Pegylated Liposomal Doxorubicin Research Articles

319P A propensity score weighted study comparing two versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of Pegylated Liposomal Doxorubicin (PLD) has been approved for the treatment of Metastatic Breast Cancer (MBC). Phase II trials have suggested interest for a 2-weekly regimen. The aim of this study was to compare efficacy and safety of these two modalities.

734P Neutrophil-lymphocyte ratio predicts survival in platinum-resistant ovarian cancer patients treated with olaparib and pegylated liposomal doxorubicin (PLD): Stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601

Identifying prognostic biomarkers of Olaparib (OLA) plus PLD efficacy is relevant to optimize the clinical benefit of this therapy in PROC pts. Neutrophil/lymphocyte (NLR), Lymphocyte/monocyte (LMR) and Platelet/lymphocyte (PLR) ratios have been identified as prognostic factors for survival but evidence at PROC is scarce.

Phase 1b study of AVB-500 in combination with paclitaxel or pegylated liposomal doxorubicin platinum-resistant recurrent ovarian cancer

ObjectiveGAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D). MethodsEligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival. ResultsNo dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach. ConclusionAVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.

Acid-responsive HPMA copolymer-bradykinin conjugate enhances tumor-targeted delivery of nanomedicine

Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor. Levulinoyl-BK (Lev-BK) was conjugated to an HPMA-based polymer via an acid-cleavable hydrazone bond (P-BK). An acid-responsive release of Lev-BK from P-BK was observed, and P-BK alone after intradermal application showed below 10% of the BK activity, thus proving a reduction in the vascular permeability activity of BK when attached to the polymer carrier. P-BK pre-treatment improved blood flow in the tumor tissue by 1.4–1.7-fold, which was maintained for more than 4 h. In addition, P-BK pre-treatment increased the tumor accumulation of pegylated liposomal doxorubicin (PLD) by approximately 3-fold. Furthermore, P-BK pre-treatment led to superior antitumor activity of PLD and significantly improved the survival of tumor-bearing mice. The release of BK from P-BK in the acidic milieu of the tumor was a prerequisite for P-BK to exert its effect, as the vascular permeability enhancing activity of P-BK was negligible. Collectively, P-BK pre-treatment improved intratumoral blood flow and augmented tumor accumulation of nanomedicine, thereby resulting in a significant suppression of tumor growth. Therefore, these findings demonstrate that P-BK is a potential concomitant drug for improving the tumor delivery of nanomedicines.

Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

Objectives: Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Methods: Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Conclusions: Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD. Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD.

Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: a cost-effectiveness analysis

