Liposomal Doxorubicin Research Articles

Risk factors for pegylated liposomal doxorubicin-induced moderate to severe hand-foot syndrome in breast cancer patients: assessment of baseline clinical parameters

BackgroundHand-foot syndrome (HFS) is a side effect of skin related to pegylated liposomal doxorubicin (PLD) application. Moderate to severe hand-foot syndrome (MSHFS) might have a serious impact on patients’ quality of life and treatment. However, information on risk factors for the development of MSHFS is still limited. To analyze the risk factors for PLD-induced MSHFS in breast cancer patients and constructed a logistic regression prediction model.MethodsWe conducted a retrospective analysis of breast cancer patients who were treated with a PLD regimen in the Tumor Hospital of Harbin Medical University from January 2017 to August 2019. A total of 26 factors were collected from electronic medical records. Patients were divided into MSHFS (HFS > grade 1) and NMHFS (HFS ≤ grade 1) groups according to the NCI classification. Statistical analysis of these factors and the construction of a logistic regression prediction model based on risk factors.ResultsA total of 44.7% (206/461) of patients developed MSHFS. The BMI, dose intensity, and baseline Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) levels in the MSHFS group, as well as good peripheral blood circulation, excessive sweat excretion, history of gallstones, and tumour- and HER2-positive percentages, were all higher than those in the NMHFS group (P < 0.05). The model for predicting the occurrence of MSHFS was P = 1/1 + exp. (11.138–0.110*BMI-0.234*dose intensity-0.018*baseline ALT+ 0.025*baseline AST-1.225*gallstone history-0.681* peripheral blood circulation-1.073*sweat excretion-0.364*with or without tumor-0.680*HER-2). The accuracy of the model was 72.5%, AUC = 0.791, and Hosmer-Lemeshow fit test P = 0.114 > 0.05.ConclusionsNearly half of the patients developed MSHFS. The constructed prediction model may be valuable for predicting the occurrence of MSHFS in patients.

A Heat‐Activated Drug‐Delivery Platform Based on Phosphatidyl‐(oligo)‐glycerol Nanocarrier for Effective Cancer Treatment

The potential of cancer drugs is not fully exploited due to low tumor uptake and occurrence of systemic side effects, limiting maximum tolerated dose. Actively targeted nanocarriers improve efficacy while minimizing off‐target toxicity. Herein, it is the first time a drug‐delivery platform for heat‐triggered intravascular drug release is described, based on synthetic phosphatidyl‐(oligo)‐glycerols from organic synthesis to preclinical investigation in feline patients. For the nanocarrier formulated doxorubicin (DOX), superior tumor drug delivery and antitumor activity compared with free DOX, conventional liposomal DOX (Caelyx), and temperature‐sensitive lysolipid‐containing DOX‐liposomes in rat sarcoma are demonstrated. In a comparative oncological study with neoadjuvant treatment of feline sarcoma, a metabolic response determined with 18 F‐FDG‐positron emission tomography/magnetic resonance imaging (PET/MRI) and histopathological response after tumor resection are significantly better compared with free DOX, potentially by overcoming drug resistance based on improved intratumoral drug distribution. This novel drug‐delivery platform has great potential for the treatment of locally advanced tumors in humans.

Exploring the transformability of polymer-lipid hybrid nanoparticles and nanomaterial-biology interplay to facilitate tumor penetration, cellular uptake and intracellular targeting of anticancer drugs

