Southwest Finland have been centralized to Turku University Hospital. Previously validated population-based electronic health records database was searched for all unselected PDAC patients from the years 2009-2019. Main outcome was median overall survival (mOS). Demographics, pathology, surgery, and oncological treatment data were collected. Results: We identified 1006 patients with PDAC, 49% male, median age 71 years and 77% presenting with metastatic disease. In total, 405 patients were treated; 92 resected, 26 dRT without resection and 287 systemic therapy only. mOS was 34.6 months for resected, 26.7 months for dRT, and 7.5 months for systemic therapy patients. Among the 88 patients with locally advanced inoperable PDAC, dRT was independently associated with longer mOS (26.7 months) as compared to systemic therapy only (mOS 10.6 months). Among the 287 patients treated with systemic therapy only, combination chemotherapy was independently associated with longer mOS (11.6 months) as compared to gemcitabine-monotherapy (6.8 months). In patients progressing to second-line systemic treatment after gemcitabine failure, mOS was the same (5.0 months) with single or combination regimens. Conclusion: Surgery remains the only curative approach for PDAC. In locally advanced PDAC, dRT was associated with longer survival as compared to systemic therapy only. Concerning first-line systemic therapy, our results support the use of combination chemotherapy over single-agent therapy.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. RESULTS: Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. CONCLUSION: The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov).

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A phase II study of FOLFOX combined with nab-paclitaxel in the treatment of metastatic or advanced unresectable gastric, gastroesophageal junction adenocarcinoma: a Big Ten Cancer Research Consortium trial.

BACKGROUND: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability. PATIENTS AND METHODS: Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate. RESULTS: The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each). CONCLUSIONS: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

Economic evaluation of NALIRIFOX vs. nab-paclitaxel and gemcitabine regimens for first-line treatment of metastatic pancreatic ductal adenocarcinoma from U.S. perspective.

BACKGROUND: The cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers. METHODS: A partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model's robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold. RESULTS: In the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction). CONCLUSIONS: NALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models.

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.

Randomized phase 2 study of valproic acid combined with simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic pancreatic adenocarcinoma patients: the VESPA trial study protocol.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. METHODS/DESIGN: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. CONCLUSIONS: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. TRIAL REGISTRATION: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.

BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer.

BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

Safety of nab-paclitaxel following an allergic reaction to paclitaxel: A single institution retrospective study.

The goal of this study was to assess the safety of nab-paclitaxel in patients with ovarian cancer or endometrial cancer who had an allergic reaction to paclitaxel. We performed a retrospective review of patients with endometrial cancer or ovarian cancer with an allergic reaction to paclitaxel who were subsequently treated with nab-paclitaxel at the Mayo Clinic Florida from January 2016 to June 2023. A total of 43 patients with ovarian cancer (31) or endometrial cancer (12) and a paclitaxel allergic reaction were identified. All patients were pre-medicated against allergic reactions prior to paclitaxel and subsequent nab-paclitaxel. Allergic reactions to paclitaxel were mild in fourteen patients (33%), moderate in twenty-five patients (58%) and severe in four (9%) patients. None of the 43 patients had an allergic reaction to subsequent nab-paclitaxel. Our data suggests that the administration of nab-paclitaxel to endometrial cancer or ovarian cancer patients with allergic reactions to paclitaxel is safe and should be considered a preferable treatment option in this clinical situation.

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers: An open-label, non-randomized, phase II clinical trial.

BACKGROUND: Biliary tract cancers (BTCs) are a heterogeneous group of tumors with high malignancy, poor prognosis, and limited treatment options. AIM: To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs. METHODS: This open-label, non-randomized, double-center, phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University. Eligible patients were administered nab-paclitaxel (150 mg/m2, day 1) and capecitabine (2000 mg/m2, twice daily, days 1-7) in 14-day cycles until experiencing intolerable toxicity or disease progression. The primary outcome was the objective response rate (ORR). The secondary outcomes included the disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety. RESULTS: A total of 44 patients successfully completed the trial, with a median age of 64.00 years (interquartile range, 35.00-76.00), and 26 (59.09%) were females. Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage. Among the remaining 43 patients undergoing at least one imaging assessment, the ORR was 23.26% [95% confidence interval (CI): 11.80%-38.60%], and the DCR was 69.77% (95%CI: 53.90%-82.80%). The median OS was 14.1 months (95%CI: 8.3-19.9), and the median PFS was 4.4 months (95%CI: 2.5-6.3). A total of 41 patients (93.18%) experienced at least one adverse event (AE), with 10 patients (22.73%) encountering grade ≥ 3 AEs, and the most frequent AEs of any grade were alopecia (79.50%), leukopenia (54.55%), neutropenia (52.27%), and liver dysfunction (40.91%), and no treatment-related deaths were documented. CONCLUSION: Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Phase II study of nab-paclitaxel with gemcitabine for relapsed/refractory small cell lung cancer.

Background: Patients with small cell lung cancer (SCLC) often respond to first-line chemoimmunotherapy. However, relapse is inevitable and is associated with a poor prognosis. Treatments for relapsed SCLC, such as lurbinectedin and topotecan, are limited by modest efficacy and significant hematologic adverse events, leaving a need for newer therapeutic agents or regimens. The combination of gemcitabine and nab-paclitaxel is active and safe in other types of malignancies, such as pancreatic cancer. Patients and methods: We conducted a phase II trial evaluating the efficacy and safety of gemcitabine and nab-paclitaxel in patients with relapsed/refractory SCLC. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with confirmed complete or partial response. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety. Results: Between October 2016 and May 2021, 32 patients were enrolled. Patients were followed for a median of 9.3 months (range 1.8-65.2). Median age was 65 years (range 48-81). Fifty percent of patients were female. Fifty-three percent of patients had platinum-resistant/refractory relapsed SCLC. The ORR was 28.1% (95% confidence interval [CI] 15.5-100%). Median PFS was 2.9 months (95% CI 2.4-3.6), and median OS was 9.3 months (95% CI 5.2-12.4). Seven patients (21.9%) developed grade 3 or 4 neutropenia. Conclusion: Our study showed that the combination of gemcitabine and nab-paclitaxel led to encouraging outcomes in relapsed/refractory SCLC. Further studies are needed to compare this combination with other treatments used for relapsed SCLC, including lurbinectedin, temozolomide, and topotecan. Clinical trial registration: https://clinicaltrials.gov/study/NCT02769832?cond=NCT02769832&rank=1, identifier NCT02769832.

Conversion chemoradiotherapy combined with nab-paclitaxel plus cisplatin in patients with locally advanced borderline-resectable or unresectable esophageal squamous cell carcinoma: a phase i/ii prospective cohort study.

BACKGROUND: To evaluate the efficacy and safety of nab-paclitaxel plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC (cT3­4, Nany, M0­1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-paclitaxel plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), event-free survival (EFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate, adverse events (AEs) and postoperative complications were calculated. RESULTS: 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1 and 2 years were 81.5%, 86.6%, 64.3%, 73.2 and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6 and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patitents and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95%CI, 1.10-23.94; P = 0.021). The toxicities during chemoradiotherapy were tolerated, and the most common grade 3-4 toxicitiy was radiation esophagitis (15.6%). The most common postoperative complication was pleural effusion (38.1%) and no grade ≥ IIIb complications were observed. CONCLUSION: nab-paclitaxel plus cisplatin are safe as the regimen of conversional chemoradiotherapy of ESCC.

First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease.

BACKGROUND/AIM: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. CASE REPORT: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

PURPOSE: This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. METHODS: A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. RESULTS: The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count. CONCLUSION: The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).