Objectives: To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with endometrial cancer without microsatellite instability who failed first-line chemotherapy. Methods: A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent microsatellite stable endometrial cancer who failed first-line chemotherapy. Clinical estimates were obtained from published data and drug cost estimates were obtained using average wholesale prices. Additional cost estimates were utilized to estimate cost of grade 3-4 toxicity treatment. The measure of effectiveness was quality-adjusted life years (QALYs). Due to the high rate of toxicity in the LP group, a health state utility (HSU) penalty of -0.05 was applied to this group. Incremental cost-effectiveness ratios (ICERs) were calculated to determine the cost per QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. Results: Costs of treatment with doxorubicin, PLD, and bevacizumab are $26.7 million (M), $51.1 M, and $225.1 M respectively. Cost of treatment with LP is $856.5M. Relative to doxorubicin, the ICER for PLD, bevacizumab, and LP are $46,279, $345,824, and $726,483 respectively. Two-way sensitivity analysis varying the cost of LP show that if the combined cost of these two drugs decreases from over $34,000 per cycle to less than $9,000 per cycle, this strategy would be cost-effective. At the current cost, even if the median overall survival was double the 16.7 months used in the base model, the ICER for LP remains above the WTP threshold. Eliminating the HSU penalty for LP decreased the ICER $567,000 while increasing the penalty to 0.10 increased the ICER to over $1M. Conclusions: LP is not cost-effective in patients with recurrent, MSS endometrial cancer who have failed first line therapy. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective. To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with endometrial cancer without microsatellite instability who failed first-line chemotherapy. A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent microsatellite stable endometrial cancer who failed first-line chemotherapy. Clinical estimates were obtained from published data and drug cost estimates were obtained using average wholesale prices. Additional cost estimates were utilized to estimate cost of grade 3-4 toxicity treatment. The measure of effectiveness was quality-adjusted life years (QALYs). Due to the high rate of toxicity in the LP group, a health state utility (HSU) penalty of -0.05 was applied to this group. Incremental cost-effectiveness ratios (ICERs) were calculated to determine the cost per QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. Costs of treatment with doxorubicin, PLD, and bevacizumab are $26.7 million (M), $51.1 M, and $225.1 M respectively. Cost of treatment with LP is $856.5M. Relative to doxorubicin, the ICER for PLD, bevacizumab, and LP are $46,279, $345,824, and $726,483 respectively. Two-way sensitivity analysis varying the cost of LP show that if the combined cost of these two drugs decreases from over $34,000 per cycle to less than $9,000 per cycle, this strategy would be cost-effective. At the current cost, even if the median overall survival was double the 16.7 months used in the base model, the ICER for LP remains above the WTP threshold. Eliminating the HSU penalty for LP decreased the ICER $567,000 while increasing the penalty to 0.10 increased the ICER to over $1M. LP is not cost-effective in patients with recurrent, MSS endometrial cancer who have failed first line therapy. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

Phase I study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma

<h3>Objectives:</h3> AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). The purpose of this study was to evaluate safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the RP2D. <h3>Methods:</h3> Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg at q2 weeks in combination with weekly Pac 80mg/m²D1, 8, 15 q28 days or PLD 40mg/m²D1 q28 days and assessed for safety, pharmacokinetics, pharmacodynamics, and response (via RECIST v1.1, assessed by investigator). A safety review committee reviewed each cohort prior to escalation to the next higher dose level. <h3>Results:</h3> A total of 53 patients with platinum-resistant HGSOC ovarian adenocarcinoma (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. No patients experienced a dose-limiting toxicity (DLT). A total of 53% (28/53)of patients experienced a grade 3-4 adverse event. No grade 5 events were observed. The majority of events were related to known chemotherapy side effects. No subject discontinued study therapy due to an adverse event. Confirmed ORR with Pac+AVB-500 was 35% (8/23) and 15% (4/26) in the PLD+AVB-500 subgroup. ORR in the Pac subgroup after 1-2 prior lines was 40% with a platinum-free interval (PFI) ≥3 months, and 60% with a PFI of <3 months. Pac treated patients who had not been exposed to bevacizumab had a 60% ORR vs 15% in the Bev pre-treated subgroup. An exposure-response analysis identified serum AVB-500 C1D15 trough levels of >13.8mg/L as the minimal efficacious concentration (MEC). Among the Pac treated subgroup, the ORR was 39% vs 22% and median overall survival (OS) was 10.3 months vs 6.7 months in the MEC-high and MEC-low groups, respectively (Figure 1). Additionally, serum soluble AXL/GAS6 ratio was measured at baseline as an indicator of pathway activation. Among the Pac treated subgroup, the ORR was 42.9% vs 0% for those with ratios >0.773 compared to those with ratios ≤0.773. <h3>Conclusions:</h3> AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and targets GAS6/AXL pathway. AVB-500was found to be safe and tolerable in this Ph1B trial in combination with Paclitaxel or PLD. The RP2D was based upon PK/PD parameters. This Ph1B trial suggesteda higher ORR in the Pac treated subgroup, particularlywith C1D15 trough levels >13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analysis also suggested that improved response rates may be observed in patients who have not been exposed to bevacizumab. The serum soluble AXL/GAS6 ratio may serve as a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. Further development of AVB-500 15 mg/kg Q2W in combination with Pac is warranted in PROC.

Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)

BackgroundThere is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status.Patients and methodsPatients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest.ResultsFrom 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%).ConclusionsThe PLD–olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination.

Long-Term Cardiac Safety and Survival Outcomes of Neoadjuvant Pegylated Liposomal Doxorubicin in Elderly Patients or Prone to Cardiotoxicity and Triple Negative Breast Cancer. Final Results of the Multicentre Phase II CAPRICE Study.

BackgroundThe CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS).MethodsIn this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m2) plus cyclophosphamide (600 mg/m2) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed.ResultsBetween Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%).ConclusionAt 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity.Trial Registration Number ClinicalTrials.gov reference NCT00563953.

Chemotherapeutic Regimens and Chemotherapy-Free Intervals Influence the Survival of Patients with Recurrent Advanced Epithelial Ovarian Carcinoma: A Retrospective Population-Based Study.

We aimed to evaluate factors influencing the outcomes of patients with platinum-sensitive recurrent epithelial ovarian carcinoma (EOC). Patients with advanced-stage EOC, who received debulking surgery and adjuvant chemotherapy for recurrence, were obtained from the National Health Insurance Research database of Taiwan between 2000 and 2013. A total of 1038 patients with recurrent advanced-stage EOC were recruited. The platinum + paclitaxel (PT) group had the best five-year overall survival (OS) compared with the other three groups (p < 0.001). The hazard ratios (HRs) of five-year OS for the platinum + liposomal doxorubicin (PD), topotecan (TOP), and pegylated liposomal doxorubicin (PLD) groups were 1.21 (p = 0.07), 1.35 (p = 0.016), and 1.80 (p < 0.001), respectively, compared with the PT group. The PT group also had lower hazard ratios of five-year OS for patients with platinum therapy-free interval (TFIp) between 6 and 12 months compared with the other three groups (p < 0.0001). However, the HRs of five-year OS did not differ between the PT and PD groups in patients with TFIp >12 months. Patients with TFIp >12 months had lower HRs of five-year OS compared with those with TFIp of 6–12 months, regardless of whether they were treated with platinum-based (p = 0.001) or non-platinum-based (p = 0.003) regimens. Chemotherapeutic regimens and TFIp influenced the outcomes of patients with recurrent EOC. For patients with TFIp of 6–12 months, the PT regimen is the first choice based on their best overall survival result. For patients with TFIp >12 months, either platinum-based or non-platinum regimens could be used because of their similar excellent overall survival.

Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis

ObjectiveTo determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with microsatellite stable (MSS), recurrent, pretreated endometrial cancer (EC). MethodsA decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent pretreated MSS EC. Published data was used to estimate quality adjusted life years (QALYs) and drug cost estimates were obtained using average wholesale prices. A health state utility (HSU) penalty of −0.10 was applied to the LP group to account for treatment toxicity. Incremental cost-effectiveness ratios (ICERs) were calculated to determine cost/QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. ResultsCosts of treatment with doxorubicin, PLD, and bevacizumab are $23.7 million (M), $56.9 M, and $250.8 M respectively. Cost of treatment with LP is $1.8 billion. Relative to doxorubicin, the ICERs for PLD, bevacizumab, and LP are $56,808, $345,824, and $1.6 M respectively. A sensitivity analysis varying the cost of LP shows that if the combined drug cost decreases from over $58,000 to less than $11,000 per cycle, this strategy would be cost-effective. Eliminating the HSU penalty for LP decreased the ICER $1.0 M while increasing the penalty to −0.20 increased the ICER to $3.7 M. ConclusionsLP is not cost-effective in patients with recurrent pretreated, MSS EC. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

Inhibition of Exosome Release Sensitizes U937 Cells to PEGylated Liposomal Doxorubicin.