ABSTRACT Background Successful delivery of anticancer drugs to intracellular targets requires different properties of the nanocarrier to overcome multiple transport barriers. However, few nanocarrier systems, to date, possess such properties, despite knowledge about the biological fate of inorganic and polymeric nanocarriers in relation to their fixed size, shape and surface properties. Herein, a polymer-lipid hybrid nanoparticle (PLN) system is described with size and shape transformability and its mechanisms of cellular uptake and intracellular trafficking are studied. Methods Pharmaceutical lipids were screened for use in transformable PLN. Mechanisms of cellular uptake and the role of fatty acid-binding proteins in intracellular trafficking of PLN were investigated in breast cancer cells. Intra-tumoral penetration and retention of doxorubicin (DOX) were evaluated by confocal microscopy. Results The lead PLNs showed time-dependent size reduction and shape change from spherical to spiky shape. This transformability of PLNs and lipid trafficking pathways facilitated intracellular transport of DOX-loaded PLN (DOX-PLN) into mitochondria and nuclei. DOX-PLN significantly increased DOX penetration and retention over free DOX or non-transformable liposomal DOX particles at 4 h post-intravenous administration. Conclusion Transformability of PLN and lipid-biology interplay can be exploited to design new nanocarriers for effective drug delivery to tumor cells and intracellular targets.

Pegylated Liposomal Doxorubicin in Vindesine-Based and Bortezomib-Based Regimens for Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study of Efficacy and Safety

PurposeAlthough pegylated liposomal doxorubicin (PLD) has been approved in combination with bortezomib for relapsed/refractory multiple myeloma (MM), the antitumor efficacy and tolerability of PLD in different regimens for patients with newly diagnosed MM (NDMM) have not been fully defined.MethodsA total of 249 NDMM patients diagnosed between January 2008 and October 2019 were included in this retrospective study. Among them, 112 patients received vindesine-based chemotherapy (35 vDD and 77 vAD) and 137 received bortezomib-based chemotherapy (58 VDD and 79 VD).ResultsIn bortezomib-containing regimens, the complete response rate (48.3 vs. 30.4%, p = 0.033) and very good partial response or better rate (74.1 vs. 57.0%, p = 0.038) of VDD were significantly higher than those of VD subgroup. While no superior survival was found between VDD and VD subgroup. In vindesine-containing regimens, no statistical significance was identified between vDD and vAD in terms of response rate and survival. The occurrence rates of all cardiac AEs were similar between VDD and VD.ConclusionsThe vDD regimen was similar with vAD in the aspect of response rate, survival, and toxicity in NDMM patients. The addition of PLD to VD brought deeper response without increased toxicity, while no superior survival was found.

Type of chemotherapy has substantial effects on the immune system in ovarian cancer

Chemotherapy induces a variety of immunological changes. Studying these effects can reveal opportunities for successful combining chemotherapy and immunotherapy. Immuno-chemotherapeutic combinations in ovarian cancer are currently not generating the anticipated positive effects. To date, only scattered and inconsistent information is available about the immune-induced changes by chemotherapy in ovarian cancer. In this study, we compared six common chemotherapeutics used in ovarian cancer patients (carboplatin, paclitaxel, pegylated liposomal doxorubicin, gemcitabine, carboplatin-paclitaxel and carboplatin-gemcitabine) and studied their effects on the immune system in an ovarian cancer mouse model. Mice received a single chemotherapy or vehicle injection 21 days after tumor inoculation with ID8-fluc cells. One week after therapy administration, we collected peritoneal washings for flow cytometry, serum for cytokine analysis with cytometric bead array and tumor biopsies for immunohistochemistry. Carboplatin-paclitaxel showed the most favorable profile with a decrease in immunosuppressive cells in the peritoneal cavity and an increase of interferon-gamma in serum. In contrast, carboplatin-gemcitabine seemed to promote a hostile immune environment with an increase in regulatory T-cells in tumor tissue and an increase of macrophage-inflammatory-protein-1-beta in the serum.

