Oral Paclitaxel Research Articles

Developing a novel P-glycoprotein inhibitor and pairing it with oral paclitaxel liposomes for enhanced cancer therapy

The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1H NMR, 13C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e., the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.

Solubilization of Paclitaxel with Natural Compound Rubusoside toward Improving Oral Bioavailability in a Rodent Model.

Paclitaxel, which features low water solubility and permeability, is an efflux pump substrate. The current paclitaxel drugs are given intravenously after resolving the solubility issue. Yet, oral delivery to achieve therapeutic bioavailability is not effective due to low absorption. This study evaluated a natural compound, rubusoside, to improve oral bioavailability in an animal model. Free paclitaxel molecules were processed into nano-micelles formed in water with rubusoside. The particle size of the nano-micelles in water was determined using dynamic light scattering. The oral bioavailability of paclitaxel in nano-micelles was determined against Cremophor/alcohol-solubilized Taxol after oral and intravenous administration to pre-cannulated Sprague Dawley rats. When loaded into the rubusoside-formed nano-micelles, paclitaxel reached a supersaturated concentration of 6 mg/mL, 60,000-fold over its intrinsic saturation of 0.1 µg/mL. The mean particle size was 4.7 ± 0.7 nm in diameter. Compared with Taxol®, maximum blood concentration was increased by 1.5-fold; the time to reach maximum concentration shortened to 0.8 h from 1.7 h; and, relative oral bioavailability increased by 88%. Absolute oral bioavailability was 1.7% and 1.3% for the paclitaxel nano-micelles and Taxol®, respectively. Solubilizing paclitaxel with rubusoside was successful, but oral bioavailability remained low. Further inhibition of the efflux pump and/or first metabolism may allow more oral paclitaxel to enter systemic circulation.

Paclitaxel oral solution versus paclitaxel injection as second-line therapy in advanced gastric cancer: A randomized, open-label, non-inferiority phase 3 trial.

4051 Background: Paclitaxel injection (paclitaxel IV) is category 1 preferred regimen in the second-line therapy of gastric cancer. Safer and more convenient paclitaxel oral solution (Liporaxel), the world’s first oral formulation, has been initially approved in Korea for treatment of gastric cancer. This study aimed to determine non-inferiority in efficacy and safety profile of paclitaxel oral solution versus paclitaxel IV, as monotherapy in larger population with unresectable locally advanced, recurrent or metastatic gastric cancer in China. Methods: This is a randomized, open-label, non-inferiority phase 3 trial conducted at 53 centers in China. Patients with unresectable or recurrent or metastatic gastric cancer progressed after fluoropyrimidine- or fluoropyrimidine plus platinum-based first-line therapy were randomly assigned 1:1 (stratified by gastrectomy, ECOG PS and prior chemotherapy) to receive oral paclitaxel (200mg/m2 twice daily on days 1, 8, 15 every 4 weeks) or paclitaxel IV (175mg/m2 on day 1 every 3 weeks). The co-primary endpoints were blind independent review committee (BIRC)-assessed progression-free survival (PFS) and overall survival (OS), with non-inferiority margin of hazard ratio (HR) of 1.18 and 1.16 in statistical comparison, respectively. Results: From April 22, 2019, to January 31, 2022 (data cut-off), 536 patients were randomized to oral paclitaxel (n=268) or paclitaxel IV (n=268), with median follow-up of 13.4 vs. 12.6 months, respectively. The PFS showed non-inferiority of oral paclitaxel to paclitaxel IV with median BIRC-assessed PFS 3.02 months (95% confidence interval [CI]: 2.69, 3.71) in oral paclitaxel vs. 2.89 months (95% CI: 2.53, 3.48) in paclitaxel IV (HR 0.894, 95% CI: 0.719, 1.112, p=0.311). The OS (cutoff on February 15, 2023) showed superiority of oral paclitaxel over paclitaxel IV with median OS 9.13 months (95% CI: 7.72, 10.97) in oral paclitaxel vs. 6.54 months (95% CI: 5.75, 7.26) in paclitaxel IV (HR 0.770, 95.5% CI: 0.635, 0.934, p=0.006). For the treatment-related adverse events (TRAEs), oral paclitaxel decreased neuropathy incidence (22.3% vs. 38.7% all grade) and no hypersensitivity occurred in oral paclitaxel without premedication. The most common ≥Grade 3 TRAEs were neutrophil count decreased (47.9% in oral paclitaxel vs. 54.5% in paclitaxel IV), white blood cell count decreased (41.5% vs. 35.3%) and anemia (16.6% vs. 10.9%). Grade 5 TRAEs were at low with comparable incidences (four [1.5%] vs. three [1.1%]). Conclusions: The study showed statistical non-inferiority of paclitaxel oral solution in PFS and statistically significant and clinically meaningful improvement in OS as compared to paclitaxel IV, with clinically manageable safety profile, supporting paclitaxel oral solution as second-line treatment option for patients with gastric cancer. Clinical trial information: CTR20190050.