AimsAcute myeloblastic leukemia (AML) is the most common type of acute leukemia in adults. Despite numerous treatment strategies including chemotherapy and radiotherapy, a large number of patients do not respond to treatment and experience relapse. The main problem of these patients is the development of resistance to anti-cancer drugs. Therefore, any endeavor to reduce drug resistance in these patients is of high priority. In general, several mechanisms such as changes in drug metabolic pathways, drug inactivation, drug target alterations and reduced drug accumulation in the cells contribute to drug resistance of cancer cells. In this context, evidence suggests that exosomes could reduce drug resistance by removing drugs from their parent cells. In the present study, we aimed to investigate the effects of exosome release inhibition on the resistance of U937 cells to PEGylated liposomal doxorubicin (PLD).Main MethodsIn order to find a suitable ABCG2 (ATP-binding cassette sub-family G member 2) transporter substrate, virtual screening was performed among a list of drugs used in leukemia and PLD was selected. U937 cells were treated with PLD with/without co-treatment with the exosome release inhibitor, GW4869. Released exosomes within different study groups were isolated and characterized to determine the differences between groups. Doxorubicin presence in the isolated exosomes was also measured by high performance liquid chromatography (HPLC) to confirm drug export through the exosomes. Finally, the effect of exosome inhibition on the cytotoxicity of PLD on U937 cells was determined using different cytotoxicity assays including the standard lactate dehydrogenase (LDH) release assay and the flow cytometric analysis of apoptotic and non-apoptotic cell death.Key FindingsGW4869 treatment caused a significant decrease in the exosome release of U937 cells compared to the untreated cells, as evidenced by the reduction of the protein content of the isolated exosomes (P<0.05). Co-treatment with GW4869 significantly increased cytotoxic cell death in the groups treated with 0.5 and 1 µM PLD, compared to the same groups without GW4869 co-treatment (P<0.05). Interestingly, co-treatment with GW4896 and 0.5 µM PLD was enough to induce the same cytotoxic effect as that of the sole 1 µM PLD group.SignificanceOur findings showed that U937 cells increase their resistance against the cytotoxic effects of PLD through the exosome-mediated expelling of the drug. Inhibition of exosome release could prevent PLD efflux and consequently increase the vulnerability of the U937 cells to the cytotoxic effects of PLD. Our results along with prior studies indicate that the integration of exosome release inhibitors into the common PLD-containing chemotherapy regimens could significantly lower the required concentrations of the drug and consequently reduce its associated side effects. Further studies are warranted to identify clinically safe inhibitors and investigate their clinical efficacy.

A phase 1b study of chemoimmunotherapy with pegylated liposomal doxorubicin and pembrolizumab in estrogen receptor-positive, endocrine-resistant breast cancer.