Efficacy Of Pegylated Liposomal Doxorubicin-based Neoadjuvant Chemotherapy In Breast Cancer: A Single Center Experience

Purpose: Neoadjuvant chemotherapy using a doxorubicin-based regimen has recently become a common therapeutic option for operable breast cancer. This study aimed to investigate the efficacy of polyethylene glycol-coated liposomal doxorubicin (PLD)-based chemotherapy for breast cancer in neoadjuvant settings.&#x0D; &#x0D; Methods: A total of 227 female operable breast cancer patients who were diagnosed between January 2009 and December 2017 and completed neoadjuvant PLD-based chemotherapy were retrospectively included. The logistic regression analysis was used to determine the associations between pathologic complete response (pCR) and preoperative clinicopathological characteristics. The breast cancer recurrence rate was estimated using the survival analysis.&#x0D; &#x0D; Results: A higher pCR rate was found in the patients with clinically negative lymph nodes and HER2-enriched patients. Moreover, the patients who achieved pCR also had a better prognosis outcome. A recurrence rate of 11.5% (n=26) was observed during a median follow-up of 11.63 months, and the recurrence rate of the pCR group (2.04%; 95% CI = 0.29-13.62) was lower than the non-pCR group (14.62%; 95% CI = 10.12-20.87). Higher histological grade was also associated high pCR rate (52.0% vs 40.0%).&#x0D; &#x0D; Conclusion: The use of PLD-containing chemotherapeutics in neoadjuvant settings might have benefits for non-metastatic operable breast cancer in Taiwanese females.

Reporting the trajectories of adverse events over the entire treatment course in patients with recurrent platinum-sensitive ovarian cancer treated with platinum-based combination chemotherapy regimens: A graphical approach to trial adverse event reporting

BackgroundClinical trials report adverse events (AEs) in a dense table focusing on the frequency of ‘worst grade’ AEs experienced over the duration of treatment. There is usually no granular information provided on the timing and trajectory of AEs or whether they are likely to worsen, improve, or remain constant over time. Patients and methodsNon-hematologic (NH) AE data was extracted from the CALYPSO trial comparing carboplatin with pegylated liposomal doxorubicin (CD) to carboplatin with paclitaxel (CP) in recurrent ovarian cancer (ROC). Generalised estimating equations (GEE) were used to assess the risk and trajectory of combined Grade 2 or higher (G2+) AE and of each specific AE. The risk of G2+AE was also compared between treatment arms. ResultsThe study included 976 patients and AE were reported for the duration of treatment. Most patients experienced at least one G2+NHAE (CP:CD, 96.0%:80.6%). Risk of combined G2+AE increased with CP (4.1% per-cycle) but decreased with CD (0.8%, P <0.01). When alopecia and sensory neuropathy were excluded, risk of G2+ AE decreased by 2.7% per-cycle, with no significant difference between treatment arms. G2+ nausea improved (15.2% per-cycle, P <0.01). G2+ sensory neuropathy worsened (29.3% per-cycle, P <0.01). Fatigue was stable (17% per-cycle, P =0.06) whilst G2+ pain decreased over time (13.4% per-cycle, P <0.01), with no difference between treatment arms. ConclusionExisting trial data can be used to provide AE trajectories as illustrated here for ROC. These trajectories have utility in guiding treatment choice and potentially optimising AE management with novel therapies and treatment combinations.

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Abstract P28: COVID-19 infection and mortality in patients with skin malignancies receiving systemic anti-cancer therapy (SACT): The Guy’s Cancer Centre experience