Abstract PO5-06-14: Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma

Abstract Background: Triple-negative (TN) invasive lobular carcinoma (ILC) of the breast is a rare entity, comprising roughly 2% of primary ILC. Clinicopathologic studies have shown that TN ILC is associated with more pleomorphism, higher nuclear grade, older patient age, and worse disease-related outcomes compared to estrogen receptor-positive (ER+) ILC. Intrinsic subtyping indicates that TN ILC less frequently expresses basal markers than TN invasive ductal carcinoma (IDC). This prompted investigation of the genomic landscape and clinical management of TN ILC to provide insight into potential therapeutic approaches. Methods: Twenty patients with TN ILC were included in this study. Three patients were treated at a single academic center and underwent comprehensive genomic profiling (CGP) of breast or metastatic tissue; clinicopathologic details were obtained from their electronic health records. Seventeen patients with TN ILC who underwent CGP of breast or metastatic biopsies were included from the Foundation Medicine, Inc. database. PD-L1 testing for all patients was determined by immunohistochemistry (IHC) using the VENTANA SP142 or Dako 22C3 commercial assays. HER2 expression was determined by IHC. Negative HER2 expression was defined as an IHC score of 0, or IHC 1+ or 2+ with non-amplified fluorescence in situ hybridization (FISH). Results: In the Foundation Medicine database of patients with TN ILC, the most frequent genomic alterations were in CDH1 (15/17 patients [88.2%]), TP53 (10/17 patients [58.8%]), and PIK3CA (10/17 patients [58.8%]). Short variant mutations in ERBB2 were found in 3/17 patients (17.6%). Fourteen patients were HER2-low (HER2 IHC 1+ or 2+ with non-amplified FISH). No cases were MSI high or expressed PD-L1 (8 of 17 cases underwent PD-L1 assessment by SP142). Median tumor mutational burden (TMB) was 5 muts/Mb. Among the three patients with TN ILC treated at a single center, the most common somatic mutations were in CDH1 and TP53, and no cases were MSI high or expressed PD-L1 (by SP142 or 22C3). All three patients had pleomorphic ILC, histologic grade 2 or 3, and HER2 IHC 0. One patient with mpT1cN1a(sn) ER+/HER2- ILC of the right breast in 2011 received adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide), breast/axillary radiation, and ten years of adjuvant endocrine therapy. She was diagnosed with TN ILC of the left supraclavicular nodes in 2022; she did not exhibit a response to docetaxel and carboplatin with pembrolizumab, and she subsequently received palliative radiation followed by capecitabine. Another patient with locally advanced TN ILC progressed on the KEYNOTE-522 regimen, immediately developed metastases, and is currently receiving palliative sacituzumab govitecan. The third patient with cT3N1 TN ILC progressed on neoadjuvant therapy (through the I-SPY 2 trial) with oral paclitaxel, encequidar, and dostarlimab, followed by dostarlimab with dose-dense doxorubicin and cyclophosphamide. Her surgical pathology demonstrated ypT3N3a disease with 10 × 7 cm of tumor, and she developed skin metastases on the chest wall within weeks post-operatively. She received comprehensive chest wall and nodal radiation and is currently receiving palliative capecitabine with neratinib given a high variant allele frequency driver somatic ERBB2 mutation. Conclusions: The most common somatic mutations among TN ILC patients included in this study were in CDH1, TP53, and PIK3CA. Currently the management of TN ILC is extrapolated from that of TN IDC, however our patients did not respond to chemoimmunotherapy. The presence of HER2-low status or somatic ERBB2 mutations may provide opportunities for treatment with an anti-HER2 antibody-drug conjugate or tyrosine kinase inhibitor. Studies with larger sample sizes of TN ILC are needed for molecular profiling and assessment of outcomes with specific therapeutic approaches. Citation Format: Hemali Batra-Sharma, Smruthy Sivakumar, Prashanth Ashok Kumar, Ethan Sokol, Rebecca Shatsky, Jeffrey Ross. Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma [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 PO5-06-14.

