Novel oral taxane therapies: recent Phase I results

Flores, John Paul; Saif, Muhammad Wasif

doi:10.4155/cli.13.18

Cited by 23 publications

(12 citation statements)

References 22 publications

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“…taxol-like agents, epothilones have advanced the clinical development of taxanes as a widely applied class of chemotherapeutics. Taxanes are a standard first-line treatment for metastatic breast cancer and are also used for ovarian, breast, and non-small cell lung cancer (72). …”

Section: Microtubule Inhibitorsmentioning

confidence: 99%

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

2017

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This review describes the pivotal roles of cell cycle and checkpoint regulators and discusses development of specific cell cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the crosstalk of signals activated by cell cycle arrest, as well as pediatric-focused drug development are critical for the advancement of drugs for rare childhood diseases.

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Section: Microtubule Inhibitorsmentioning

confidence: 99%

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

2017

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“…Similarly, semisynthetic analogs of taxanes have been utilized in the development of several novel compounds with significantly higher efficiency against paclitaxel-resistant cancers. These include cabazitaxel (FDA approved) and ortataxel which have been shown to be efficient in hormone refractory metastatic prostrate cancer (81,82). Further, these compounds have been shown to be less amenable to efflux by P-gp.…”

Section: P-gp Substrate and Drug Interactionsmentioning

confidence: 99%

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

2020

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Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor M 2-macrophages and, anti-tumor NK-cell and Th17/CD4 + T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

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“…Given these advantages, several different oral taxane formulations are currently in clinical development. 18 However, oral administration of paclitaxel is hampered by its poor bioavailability, because of the poor water solubility and the high first-pass effect after oral intake due to the metabolic enzyme cytochrome P450 (CYP) 3A4 and the P-glycoprotein (P-gp) drug transporter in the gastrointestinal and hepatic cells. 19 We decreased this first-pass effect by the coadministration of different P-gp and a CYP3A4 inhibitors in preclinical studies.…”

Section: In Combinationmentioning

confidence: 99%

A Phase 1 Dose‐Escalation Study of Low‐Dose Metronomic Treatment With Novel Oral Paclitaxel Formulations in Combination With Ritonavir in Patients With Advanced Solid Tumors

Weger

Vermunt

Stuurman

et al. 2020

Clinical Pharm in Drug Dev

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ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted.

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Novel oral taxane therapies: recent Phase I results

Cited by 23 publications

References 22 publications

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

A Phase 1 Dose‐Escalation Study of Low‐Dose Metronomic Treatment With Novel Oral Paclitaxel Formulations in Combination With Ritonavir in Patients With Advanced Solid Tumors

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