Abstract Background: The COVID-19 pandemic has influenced treatment decisions in cancer patients. There is increasing evidence that not all oncology patients are at increased risk of COVID-19 infection or death. This study aimed to look at rate of SARS-CoV-2 infection and mortality in patients with skin malignancies receiving systemic anti-cancer therapy (SACT) during the pandemic in Guy’s Cancer Centre. Methods: All patients with skin cancer receiving SACT at Guy’s Cancer Centre between March 1st and May 31st 2020 were included. Demographic data: sex, age, socio-economic status (SES), ethnicity, comorbidities, medications and smoking history were collected along with cancer characteristics: cancer type, stage, treatment paradigm, modality and line. COVID-19 infection was confirmed by PCR and severity defined by the World Health Organisation classification. Patients with radiological or clinical diagnoses alone were excluded. Results: Of 116 skin cancer patients on SACT over the 3-month period, 89% had Melanoma, 5% Kaposi’s Sarcoma (KS), 3% Squamous Cell, 2% Merkel Cell, 1% Basal Cell Carcinoma and 1% Angiosarcoma. 53% were male and 78% were of low SES. 62% were being treated with palliative intent and 70% of these were on first line palliative treatment. The median age was 57.6 years in COVID-19 positive patients (n=3) compared to 60.3 years in the negative group (n=113). 58.6% received immunotherapy, 28.4% targeted therapy, 7.8% chemotherapy and 4.3% combined treatment. Of the 3 patients (2.6%) with confirmed COVID-19 infection, the two patients with KS were receiving liposomal doxorubicin hydrochloride and the other paclitaxel chemotherapy and the patient with Melanoma was receiving encorafenib and binimetinib. All COVID-19 positive patients were of low SES, 2 females and 1 male. There was a low rate of co-morbidities with hypertension in 1 COVID-19 positive patient and none in the negative group. All 3 confirmed COVID-19 patients developed severe pneumonia and were diagnosed within 7 days of the onset of symptoms. There were no COVID related deaths and one disease-related death in the negative cohort. Conclusion: There was a low rate of COVID-19 infection in the 116 skin cancer patients on SACT (2.6%) with 60% of patients on immunotherapy. All 3 confirmed cases had severe pneumonia with no COVID-19 related deaths (0%); 2 were receiving chemotherapy and 1 on targeted therapy. Patients on treatment were encouraged to shield between hospital attendances during this period which may account for the reduced rate of SARS-CoV-2 infection. This data supports the emerging observations that immunotherapy does not confer an increased risk of severe COVID-19 infection in cancer patients. This observation is confounded by the relatively young age and low co-morbidity rates in the cohort which may have contributed to the low infection and mortality rate. Citation Format: Lucy Flanders, Beth Russell, Charlotte Moss, Kieran Palmer, Rushan Sylva, Gincy George, Danielle Crawley, Harriet Wylie, Fidelma Cahill, Anna Haire, Andrea D'Souza, Simon Gomberg, Richard Sullivan, Anne Rigg, Mieke Van Hemelrijck, Mark Harries, Irene De Francesco, Stephen Morris, Sophie Papa, Saiorse Dolly. COVID-19 infection and mortality in patients with skin malignancies receiving systemic anti-cancer therapy (SACT): The Guy’s Cancer Centre experience [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P28.

The impact of Pegylated liposomal doxorubicin in recurrent ovarian cancer: an updated meta-analysis of randomized clinical trials

BackgroundPrevious meta-analysis studies suggested that pegylated liposomal doxorubicin (PLD) may improve the survival rate of patients with recurrent ovarian cancer. The aim of the present meta-analysis, then, was to further update the role of PLD in the treatment of recurrent ovarian cancer.MethodsWe performed a literature search using the electronic databases Medicine, EMBASE, Web of Science, and the Cochrane Library to 27 July 2020. We only restricted the randomized clinical trials. Study-specific hazard ratios and 95% confidence interval (HR/95% CI) and risk ratios and 95% confidence interval (RR/95% CI) were pooled using a random-effects model.ResultsTen studies (12 trials) were included after screening 940 articles. We categorized the eligible studies into two groups: the doublet regimens (four trials, 1767 patients) showed that PLD plus carbo provided superior progression-free survival (PFS) (HR, 0.85; 95% CI, 0.74–0.97) and similar overall survival (OS) (HR, 1.00; 95% CI, 0.88–1.14) compared to paclitaxel (PAC) plus carboplatin (carbo). PLD plus carbo was associated with significantly more anemia and thrombocytopenia, and other side effects were well tolerated. The monotherapy regimens (eight trials, 1980 patients) showed that PLD possessed a similar PFS (HR, 1.02; 95% CI, 0.90–1.16) and OS (HR, 0.88; 95% CI, 0.77–1.01) relative to other monotherapies. PLD alone was also more associated with mucositis/stomatitis and hand-foot syndrome, while other side effects were well tolerated.ConclusionsIn platinum-sensitive recurrent ovarian cancer, PLD plus carbo was more effective than PAC plus carbo, while in platinum-resistant or -refractory recurrent ovarian cancer, PLD exhibited similar survival to other monotherapies. Regarding side effects, PLD plus carbo and mono chemotherapy were both well tolerated.