Abstract LB023: A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics

Abstract The therapeutic efficacy of a novel oral Paclitaxel formulation was evaluated and compared in Balb/c nude mice bearing PDX NSCLC, gastric cancer, liver cancer, breast cancer, and ovarian cancer treated with Abraxane, Taxol, Lenvatinib and Sorafenib. Therapeutic parameters including tumor volume, tumor growth inhibition (TGI), and treatment-to-control ratio (T/C) were compared among different treatment groups. The drug tolerance, cytotoxicity and safety profile of the oral Paclitaxel formulations were evaluated in Balb/c nude mice and beagle dogs. The tumor distribution of Paclitaxel in NCI-N87 gastric cancer-bearing mice after administration of oral Paclitaxel formulation and Paclitaxel Injection was investigated. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Albumin-bound Paclitaxel for Injectable Suspension at 30 mg/Kg and Paclitaxel Injection at 15 mg/Kg for NCI-N87 gastric cancer-bearing mice, while the same 100 mg/Kg dose demonstrated noninferior therapeutic efficacy to Abraxane and significant better therapeutic efficacy than Taxol in Hs467T gastric cancer-bearing mice. The oral Paclitaxel formulation administrated at 180 mg/Kg demonstrated noninferior therapeutic efficacy compared with Lenvatinib at 40 mg/Kg, and significant better therapeutic efficacy than Sorafenib at 30 mg/Kg for Hep G2 liver cancer-bearing mice, while the oral paclitaxel at 180 mg/Kg showed inferior therapeutic efficacy than Lenvatinib at 30 mg/Kg but noninferior therapeutic efficacy to Sorafenib at 30 mg/Kg for Huh-7 liver cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Abraxane for Injectable Suspension at 30 mg/Kg and Taxol at 15 mg/Kg for NCI-H358 NSCLC-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane for Injectable Suspension at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for MDA-MB-231 breast cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for SK-OV-3 ovarian cancer-bearing mice. The gastric tumor distribution of Paclitaxel between 6-24 hour was similar after oral and intravenous administration. The Maximum Tolerated Dose (MTD) of the oral Paclitaxel was determined to be ≥ 200 mg/Kg in mice and ≥ 8.0 mg/Kg in beagle dogs when dosing at Q3DX3Weeks, there were no significant body weight losses, tissue damages and animal death observed during the long-term safety assessment study. The oral Paclitaxel formulation demonstrated better or noninferior therapeutic efficacy in five different PDX tumor-bearing mice compared with standard treatment drugs, good safety and low cytotoxicity at high doses in long-term safety and toxicity studies were observed in both mice and beagle dogs. The oral Paclitaxel formulation showed promising therapeutic potential for various cancer treatment and conducting “chemotherapy at home” with lower medical costs. Citation Format: Hui Yu Huang, Richard Jun Huang. A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB023.

Co-release of paclitaxel and encequidar from amorphous solid dispersions increase oral paclitaxel bioavailability in rats

The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.

