In recent years, disease treatment has evolved strategies that require increase in pharmaceutical agent’s efficacy and selectivity while decreasing their toxicity in normal tissues. These requirements have led to the development of nanoscale liposome systems for drug release. This review focuses on lipid features, pharmacological properties of liposomal formulations and the clinical studies of their application. Several lipids are available, but their properties could affect pharmacological or clinical efficiency of drug formulations. Many liposomal formulations have been developed and are currently on the market. Proper selection of lipid is essential for the pharmacological effect to be improved. Most of the formulations use mainly zwitterionic, cationic or anionic lipids, PEG and/or cholesterol, which have different effects on stability, pharmacokinetics and delivery of the drug formulation. Clinical trials have shown that liposomes are pharmacologically and pharmacokinetically more efficient than drug-alone formulations in treating acute myeloid leukemia, hepatitis A, pain management, ovary, gastric breast and lung cancer, among others. Liposomal formulations are less toxic than drugs alone and have better pharmacological parameters. Although they seem to be the first choice for drug delivery systems for various diseases, further research about dosage regimen regarding dose and time needs to be carried out.

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Nanomedicine review: clinical developments in liposomal applications

Molecular self-assembly has enabled the fabrication of biologically inspired, advanced nanostructures as lipid-based nanovesicles (L-NVs). The oldest L-NVs, liposomes, have been widely proposed as potential candidates for drug delivery, diagnostic and/or theranostic applications and some liposome-based drug products have already stepped from the lab-bench to the market. This success is attributed to their ability to encapsulate both hydrophobic and/or hydrophilic molecules, efficiently carry and protect them within the body and finally deliver them at the target site. These positive features are also coupled with high biocompatibility. However, liposomes still present some unsolved drawbacks, such as poor colloidal stability, short shelf-life, restricted and expensive conditions of preparation because of the inherent nature of their fundamental constituents (phospholipids). The new tools available in the self-assembly of controlled molecules have significantly advanced the field of L-NV design and synthesis, and non-liposomal L-NVs have been recently developed; this new generation of nanovesicles can represent a paradigm shift in nanomedicine: they may complement liposomes, showing their advantages and overcoming most of their drawbacks. Clearly, being still young, their rocky way to the clinic first and then to the market has just started and it is still long, but they have all the potentialities to reach their objective target. The purpose of this review is to first present the large plethora of L-NVs available, focusing on this new generation of non-liposomal L-NVs and showing their similarities and differences with respect to their ancestors (liposomes). Since the overspread of a nanomaterial to the market is also strongly dependent on the availability of technological-scale preparation methods, we will also extensively review the current approaches exploited for L-NV production. The most cutting-edge approaches based on compressed fluid (CF) technologies will be highlighted here since they show the potential to represent a game-change in the production of L-NVs, favouring their step from the bench to the market. Finally, we will briefly discuss L-NV applications in nanomedicine, looking also for their future perspectives.

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Lipid-based nanovesicles for nanomedicine.

Development of drug-delivery systems that selectively target neoplastic cells has been a major goal of nanomedicine. One major strategy for achieving this milestone is to install ligands on the surface of nanocarriers to enhance delivery to target tissues, as well as to enhance internalization of nanocarriers by target cells, which improves accuracy, efficacy, and ultimately enhances patient outcomes. Herein, recent advances regarding the development of ligand-installed nanocarriers are introduced and the effect of their design on biological performance is discussed. Besides academic achievements, progress on ligand-installed nanocarriers in clinical trials is presented, along with the challenges faced by these formulations. Lastly, the future perspectives of ligand-installed nanocarriers are discussed, with particular emphasis on their potential for emerging precision therapies.

Ligand-Installed Nanocarriers toward Precision Therapy.

https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2250&context=ihmri

Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities.

New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab – however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody–liposomal doxorubicin conjugate that specifically targets HER2­overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naive, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations. HERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naive patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab. The HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage. Clinicaltrials.gov identifier: NCT02213744
 . Registration date: 06AUG2014.