Improving anti-tumour efficacy of PEGylated liposomal doxorubicin by dual targeting of tumour cells and tumour endothelial cells using anti-p32 CGKRK peptide

The aim of this study was to surface-functionalize PEGylated liposomal doxorubicin (PLD) using anti-p32 CGKRK peptide to evaluate its anti-angiogenic and anti-tumour activities. CGKRK was conjugated to DSPE-mPEG2000-maleimide and post-inserted into PLD at 25, 50, 100, 200 and 400 peptides per each liposome and characterised for their size, zeta potential, drug loading, release properties; and cell binding, cell uptake and cytotoxicity on three C26, 4T1 and human umbilical vein endothelial cell (HUVEC) cell lines. The in vitro results indicated the better efficiency of the PLD-100 (PLD with 100 CGKRK) formulation on 4T1 and HUVEC cell lines. The results of anti-tube formation and spheroid assay indicated the efficiencies of the PLD-100 formulation compared with Caelyx® in vitro. The in vivo studies indicated the higher tumour accumulation of PLD-100 formulation in comparison with Caelyx® which also implied the higher survival rates in mice treated with PLD-100 formulation. Histological evaluations demonstrated that PLD-100 had no side-effects on major organs. In conclusion, the results of this study indicated that PLD-CGKRK- could efficiently target endothelial and tumour parenchymal cells which enhance the therapeutic efficacy of PLD and merits further investigation.

Lipidated Peptidomimetic Ligand-Functionalized HER2 Targeted Liposome as Nano-Carrier Designed for Doxorubicin Delivery in Cancer Therapy.

The therapeutic index of chemotherapeutic agents can be improved by the use of nano-carrier-mediated chemotherapeutic delivery. Ligand-targeted drug delivery can be used to achieve selective and specific delivery of chemotherapeutic agents to cancer cells. In this study, we prepared a peptidomimetic conjugate (SA-5)-tagged doxorubicin (Dox) incorporated liposome (LP) formulation (SA-5-Dox-LP) to evaluate the targeted delivery potential of SA-5 in human epidermal growth factor receptor-2 (HER2) overexpressed non-small-cell lung cancer (NSCLC) and breast cancer cell lines. The liposome was prepared using thin lipid film hydration and was characterized for particle size, encapsulation efficiency, cell viability, and targeted cellular uptake. In vivo evaluation of the liposomal formulation was performed in a mice model of NSCLC. The cell viability studies revealed that targeted SA-5-Dox-LP showed better antiproliferative activity than non-targeted Dox liposomes (Dox-LP). HER2-targeted liposome delivery showed selective cellular uptake compared to non-targeted liposomes on cancer cells. In vitro drug release studies indicated that Dox was released slowly from the formulations over 24 h, and there was no difference in Dox release between Dox-LP formulation and SA-5-Dox-LP formulation. In vivo studies in an NSCLC model of mice indicated that SA-5-Dox-LP could reduce the lung tumors significantly compared to vehicle control and Dox. In conclusion, this study demonstrated that the SA-5-Dox-LP liposome has the potential to increase therapeutic efficiency and targeted delivery of Dox in HER2 overexpressing cancer.

Pegylated liposomal doxorubicin-induced hand-foot syndrome predicted by serum metabolomic profiling and prevented by calcium dobesilate

Pegylated liposomal doxorubicin-induced hand-foot syndrome predicted by serum metabolomic profiling and prevented by calcium dobesilate

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P= 0.897] or the FRα high population (HR, 0.69, P= 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

99mTc-Radiolabeled Silica Nanocarriers for Targeted Detection and Treatment of HER2-Positive Breast Cancer.

IntroductionThe overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC.MethodsFirstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors.ResultsSiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls.ConclusionThese findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.