Paclitaxel combined with Compound K inducing pyroptosis of non-small cell lung cancer cells by regulating Treg/Th17 balance

BackgroundImmune checkpoint inhibitors, which have attracted much attention in recent years, have achieved good efficacy, but their use is limited by the high incidence of acquired drug resistance. Therefore, there is an urgent need to develop new immunotherapy drugs. Compound taxus chinensis capsule (CTC) is an oral paclitaxel compound drug, clinical results showed it can change the number of regulatory T cells and T helper cell 17 in peripheral blood. Regulating the balance between regulatory T cells and T helper cell 17 is considered to be an effective anticancer strategy. Paclitaxel and ginsenoside metabolite compound K are the main immunomodulatory components, it is not clear that paclitaxel combined with compound K can inhibit tumor development by regulating the balance between regulatory T cell and T helper cell 17.MethodsMTT, EdU proliferation and plate colony formation assay were used to determine the concentration of paclitaxel and compound K. AnnexinV-FITC/PI staining, ELISA, Western Blot assay, Flow Cytometry and Immunofluorescence were used to investigate the effect of paclitaxel combined with compound K on Lewis cell cultured alone or co-cultured with splenic lymphocyte. Finally, transplanted tumor C57BL/6 mice model was constructed to investigate the anti-cancer effect in vivo.ResultsAccording to the results of MTT, EdU proliferation and plate colony formation assay, paclitaxel (10 nM) and compound K (60 μM) was used to explore the mechanism. The results of Flow Cytometry demonstrated that paclitaxel combined with compound K increased the number of T helper cell 17 and decreased the number of regulatory T cells, which induced pyroptosis of cancer cells. The balance was mediated by the JAK–STAT pathway according to the results of Western Blot and Immunofluorescence. Finally, the in vivo results showed that paclitaxel combined with compound K significantly inhibit the progression of lung cancer.ConclusionsIn this study, we found that paclitaxel combined with compound K can activate CD8+ T cells and induce pyroptosis of tumor cells by regulating the balance between regulatory T cells and T helper cell 17. These results demonstrated that this is a feasible treatment strategy for lung cancer.

Anti-cancer effects of DHP107 on canine mammary gland cancer examined through in-vitro and in-vivo mouse xenograft models

BackgroundCanine mammary gland cancer (CMGC) is a common neoplasm in intact bitches. However, the benefit of adjuvant chemotherapy is unclear. The aim of this study was to investigate the anti-proliferative effects of paclitaxel on CMGC in in-vitro and in-vivo settings.ResultsPaclitaxel dose-dependently inhibited viability and induced G2/M phase cell cycle arrest and apoptosis in both primary and metastatic CMGC cell lines (CIPp and CIPm). In animal experiments, the average tumour volume decreased significantly in proportion to the administered oral paclitaxel dose. By examining tumour tissue using a TUNEL assay and immunohistochemical staining with anti-CD31 as a marker of endothelial differentiation, respectively, it was confirmed that oral paclitaxel induced apoptosis and exerted an anti-angiogenetic effect in tumour tissues. Further, downregulation of cyclin D1 in tumour tissues suggested that oral paclitaxel induced cell cycle arrest in tumour tissues in-vivo.ConclusionsOur results suggest that paclitaxel may have anti-cancer effects on CMGC through cell cycle arrest, induction of apoptosis, and anti-angiogenesis. This study could provide a novel approach to treat CMGC.

Porous Starch-Based Capsule as an Effective Colon-Targeting Carrier for Oral Paclitaxel Delivery

Porous Starch-Based Capsule as an Effective Colon-Targeting Carrier for Oral Paclitaxel Delivery

Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The invitro and invivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase invivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Oral paclitaxel and dostarlimab with or without trastuzumab in early-stage, high-risk breast cancer: Results from the neoadjuvant ISPY 2 TRIAL.

