Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial

Keefe, Stephen Michael; Hoffman-Censits, Jean H.; Cohen, Roger B.; Mamtani, Ronac; Heitjan, Daniel F.; Eliasof, Scott; Nixon, Andrew B.; Turnbull, Barry; Garmey, Edward G.; Gunnarsson, Örvar; Waliki, M.; Ciconte, Joanne; Jayaraman, Lata; Senderowicz, Adrian M.; Tellez, Andres; Hennessy, Meliessa; Piscitelli, A.; Vaughn, David J.; Smith, Amanda M.; Haas, Naomi B.

doi:10.1093/annonc/mdw188

Cited by 42 publications

(32 citation statements)

References 21 publications

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“…Prolonged stable disease with clear evidence of tumor shrinkage was observed in one patient with renal cell carcinoma (RCC) and in one patient with hepatocellular carcinoma (34). In the phase-I/IIa trial, CRLX101, a nanoparticle-drug conjugate containing camptothecin and polyethylene glycol that downregulated HIF-1α expression, was tested against metastatic RCC in combination with bevacizumab; five out of 22 patients (23%) achieved a partial response (35). The results of a phase-II trial of CRLX101 against recurrent ovarian, fallopian tube, or primary peritoneal cancer have also been reported (36).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells

et al. 2020

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Background/Aim: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. Materials and Methods: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. Results: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-timedependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. Conclusion: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor. Malignant pleural mesothelioma (MPM) is an aggressive type of neoplasms arising from the pleural cavity (1, 2). It has been reported that about 80% of MPM cases are related to asbestos exposure (3). Genetic predisposition, simian Virus 40 infection (SV40), radiotherapy, and exposure to fibers with physical properties similar to asbestos, may trigger to MPM development (4-7). As MPM patients are typically diagnosed at advanced stages of cancer, which are mostly unresponsive to conventional chemotherapy, the prognosis remains poor. The median survival of patients with MPM ranges from 9 to 12 months, regardless of treatment with chemotherapy combining cisplatin and pemetrexed or raltitrexed (8, 9). Recently, molecular targeted therapy has gained much attention. In cancers such as non-small-cell lung cancer and breast cancer, somatic mutations and gene amplifications are thought to be oncogenic, and treatment with inhibitors specific to tumors with such drivers are beneficial for survival (10) and efforts are being undertaken to assess the genetic abnormalities in solid tumors (11-13). Recently, immune checkpoint inhibitors have shown immense efficacy in various malignancies. Nivolumab elicits significant effects in patients with MPM and has been approved for the treatment of MPM in Japan (14, 15). Despite these advances, improvements in chemotherapy, especially with respect to molecular targeted agents for MPM treatment, are quite slow, partly because the number of patients is small. However, thus far, several studies on the genetic alterations in MPM have been published. A homozygous deletion in PTEN was detected in two of 21 MPM cell lines and this mutation was related to Akt activation (16, 17). Thomas et al. have reported NRAS mutations in three of 37 patients with mesothelioma (18). Appro...

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Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells

et al. 2020

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“…Another paclitaxel-based PEG-co-PLA nanomedicine is under phase III trial, Genexol-PM, has shown lower toxicity in the treatment of non-small cell lung cancer (NSCLC) and metastatic breast cancer [169]. CRLX-101, a cyclodextrin-conjugated camptothecin, is under clinical phase I/II trial for rectal cancer [170]. New targeted polymeric nanomaterials are also being introduced into clinical trials.…”

Section: Fda Approval and Clinical Trialsmentioning

confidence: 99%

Evolution and clinical translation of drug delivery nanomaterials

et al. 2017

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With the advent of technology, the role of nanomaterials in medicine has grown exponentially in the last few decades. The main advantage of such materials has been exploited in drug delivery applications, due to their effective targeting that in turn reduces systemic toxicity compared to the conventional routes of drug administration. Even though these materials offer broad flexibility based on targeting tissue, disease, and drug payload, the demand for more effective yet highly biocompatible nanomaterial-based drugs is increasing. While therapeutically improved and safe materials have been introduced in nanomedicine platforms, issues related to their degradation rates and bio-distribution still exist, thus making their successful translation for human use very challenging. Researchers are constantly improving upon novel nanomaterials that are safer and more effective not only as therapeutic agents but as diagnostic tools as well, making the research in the field of nanomedicine ever more fascinating. In this review stress has been made on the evolution of nanomaterials that have been approved for clinical applications by the United States Food and Drug Administration Agency (FDA).

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“…For example, bevacizumab free drug has implications such as poor patient compliance due to the dosage frequency and drug resistance, however in the encapsulated form, there is sustained slow delivery of the drug and increased time between administrations, making the nanoparticle form more desirable [ 76 ]. Bevacizumab has also demonstrated promising synergistic response when combined with CRXL101, the nanoparticle form of camptothecin, in preclinical models [ 77 , 78 ]. CRLX101 in the nano form has a half-life of nearly 24 h, compared to a mere 2 h as a free drug, resulting in prolonged drug exposure and further emphasizing the significance of encapsulating drugs [ 78 ].…”

Section: Targeting Tumor Vasculaturementioning

confidence: 99%

“…Bevacizumab has also demonstrated promising synergistic response when combined with CRXL101, the nanoparticle form of camptothecin, in preclinical models [ 77 , 78 ]. CRLX101 in the nano form has a half-life of nearly 24 h, compared to a mere 2 h as a free drug, resulting in prolonged drug exposure and further emphasizing the significance of encapsulating drugs [ 78 ]. As a monotherapy treatment for platinum-resistant ovarian cancer in preclinical studies, CRLX101 is effective at maximum tolerated dosages, however frequent low-dose CRLX101 given in combination with bevacizumab yielded superior tumor reduction and minimal toxicity when compared to both drugs given as monotherapies [ 77 ].…”

Section: Targeting Tumor Vasculaturementioning

confidence: 99%

Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems

et al. 2017

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Cancer cells have characteristics of acquired and intrinsic resistances to chemotherapy treatment—due to the hostile tumor microenvironment—that create a significant challenge for effective therapeutic regimens. Multidrug resistance, collateral toxicity to normal cells, and detrimental systemic side effects present significant obstacles, necessitating alternative and safer treatment strategies. Traditional administration of chemotherapeutics has demonstrated minimal success due to the non-specificity of action, uptake and rapid clearance by the immune system, and subsequent metabolic alteration and poor tumor penetration. Nanomedicine can provide a more effective approach to targeting cancer by focusing on the vascular, tissue, and cellular characteristics that are unique to solid tumors. Targeted methods of treatment using nanoparticles can decrease the likelihood of resistant clonal populations of cancerous cells. Dual encapsulation of chemotherapeutic drug allows simultaneous targeting of more than one characteristic of the tumor. Several first-generation, non-targeted nanomedicines have received clinical approval starting with Doxil® in 1995. However, more than two decades later, second-generation or targeted nanomedicines have yet to be approved for treatment despite promising results in pre-clinical studies. This review highlights recent studies using targeted nanoparticles for cancer treatment focusing on approaches that target either the tumor vasculature (referred to as ‘vascular targeting’), the tumor microenvironment (‘tissue targeting’) or the individual cancer cells (‘cellular targeting’). Recent studies combining these different targeting methods are also discussed in this review. Finally, this review summarizes some of the reasons for the lack of clinical success in the field of targeted nanomedicines.

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Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial

Abstract: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

Cited by 42 publications

References 21 publications

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells

Evolution and clinical translation of drug delivery nanomaterials

Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems

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