Abstract PS12-12: Efficacy and safety of AB928 plus pegylated liposomal doxorubicin (PLD) with or without IPI-549 in participants with metastatic ovarian and triple negative breast cancer

Abstract Background: Adenosine, derived from ATP released by dying cancer cells in response to chemotherapy, activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Adenosine receptor blockade may improve the efficacy of chemotherapy, notably anthracycline regimens, by enhancing immunogenicity within the tumor microenvironment. AB928, the first clinical-stage small molecule dual A2aR/A2bR antagonist, is highly potent and well tolerated in combination with chemo/immunotherapy. Novel combinations of AB928 with PLD +/- IPI-549, a PI3Kgamma inhibitor believed to shift tumor associated macrophages toward an anti-tumor phenotype, may offer potential clinical benefit for tumors previously considered immunotherapy-resistant. Methods: ARC-2 (NCT03719326) is an ongoing Phase (Ph) 1/1b, open-label study in patients (pts) with metastatic or locally advanced, unresectable ovarian or triple negative breast (TNBC) cancer. Eligible pts must have ECOG performance status 0-1 and at least one measurable lesion. In dose escalation, AB928 (75 or 150 mg) administered orally once daily was given with standard PLD in a 3+3 design. Once a tolerable doublet regimen was established, escalating doses of oral IPI-549 (30 or 40 mg once daily) were added. Two expansion cohorts, the doublet of AB928 150 mg + standard PLD and the triplet (+ IPI549 40 mg), are ongoing in pts with TNBC. Results: As of 19Jun2020, 29 pts received AB928 as part of the doublet or triplet regimen (Table 1). The number of prior therapies for escalation and expansion range from 0-11 (median=2) and 0-5 (median=1), respectively. Across both regimens, most treatment emergent AEs (TEAEs) were Grade (Gr) 1 or 2. The most common TEAEs (&amp;gt;6 pts) were fatigue, anemia, constipation, stomatitis, cough, and nausea. Four pts reported 6 Gr ≥3 SAEs; none were related to AB928 or IPI-549 and one event (pleural effusion) was at least possibly related to PLD. One pt discontinued study treatment for an AE (Gr 3 peripheral neuropathy) related to the triplet regimen; this pt had a complete response (CR) at the time of discontinuation. Of those pts treated with AB928 + PLD, 16 pts had at least one on-study disease evaluation, 2 pts (1 TNBC, 1 ovarian) achieved a partial response (PR), 8 stable disease (SD) and 6 progressive disease (PD) as best response. The addition of IPI-549 (n=11) resulted in 1 complete response (CR; ovarian), 3 PR (2 ovarian, 1 TNBC), 4 SD, and 3 PD. Nine pts received prior immunotherapy as part of an anticancer regimen; 2/9 achieved a PR on study treatment (1 confirmed, 1 pending). Thirteen pts had prior anthracycline; 6/13 achieved SD as best overall response, including 1 pt who received doublet therapy &amp;gt;1 year. Conclusions: AB928 and PLD +/- IPI-549 is tolerable in pts with advanced ovarian cancer and TNBC. Doublet and triplet combination treatment were associated with clinical benefit, including responses in those with progression after prior immunotherapy. The promising observation that late-line pts, including those previously treated with an anthracycline and/or immunotherapy, can experience clinical benefit with AB928 combination therapy warrants further investigation. Table 1. ARC-2 Cohort Enrollment and AB928 +/- IPI-549 Dose ReceivedStudy Part:Phase 1Phase 1bRegimen:DoubletTripletDoubletTripletAB928 dose:75 mg150 mg150 mg150 mg150 mgIPI-549 dose:––30 mg40 mg–40 mgEnrolled, nOvarian3431––TNBC020286 Citation Format: Jasgit C. Sachdev, Amy Prawira, Arvind Chaudhry, Vinod Ganju, Caroline Trudeau, Jennifer Scott, Rachel Woloski, Melissa Paoloni, Halle Zhang, Olivia Gardner. Efficacy and safety of AB928 plus pegylated liposomal doxorubicin (PLD) with or without IPI-549 in participants with metastatic ovarian and triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-12.