LBA612 Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) status to evaluate novel neoadjuvant agents in high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Oral Paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar. Dostarlimab (D) is an intravenous (IV) PD-1 inhibitor. Methods: Women with tumors ≥ 2.5cm and MP high risk cancers (MP1 = MP high; MP2 = MP ultra-high) were treated starting Oct 5, 2020. Treatment included OPE (Oral P 205mg/m2 + encequidar 12.9mg) on days 1-3 weekly x 12 and D 500 mg IV given q 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q 2-3 weeks x 4. Patients with HER2+ disease received IV weekly trastuzumab (T) during the first 12 weeks. The control arm was weekly IV P x 12 with or without trastuzumab followed by AC q 2-3 weeks x 4. OPE + D was eligible to graduate [85% chance of success in a 300-person phase 3 neoadjuvant trial with a pCR endpoint] in any of the pre-defined signatures. Results: 113 (78 HR+HER2-, 17 HR-HER2- and 18 HER2+ patients) received OPE + D +/- T. The control arm included 388 historical controls (201 HR+Her2-, 156 HR-HER2-, 31 HER2+). 77 patients (70 HR+ and 7 HR-) were MP1 and 36 patients (24 HR+ and 12 HR-) were MP2. Safety events of note for OPE + D versus IV P include increased rates of nausea (85% vs. 72%) diarrhea (77% vs. 41%). There was no significant difference in rates of neutropenia (23% vs.17%). Peripheral neuropathy (37% vs. 64%) and alopecia (59% vs. 66%) were significantly decreased. Immune related adverse events (irAEs) were lower than expected. Conclusions: Although both OPE and D have both been shown to have efficacy in other settings, combination therapy with OPE + D did not graduate in any of the predefined subtypes. In the HR+ signature where we would not expect a benefit of D, we see equal response to OPE with decreased rates of peripheral neuropathy and alopecia, which suggest this oral agent may be an attractive alternative to IV P in this subgroup and is under consideration in ISPY 2.2. We did not observe the expected improvement in pCR rates seen with PD-1 inhibitors in the HR- or MP2 subtypes (over P alone historic control). In addition, the irAEs were less than expected. Together these findings suggest interference of OPE with D. A potential mechanism of interference could be change in microbiome with the use of OPE vs. IV P, as the microbiome is known to influence the efficacy of immunotherapy. The source of interference is being investigated. Clinical trial information: NCT01042379 . [Table: see text]

Oral paclitaxel, carboplatin, and dostarlimab (OPE/Cb/D) without and with trastuzumab in early-stage, high-risk breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL.

LBA520 Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . [Table: see text]

Oral paclitaxel and encequidar in patients with breast cancer: a pharmacokinetic, safety, and antitumor activity study.

Paclitaxel is widely used for the treatment of metastatic breast cancer (MBC). However, it has a low oral bioavailability due to gut extrusion caused by P-glycoprotein (P-gp). Oral paclitaxel (oPAC) may be more convenient, less resource-intensive, and more tolerable than its intravenous form. Encequidar (E) is a first-in-class, minimally absorbed, gut-specific oral P-gp inhibitor that facilitates the oral absorption of paclitaxel. To investigate the pharmacokinetics (PK), overall response rate (ORR), and safety of weekly oral paclitaxel with encequidar (oPAC + E) in patients with advanced breast cancer. This is a multicenter, single-arm, open-label study in six medical centers in Taiwan. Patients with advanced breast cancer were administered 205 mg/m2 oPAC and 12.9 mg E for 3 consecutive days weekly for up to 16 weeks. Plasma samples were collected at weeks 1 and 4. PK, ORR, and safety were evaluated. In all, 28 patients were enrolled; 27 had MBC; 23 had prior chemotherapy; and 14 had ⩾2 lines of prior chemotherapy. PK were evaluable in 25 patients. Plasma paclitaxel area under the curve (AUC)(0-52 h) at week 1 (3419 ± 1475 ng h/ml) and week 4 (3224 ± 1150 ng h/ml) were equivalent. Best overall response in 28 evaluable patients was partial response (PR) in 11 (39.3%), 13 (46.4%) stable disease (SD), and 1 (3.6%) with progressive disease (PD). No patient achieved complete response (CR). The clinical benefit rate (CR + PR + SD) was 85.7%. Major adverse events among the 28 treated patients were grade 3 neutropenia (25%), grade 4 neutropenia (18%), with febrile neutropenia in 4%, and grade 3 diarrhea (4%). No treatment-related deaths occurred. Grade 2 peripheral neuropathy occurred in 1 (4%) patient and grade 3 peripheral neuropathy in 1 (4%) patient. oPAC + E produced a consistent therapeutic plasma paclitaxel exposure during treatment. There was a high rate of radiologically assessed clinical benefit, and a low rate of neurotoxicity which may provide advantages over IV paclitaxel. ClinicalTrials.gov Identifier: NCT03165955.