1049 Background: This is a single center phase 1b study of a regimen of pembrolizumab (PBZ) and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer. PLD was chosen as chemotherapy component because it is mildly myelosuppressive and non-immunosuppressive and contains doxorubicin, a strong immunogenic cell death inducer. Methods: Patients with estrogen receptor positive, HER2 negative, metastatic breast cancer, whose disease progressed on hormonal and biological therapy and up to 2 chemotherapy lines were eligible for enrollment. PLD, 30 mg/m2, and PBZ, 200 mg flat dose, were infused on day 1 of every 3-week cycles. The main study objectives were safe dose clearance, characterization of dose-limiting toxicities (DLT), tumor response, and pharmacokinetic analysis of PLD and PBZ during the first 3 cycles of treatment in a 1st cohort of 6 patients and a 2nd confirmatory cohort of 6-9 patients. Patients with partial response (PR) or stable disease (SD) continued on the extended phase of the study consisting of 9 additional cycles during which further safety information was collected. All patients were followed-up for survival. Results: 12 patients were recruited (median age 61 y, range 45-91). 9 patients had received prior doxorubicin treatment. 82 treatments have been administered (median: 7, range 2-13). Overall, treatment was well tolerated. DLT including infusion reactions, grade ≥2 myelosuppression, hair loss and mucocutaneous toxicity were not observed in the first 3 cycles. Subsequently, skin toxicity (grade 2-3 palmar-plantar erythema) was observed forcing treatment delays of 1-2 weeks. Except for 2 cases of subclinical hypothyroidism, there were no other apparent PBZ-related side-effects. There was no evidence of cardiac toxicity. There were 2 early deaths (days 25 and 45) probably related to disease progression. Upon reevaluation on week 9, we observed: 2 patients with PD, 4 with SD, 2 with PR (15+ and 5+ mth), 1 with no measurable disease, and 1 early to evaluate. Three out of 5 patients responded well to post-study chemotherapy with durable improvement or stabilization (range, 5 to 11+ mth). Median follow-up is 14 mth. Median survival has not been reached with 4 deaths and a longest survivor of 19+ mth. Median progression-free survival is 6.0 mth. The clearance of PLD was slow with high Cmax, long T½ and small Vd. There was a significant increase in the AUC of PLD between the 1st and 3rd cycle (median: 2,649 vs 3,422 mg*h/l, p = 0.039). Analysis of PBZ plasma levels is ongoing. Conclusions: The combination of PLD and PBZ is well tolerated and feasible for extended treatment. Dose interval of PLD should be lengthened to 4 weeks after 2-3 cycles to prevent skin toxicity. The late appearance of skin toxicity is probably related to a delay in PLD clearance after 2 treatment cycles with PLD and PBZ. Clinical trial information: NCT03591276 .

Phase 1b study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma.

5566 Background: AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). This study evaluated safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the recommended Phase 2 dose (RP2D). Methods: Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg q2 weeks in combination with weekly Pac 80mg/m2 D1, 8, 15 q28 days or PLD 40mg/m2 D1 q28 days and assess for safety, pharmacokinetics, pharmacodynamics, and response by investigator, via RECIST v1.1. Results: A total of 53 patients with platinum-resistant HGSOC (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. Grade 3 or 4 treatment-related adverse events were observed in 4/23 (17%) and 2/30 (7%) PAC and PLD, respectively. No patients discontinued therapy due to an adverse event. Most events were related to known chemotherapy side effects. RP2D was identified as 15mg/kg. Confirmed overall response rate (ORR) with Pac+AVB-500 was 35% (8/23) including 2 CRs and 11% (3/28) in the PLD+AVB-500 subgroup. ORR was 19% (3/16) in patients with platinum free interval (PFI) of &lt; 3 months versus (vs) 23% (8/35) in patients with PFI of 3-6 months. ORR was 11% (2/18) in patients with 1 prior treatment vs 27% (9/33) in patients with 2-3 prior lines of therapy. ORR in patients without prior bevacizumab was 33% (9/27) vs 8% (2/24) in those with prior bevacizumab. Patients treated with Pac combination and whose AVB-500 trough levels were above the minimal efficacious concentration (MEC) of 13.8mg/L achieved the greatest benefit with ORR, median PFS, and median OS of 43% (6/14), 3.9 months, and 17.8 months vs 22% (2/9), 2.8 months, and 8.7 months observed in those whose trough was below the MEC. Among the Pac treated subgroup, the ORR was 47% (13% CR) vs 0% for those with sAXL/GAS6 ratios &gt; 0.773 compared to ratios &lt;0.773. 67% of patients had baseline sAXL/GAS6 &gt; 0.773. Conclusions: AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and inhibits AXL signaling. AVB-500 was well-tolerated in combination with Pac or PLD. This Ph1b trial suggested a higher ORR in the Pac treated subgroup, with C1D15 trough levels &gt; 13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analyses suggested that improved ORR may be observed in patients who have not been exposed to bevacizumab. The serum sAXL/GAS6 ratio may be a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. The ORR in patients with PFI &lt; 3 months or who had &gt; 1 line of prior therapy were similar to those with 3-6 months PFI or ≤1 lines of therapy. Further development of AVB-500 15 mg/kg q2 weeks in combination with Pac is warranted in PROC. Clinical trial information: NCT03639246.