GMP-grade nanoparticle targeted to nucleolin downregulates tumor molecular signature, blocking growth and invasion, at low systemic exposure

Patients with breast or ovarian cancer have not benefited from improved efficacy with pegylated liposomal doxorubicin relative to free drug, likely due to the limited extent of the enhanced permeability and retention (EPR) effect, further compromising drug bioavailability in the tumor. Herein it is hypothesized that targeting nucleolin overexpressed in tumor endothelial cells (readily accessible from the vascular compartment), besides cancer cells, with PEGASEMP (doxorubicin hydrochloride in a lipid-based pegylated nanoparticle functionalized with a 31-aminoacid peptide targeting nucleolin), lessens the dependence on high systemic exposures and EPR effect for successful tumor targeting. This strategy has resulted in improved intracellular tumor bioavailability of doxorubicin, at low systemic exposure, associated with a safe toxicological profile. Levels of cell surface nucleolin dictated the antitumor activity of PEGASEMP against nucleolin-overexpressing solid tumors of diverse histological origin, evidencing a significant growth inhibition of malignant mesothelioma over the standard of care. Those observations were paralleled by an impairment of the nucleolin-positive vasculature and downregulation of typically overexpressed genes. Patient stratification based on nucleolin mRNA expression correlated with prognosis and enabled identification of breast and mesothelioma tumors that may potentially benefit from PEGASEMP. Overall, a novel principle of drug delivery is presented with potential therapeutic impact across nucleolin-overexpressing human cancers. The data that support the findings of this study are available from the corresponding author upon reasonable request.

A randomised controlled feasibility trial to evaluate Lawsonia inermis (henna)'s effect on palmar-plantar erythrodysesthesia induced by capecitabine or pegylated liposomal doxorubicin.

To test the effectiveness of henna in the management of palmar-plantar erythrodysesthesia (PPE) in patients receiving treatment with capecitabine or pegylated liposomal doxorubicin (PLD). This was a randomized controlled feasibility study in three specialized tertiary cancer centers with 56 patients with a PPE grade 1 or above and various cancer diagnoses. The intervention included the local application of henna to the affected areas. The control group followed the same process with a henna inert. Primary outcome was PPE grade and secondary outcomes were the EORTC QLQ-C30, PPE-related QoL (HFS-14), activities of daily living (ECOG) and pain. Patients in both groups were assessed at baseline and then weekly at four follow-ups. PPE grade in the intervention group (1-3.8%) was lower compared to the control group (4-13.38%) and also lower levels of pain were reported by the patients in the intervention group (2.46±1.17) compared to the control (5.57±2.01). ECOG status in the intervention group was improved compared to the control (p=0.039). The intervention group, experienced higher Global Health Status (p≤0.008), Physical function (p≤0.001), Emotional Function (p=0.029), Social function (p≤0.001) and lower Fatigue (p≤0.001) and Pain (p≤0.001) compared to the Control group. A statistically significant interaction was found between Group and Time over the weekly measurements of HFS-14 scores (F=5,009, p≤0.002) indicating the significant effect of the intervention throughout the weekly assessments. The trial provided preliminary evidence on henna's effectiveness for treating PPE during treatment with capecitabine or PLD, with lower PPE grades, better performance status and better HRQoL observed in the henna group. CLINICALTRIALS. NCT01751893.