The effect and mechanistic study of encequidar on reversing the resistance of SW620/AD300 cells to doxorubicin

Encequidar, a gut-specific P-glycoprotein (P-gp) inhibitor, makes oral paclitaxel possible, and has been used in clinical treatment of metastatic breast cancer, however, its pharmacological effect and mechanism of reversal of drug resistance in drug-resistant colon cancer cells SW620/AD300 are still unknown. Herein, we first synthesized encequidar and demonstrated that it could inhibit the transport activity of P-gp, reduced doxorubicin (DOX) efflux, enhanced DOX cytotoxicity and promoted tumor-apoptosis in SW620/AD300 cells. Metabolomic analysis of cell samples was performedusing liquid chromatography Q-Exactive mass spectrometer, the results of metabolite enrichment analysis and pathway analysis showed that the combination of encequidar and DOX could: i) significantly affect the citric acid cycle (TCA cycle) and reduce the energy supply required for P-gp to exert its transport activity; ii) affect the metabolism of glutathione, which is the main component of the anti-oxidative stress system, and reduce the ability of cells to resist oxidative stress; iii) increase the intracellular reactive oxygen species (ROS) production and enhance ROS-induced cell damage and lipid peroxidation, which in turn restore the sensitivity of drug-resistant cells to DOX. In conclusion, these results provide sufficient data support for the therapeutical application of the P-gp inhibitor encequidar to reverse MDR, and are of great significance to further understand the therapeutic advantages of encequidar in anti-tumor therapy and guide clinical rational drug use.

265P Phase II study of DHP107 oral paclitaxel compared to IV paclitaxel in patients with HER2-negative recurrent or metastatic breast cancer (MBC): Opera (NCT03326102)

Paclitaxel is an antimitotic agent with demonstrated antineoplastic effect in various cancers including breast cancer. DHP107 (Liporaxel®) is an oral paclitaxel based on a novel lipid formulation approved in Korea for gastric cancer in 2016. This phase II randomized trial aimed to evaluate the efficacy and safety of DHP107 compared with IV paclitaxel (ptx).

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies

PurposeOrally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1).MethodsFifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling.ResultsA pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67–1.33) and 0.46 (95%CI: 0.34–0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122–724).ConclusionThe developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

A Review on Formulation and Evaluation of Nanoniosomal Topical gel of Paclitaxel for skin cancer

Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the goal for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Paclitaxel (PCT) is a chemotherapeutic agent used as a first-line treatment for a wide range of cancers, such as lung, ovarian, breast, prostate, head, and neck cancers, and AIDS-related Kaposi sarcoma. Currently, the marketed forms of Paclitaxel are intravenous formulations. Oral administration of Paclitaxel is unfortunately hampered due to its low bioavailability. This is explained by its low aqueous solubility, low permeability, high affinity for cytochrome P450 and P-glycoprotein. As another approach, drug carrier systems are extensively studied to enhance oral Paclitaxel bioavailability and reduce side effects. The niosomes provides several important advantages over conventional drug therapy. Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non-ionic surface-active agents rather than phospholipids as seen in case of liposomes. Niosome nanoparticles are among these drug delivery systems, which have numerous applications in drug delivery and targeting. Niosomes are frequently used for loading drugs serving different purposes (e.g., anticancer, antiviral, and antibacterial agents). The aim of this review is to evaluate the extent of nanotherapeutics used in anti-cancer activity.