Health-related quality of life (QoL) in platinum-resistant ovarian cancer patients treated with olaparib and pegylated liposomal doxorubicin (PLD), a multicenter single-arm phase II clinical trial (ROLANDO, GEICO-1601).

5549 Background: The prognosis for patients with platinum-resistant/refractory ovarian cancer (PROC) is poor, and the aim of treatment is focused primarily on symptom control and maintenance of QoL. The objective of this study was to assess the impact on QoL of the combination of pegylated liposomal doxorubicin (PLD) with olaparib (OLA) in PROC patients (pts). Methods: ROLANDO is a single arm phase II trial that enrolled pts with high-grade serous or endometrioid and at least one previous PROC recurrence (between 28 days - 6 months after last platinum). Up to 4 previous lines (up to 5 in BRCA-mut) were allowed. Pts received 6 cycles of PLD 40 mg/m2 intravenously every 28 days + OLA 300 mg b.i.d. followed by OLA 300 mg b.i.d. monotherapy until progression or unacceptable toxicity. QoL was measured by European Organization for Research and Treatment of Cancer QLQ C30 questionnaire evaluating functional status, and symptom intensity and QLQ OV-28 ovarian cancer specific module, both filled out by pts every 4 months (mo) regardless of disease progression. Questionnaire compliance was reported as percentage of the initial number of pts. Changes between baseline and subsequent visits (Wilcoxon rank test) were evaluated. P values &lt; 0.05 were considered significant. Results: From 2017 to 2020, 31 pts were recruited. Median age was 57 y.o., ECOG 0/1: 32.3%/67.7%. Median of prior lines was 2 (range 1-5) and pts were on study treatment for a median of 5 mo (range 1.4-19.5) for OLA and 5 cycles (range 2 - 6) for PLD. QoL information was available at baseline for 30 (97%) pts and decayed to 22 (71%), 13 (42%), 6 (19%) and 4 (13%) pts at 4, 8, 12, and 16 mo respectively. Global health status measured by QLQ C30 and QLQ OV-28 scores was maintained throughout all time points with no significant differences. Significant transient improvement was seen in social functioning after 12 mo (p = 0.013). Nausea-vomiting (p = 0.02), hair loss (p = 0.012) and constipation (p = 0.037) showed a significant increase at 4 mo overlapping with PLD administration, and returned to baseline levels afterwards. This was in line with the reported adverse reactions frequency of nausea (58.1%) and vomiting (45.2%). Dyspnea showed a transient significant increase at 12 mo (p = 0.012), whereas insomnia (p = 0.038) and attitude towards disease (p = 0.007) improved at 16 mo. Symptoms such as appetite and constipation did not change after 12 mo. Most functional scales (physical, role, emotional, cognitive, body, sexuality) and symptom scales (fatigue, pain, appetite loss, diarrhoea, neurologic, hormonal and economic burden) had no statistically significant changes. Conclusions: Pts treated with OLA+PLD combination reported no signs of clinically relevant deterioration of QoL while on treatment. All QoL items changes were transient in no more than 1 time-point. Clinical trial information: NCT03161132.

Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer.

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (&gt;6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]

Monocytes Do Not Contribute to Sex Differences Seen in the Pharmacokinetics of Pegylated Liposomal Doxorubicin.

Pegylated liposomal doxorubicin (PLD) is widely utilised in cancer chemotherapy, but exhibits large inter-individual pharmacokinetic variability and sex differences in plasma clearance. Population pharmacokinetic modelling has suggested PLD plasma clearance correlates with peripheral monocyte counts, while sex hormones are known to affect endocytosis and phagocytosis in mononuclear cells. This study investigated whether sex hormones affect the uptake of PLD by human monocytes and macrophages in vitro. 17β-estradiol, but not testosterone, inhibited the uptake of PLD in a concentration dependent manner in undifferentiated (but not differentiated) THP-1 cells, and primary monocytes obtained from women, but not men. Effects of estradiol were only evident at very high concentrations seen during pregnancy. No differences were observed in monocyte count or monocyte subtypes between males and females. These data show that monocytes do not contribute to sex differences seen in PLD clearance in humans of reproductive age.