Abstract PS13-38: Cardiotoxicity among patients with breast cancer treated with doxorubicin: A real-world database study

Abstract Background While novel targeted agents are increasingly used to care for patients with breast cancer, doxorubicin (DOX) continues to play a role in management of patients, particularly those with aggressive disease. Dose-dependent cardiomyopathy is a challenge in its use. Strategies have been proposed to mitigate this, including administration by continuous intravenous (CIV) infusion as an alternative to bolus (BOL) administration. This study used real world data to explore the impact of DOX administration mode on cardiotoxicity, duration of DOX and time to treatment failure (TTF). Methods IBM MarketScan claims were used to identify patients age ≥ 18 who received at least 2 DOX administrations (excluding liposomal DOX) after cancer diagnosis. Patients with history of cardiac events were excluded. Cardiac events based on a range of International Classification of Disease (ICD) codes were compared for BOL versus CIV overall, by tumor site and by regimen during three follow-up periods, early (within 1 year), middle (&amp;gt;1 to 5 years) and late (&amp;gt;5 years), from DOX initiation using Fisher’s exact test. Duration of DOX and TTF, defined as time from initiation of DOX to subsequent systemic therapy, hospice or death, were evaluated using Kaplan-Meier method and unadjusted Cox proportional hazards models. Results: A total of 38,924 patients with breast cancer met eligibility criteria (13,186 with confirmed metastatic disease). The most common regimen used was DOX plus cyclophosphamide (n=31,815, 81.7%). Most patients had codes for both modes on the same claim date and could not be definitely assigned to BOL or CIV infusion groups; however, 917 and 5,433 patients had exclusive BOL and CIV codes, respectively. Among patients receiving DOX monotherapy (n=687), 361 and 100 had exclusive BOL and CIV codes, respectively. For patients with exclusive infusion type codes, the mean duration of DOX treatment was not significantly different for BOL vs CIV (58.9 vs 56.2 days, p=0.33 overall; 74.4 vs 74.8 days for monotherapy, p=0.97). Overall, cardiac events for BOL vs CIV were 5.1% vs 4.7% (p=0.55) during the early period, 3.1% vs 5.0%, (p=0.01) during the middle period, and 0.4% vs 1.0% (p=0.10) in the late period. There were no differences in cardiac events for BOL vs CIV among those treated with DOX monotherapy (p=0.90, 0.56 and 0.52 for the early, middle, and late period, respectively). TTF was shorter for BOL vs CIV (262.3 vs 366.0 days, p&amp;lt;0.001). However, when evaluating TTF, there was a significant relationship between cardiotoxicities and longer TTF (hazard ratio, HR=0.85, 95% confidence interval, CI: 0.81-0.88, p&amp;lt;0.001). This relationship was statistically significant for the early, middle and late periods, respectively (all p&amp;lt;0.001). Conclusions: These data suggest that cardiac events may occur at a similar rate for BOL and CIV. This study is limited by the retrospective nature of this study and the ability to determine causality; the use of strict coding rules to correctly assign patients to BOL vs CIV groups maintained scientific integrity and a large sample size but did result in the loss of eligible patients. Future research, including adjusted analyses, are needed to further investigate the relationship between mode of infusion and clinical outcomes. Citation Format: Poorni Manohar, Hannah M Linden, Lisa M Hess, Tomoko Sugihara, Yajun E Zhu, Howard G Muntz, Lee D Cranmer. Cardiotoxicity among patients with breast cancer treated with doxorubicin: A real-world database study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-38.

Tumor acidity-induced charge-reversal liposomal doxorubicin with enhanced cancer cell uptake and anticancer activity

Concerning that the polyethylene glycol surface layer of DOXIL hinders cancer cell uptake, thus leading to low anticancer activity, it is of great importance to promote the cancer cell uptake of liposomal doxorubicin. Herein, we developed the charge-reversal PEGylated liposomal doxorubicin CRDOXIL with enhanced cancer cell uptake and high anticancer activity. Based on the tumor acidity-induced charge-reversal property, the cancer cell uptake of CRDOXIL could be significantly enhanced and the efficient caveolae-mediated endocytosis was achieved. Moreover, CRDOXIL maintained its stable PEGylated structure in neutral normal physiological environment, thus decreasing the side effects of doxorubicin on normal cells. Therefore, CRDOXIL exhibits high anticancer activity to cancer cells and low cytotoxicity against normal cells. It is anticipated that the charge-reversal strategy could be applied in diverse drug delivery systems to meet the requirement in chemotherapy.