A novel oral paclitaxel and HM10381 (oraxel)-treated metastatic breast cancer: A phase I study (KX-ORAX-CN-007).

1104 Background: This phase I study assessed the pharmacokinetics, safety, antitumor activity of oral paclitaxel and HM10381 (Oraxel) in patients with metastatic breast cancer. Methods: Oraxol (oral paclitaxel 205 mg/m2 plus HM30181A 15 mg) daily for 3 consecutive days weekly for up to 16 weeks was administered to patients. The primary objective endpoint was pharmacokinetic analysis. The secondary endpoint were objective response rate (ORR) and safety. For pharmacokinetic analysis, timed blood samples were collected. Results: Twenty-four female patients were enrolled from Apr 2019 to Aug 2019. The median age was 53 years (range: 35 to 70 years). The mean lines and median line of treatment were 2.5 and 2, respectively. Previous breast cancer treatments included chemotherapy in 23 (96%) patients, hormonal therapy in 20 (83%) patients. Prior taxanes therapy was reported in 20 (83%) patients. There were 15 patients in efficacy dataset. The best ORR (Investigator) was PR in 40%, SD in 53%, and PD in 7%. The best overall response rate (ICRRC) was PR in 36%, SD in 57%, and PD in 7% of patients. There were no hypersensitivity-type reactions. Adverse events of interest neutropenia, neurotoxicity, and diarrhea were reported as 20 (83%)，7 (29%) and 11 (46%), retrospectively. A total of 15 (63%) patients experienced Grade ≥3 TEAEs, including neutrophil count decreased in 11 (46%) patients, WBC count decreased in 8 (33%) patients. Treatment related SAE was reported in 1 (4.17%) patient experienced febrile neutropenia, pneumonia, and septic shock. The PK data indicated that the efficacy response is not associated with oral paclitaxel exposure parameters AUC or Cmax. Conclusions: The study showed that Oraxol as novel oral chemotherapy agent shows promising antitumor activity in patients with metastatic breast cancer, manageable toxicity, and no hypersensitivity-type reactions. Clinical trial information: NCT04993040.

Retrospective analysis of efficacy and safety of oral paclitaxel for treatment of various cancers in dogs (2017-2021).

BackgroundIn humans, several safety evaluations have shown minimal adverse events with oral paclitaxel; however, its therapeutic efficacy and safety has not been well established in dogs with various cancers.ObjectivesWe aimed to retrospectively evaluate the efficacy and safety of oral paclitaxel in dogs with various cancers.MethodsTwenty‐one dogs diagnosed with various cancers were administered several doses of oral paclitaxel three times a month (group 1) or six times a month (group 2).ResultsThe overall response rate was 6.25% (6.25%, complete response; 56.25%, stable disease; 37.5%, progressive disease) in dogs for which the treatment response could be evaluated. The median overall survival (OS) and progression‐free survival (PFS) were 74 and 60.5 days, respectively. Regardless of the administration group, differences in OS and PFS of the two groups did not reach statistical significance. Most dogs tolerated the treatment regimen well, and although minor adverse events were observed in some dogs, they recovered after temporary drug discontinuation, dose reduction or symptomatic treatment. There was no significant difference in the prevalence of adverse events between the two groups.ConclusionsBased on the observed responses in certain types of cancers and the minimal adverse events, the study findings supported the efficacy and safety of oral paclitaxel administration in dogs. Thus, oral paclitaxel could play a role in the management of cancer in dogs.

Population pharmacokinetics for oral paclitaxel in patients with advanced/metastatic solid tumors.

Oraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P‐glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two‐compartment structural model containing first‐order absorption with a short lag time and first‐order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m2 once daily ×3 days per week) to predict exposure of oral paclitaxel and to support treatment benefits observed in a pivotal phase III trial.