Enhanced antitumor activity of combined lipid bubble ultrasound and anticancer drugs in gynecological cervical cancers.

Chemotherapy plays an important role in the treatment of patients with gynecological cancers. Delivering anticancer drugs effectively to tumor cells with just few side effects is key in cancer treatment. Lipid bubbles (LB) are compounds that increase the vascular permeability of the tumor under diagnostic ultrasound (US) exposure and enable the effective transport of drugs to tumor cells. The aim of our study was to establish a novel drug delivery technique for chemotherapy and to identify the most effective anticancer drugs for the bubble US‐mediated drug delivery system (BUS‐DDS) in gynecological cancer treatments. We constructed xenograft models using cervical cancer (HeLa) and uterine endometrial cancer (HEC1B) cell lines. Lipid bubbles were injected i.v., combined with either cisplatin (CDDP), pegylated liposomal doxorubicin (PLD), or bevacizumab, and US was applied to the tumor. We compared the enhanced chemotherapeutic effects of these drugs and determined the optimal drugs for BUS‐DDS. Tumor volume reduction of HeLa and HEC1B xenografts following cisplatin treatment was significantly enhanced by BUS‐DDS. Both CDDP and PLD significantly enhanced the antitumor effects of BUS‐DDS in HeLa tumors; however, volume reduction by BUS‐DDS was insignificant when combined with bevacizumab, a humanized anti‐vascular endothelial growth factor mAb. The BUS‐DDS did not cause any severe adverse events and significantly enhanced the antitumor effects of cytotoxic drugs. The effects of bevacizumab, which were not as dose‐dependent as those of the two drugs used prior, were minimal. Our data suggest that BUS‐DDS technology might help achieve “reinforced targeting” in the treatment of gynecological cancers.

Primary angiosarcoma of the spleen, a rare indication for splenectomy: a case report.

Introduction and importancePrimary angiosarcoma of the spleen is a rare condition with a nonspecific clinical presentation and is associated with a poor prognosis. We describe two patients with primary splenic angiosarcoma successfully treated with splenectomy and adjuvant chemotherapy.Case presentationsCase 1: A 50-year-old female presented with fatigue and left-sided rib, shoulder, and abdominal pain. A CT scan demonstrated a large splenic mass, and biopsy was diagnostic of angiosarcoma. An open en bloc resection of the spleen was performed, and pathologic examination confirmed high-grade angiosarcoma; the surgical margins were negative. The patient received pegylated liposomal doxorubicin (PLD) and ifosfamide; she demonstrated no evidence of recurrence with four years of follow-up. Case 2: A 70-year-old male presented with acute back pain. A CT scan demonstrated a splenic mass; biopsy was diagnostic of angiosarcoma. The patient underwent open splenectomy, and pathology revealed high-grade angiosarcoma; the surgical margins were positive. The patient received PLD and ifosfamide but presented three years later with metastatic tumor to the spine. The patient had a favorable tumor response to pembrolizumab. The patient's tumor burden remains stable at 5 years following splenectomy.Clinical discussionAngiosarcoma of the spleen is a rare clinical entity and is often challenging to diagnose early. Moratality is high, especially in the case of metastasis or spontaneous rupture.ConclusionDue to the rare nature of this tumor, optimal treatment is not known. Here, we show excellent response in two patients to surgery combined with adjuvant therapy.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature

BackgroundHypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. Patients and methodsWe retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. ResultsFour hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00–3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004–0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. ConclusionsIn OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.