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HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

Background: Although HER2-targeted therapies such as pertuzumab and T-DM1 have improved patient outcomes, treatment resistance typically occurs. MM-302 is a HER2-targeted liposomal doxorubicin in development by Merrimack Pharmaceuticals. In a Phase 1 study, patients with HER2-positive metastatic breast cancer (MBC) were treated with MM-302 alone and in combination with trastuzumab with or without cyclophosphamide. MM-302 had an acceptable safety profile and promising efficacy was observed in patients not previously exposed to an anthracycline. Trial design: HERMIONE (NCT02213744) is a randomized Phase 2, two-arm, open-label trial designed to evaluate if MM-302 can address an unmet medical need in patients with anthracycline naive, trastuzumab-, pertuzumab- and T-DM1-pretreated HER2-positive locally advanced breast cancer (LABC)/MBC. Patients are randomized 1:1 to receive MM-302 (30mg/m2, Q3W) plus trastuzumab (6mg/kg, Q3W) or chemotherapy of physician9s choice (vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6mg/kg, Q3W). Eligibility criteria: Centrally confirmed HER2-positive LABC/MBC, no prior anthracycline exposure, prior trastuzumab in any setting, prior pertuzumab and T-DM1 in the LABC/MBC setting, unlimited prior lines of therapy, ECOG 0-1 and LVEF ≥50%. CNS metastases are permitted if stable and without symptoms or steroids for 4 weeks. Specific aims: The primary endpoint is independently assessed progression free survival (PFS). Secondary endpoints include investigator assessed PFS, overall survival, response rate, safety and patient related outcomes. Statistics: 250 patients will be enrolled to observe 191 PFS events for 90% power to detect a Hazard Ratio of 0.625. The MM-302 arm will be compared to the control arm on the primary endpoint of PFS using a stratified log-rank test at one-sided 0.025 level. Accrual status: First patient in was December 2014 and enrollment is expected to be complete in late 2016. Sites are open in the US, Canada and Western Europe and are currently enrolling patients. Citation Format: Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, Riahi K, Reynolds JG, Wickham T, Molnar I, Yardley DA. HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician9s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-01.

Abstract OT3-01-01: HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1)

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

1501 Background: Delays in cancer diagnosis can lead to increased mortality, leading to specialized diagnostic pathways for symptomatic patients when cancer is suspected. Identification of circulating tumour DNA can stratify individuals into those more or less likely to have cancer and predict the cancer origin. This could both expedite cancer diagnosis and reduce harm and inefficient investigation in those who do not have cancer. We evaluated the performance of a next-generation sequencing MCED test (GRAIL, LLC) using cell-free DNA (cfDNA) isolated from whole blood in symptomatic patients referred to cancer diagnostic clinics by their primary care physician. Methods: Patients referred for urgent imaging, endoscopy or other diagnostic modalities to investigate symptoms suspicious for cancer were invited to take part. Participants with non-specific symptoms or being tested for lung, gynaecological, upper gastrointestinal (GI) or lower GI cancers gave a blood sample on the day they attended for urgent standard of care investigations. cfDNA was isolated from blood samples and stored until the MCED test was performed in batches, blinded to clinical outcome. The test’s predictions (cancer signal detected yes/no; predicted signal origin) were compared with the diagnosis obtained by standard care to establish the positive and negative predictive value (PPV & NPV), sensitivity and specificity across the whole study population, by referral pathway, and by presenting symptom. In addition, sensitivity was analysed by cancer site and stage. Results: 6238 participants were recruited over 5 months from the 5 clinical pathways at 44 hospital sites in England and Wales. 5461 individuals had an MCED test result and diagnostic outcome and were evaluable. Mean age was 62.1 years (SD, 13.8), 3609 (66.1%) female, 2533 (46.4%) current or former smokers. 368 (6.7%) evaluable patients had a cancer diagnosed. The MCED test detected a cancer signal in 323 cases, 244 in whom cancer was diagnosed and 79 where it was not, yielding a PPV of 75.5% (95% CI 70.5-80.1%), NPV 97.6% (97.1-98.0%), sensitivity 66.3% (61.2-71.1%), and specificity 98.4% (98.1-98.8%). Sensitivity increased with increasing age and cancer stage, from 24.2% (16.0-34.1%) in Stage I to 95.3% (88.5-98.7%) in Stage IV. Sensitivity 80.4% (66.1-90.6%) and NPV 99.1% (98.2-99.6%) were highest for patients referred with symptoms qualifying for the upper GI pathway. Conclusions: This is the first large-scale prospective evaluation of an MCED test in a symptomatic population. These data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms with low, but higher than background, probability of being due to cancer. Study data are also being used to enhance the negative predictive value of the current MCED classifier for a symptomatic population. Clinical trial information: ISRCTN10226380 .

Large-scale observational prospective cohort study of a multi-cancer early detection (MCED) test in symptomatic patients referred for cancer investigation.

Kaveh Riahi

Papers

HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

Large-scale observational prospective cohort study of a multi-cancer early detection (MCED) test in symptomatic patients referred for cancer investigation.