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Background Recent studies suggest that carboplatin with pegylated liposomal doxorubicin (C+PLD) is as efficacious as carboplatin with paclitaxel (C+P) and possibly is more tolerable for ovarian cancer therapy. Pegylated liposomal doxorubicin (PLD) may also be efficacious and tolerable as monotherapy in recurrent or platinum-resistant disease. We performed a meta-analysis of randomized trials in order to elucidate the role of PLD in ovarian cancer. Methods We searched PubMed, Scopus, and ISI Web of Knowledge for studies comparing C+PLD with C+P and comparing PLD with another monotherapy. Summary hazard ratios (HRs) and relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a fixed-effects model. Results Three trials were included in the doublet regimen analysis, and five trials were included in the monotherapy regimen analysis. C+PLD provided superior progression-free survival (PFS) (HR, 0.87; 95% CI, 0.78-0.96) and similar overall survival (OS; HR, 0.95; 95% CI, 0.84-1.07) compared with C+P. There was no evidence of improved tolerability: C+PLD had more gastrointestinal toxicity, anemia, thrombocytopenia, cutaneous toxicity, and mucositis/stomatitis, although there was less neutropenia, neuropathy, and alopecia. PLD monotherapy had similar PFS (HR, 0.99; 95% CI, 0.89-1.11) and OS (HR, 0.99; 95% CI, 0.88-1.11) to other monotherapies, but it was more tolerable. There was less neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity, although cutaneous toxicity was increased. Conclusion C+PLD had better PFS and similar OS compared with C+P and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. PLD is as efficacious as other monotherapies and is more tolerable.

Introduction: Liposomes are commonly used as drug carriers and the majority of approved anticancer nanoparticles utilize this platform. We have reported that liposomes similar to those used in patients can enhance tumor growth through inhibition of the antitumor immune response. However, it is not clear how the drug cargo impacts the immune modulatory effects of the carrier. The primary purpose of this study was to determine how loading of alendronate, an immune modulatory drug, into liposomes affects tumor progression and functionality of immune cells in tumor and spleen. Methods: Tumor free C57BL/6 mice (n = 12) and mice bearing s.c. TC-1 tumors (n = 24) were treated with up to 2 weekly i.v. injections of empty liposomes similar to the pegylated liposomal carrier used in Doxil, liposomes containing alendronate (PLA), or vehicle control. Tumor size was monitored biweekly and mice were sacrificed at endpoint to obtain tumors and spleens for single cell suspensions. To enumerate myeloid and lymphoid cell populations, cells were stained for CD11b, CD11c, Gr1, and F4/80, or TCR-β, CD8b and CD4 respectively. Separate aliquots of cells were also stimulated ex vivo with CpG (myeloid cells) or PMA/ionomycin (T cells), with monensin followed by intracellular staining for IL-2, IFN gamma, perforin and TNF alpha. All assays included Fc-blocking, CD45 stain, viability dye, and were analyzed by flow cytometry (BD LSR Fortessa). Results: In tumor free mice, liposomes increased the infiltration of macrophages and MDSC's in the spleen with lowered iNOS production, and increased IL-2, IFN gamma, and perforin production in CD8+ and CD4+ T cells. Loading alendronate into the liposomes mitigated the splenic infiltration of both macrophages and MDSC's and potentiated the T cell cytokine responses (IL-2, IFNg, perforin and TNF alpha). In tumor bearing mice, liposomes increased the infiltration of TAMs and inhibited tumor CTLs. Loading Alendronate (PLA) decreased the iNOS and arginase producing TAMs and mitigated the liposome-associated inhibition of CTL infiltration. Importantly, we found that mean tumor volumes were significantly smaller in PLA treated mice (288.9 mm3) as compared with liposomes (885.7 mm3). Conclusions: We found that loading alendronate into liposomes mitigates the tumor-promoting potential of the carrier through modulation of macrophage, MDSC, and T cell infiltration and functionality in spleen and tumor. Ongoing studies will identify the mechanisms underlying the interactions between the carrier, drug cargo, and tumor immunologic milieu. This will be especially critical to the successful translation of carrier-mediated immunotherapies into the clinic. Citation Format: Robin Rajan, Manoj K. Sabnani, Laurence M. Wood, Vikram Mavinkurve, Alberto A. Gabizon, Ninh M. La-Beck. Pegylated liposomal alendronate: The impact of the drug cargo on carrier-induced immune modulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4008.

There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD.Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi's sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined.There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m(2), respectively (P 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m(2), respectively (P 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance.Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

Aim: Promitil® is a pegylated liposome formulation of a lipid-based prodrug of mitomycin C (MLP). MLP is activated to mitomycin C (MMC) by thiolytic cleavage. Pre-clinical studies of Promitil have shown long circulation time, reduced toxicity, and improved therapeutic index over MMC. The primary objectives of this study were to determine the maximal tolerated dose (MTD), identify dose-limiting toxicities (DLT), and characterize the pharmacokinetic (PK) profile of Promitil. Secondary objectives were to evaluate the safety profile of Promitil and anti-tumor responses. Plasma levels of sC5b-9 complex were measured to detect liposome infusion-related complement activation. Methods: Enrolled patients were diagnosed with advanced solid tumors. Promitil was administered i.v. at 4-week intervals starting with an MLP dose of 0.5 mg/kg and escalating at 0.5 mg/kg stepwise increments. Each dose level cohort consisted of 3-6 patients. Dose escalation proceeded if no DLT observed after the 1st cycle. Each patient was scheduled to receive 3 cycles with PK analysis in 1st and 3rd cycles, and undergo re-evaluation in the 12th week, unless early discontinuation was clinically indicated. Treatment continuation beyond 3 cycles was at the discretion of the investigators. Results: 27 patients received 100 Promitil infusions (median = 3 cycles/patient; range = 1-12) between 18Nov2012 and 04May2014. The highest dose level tested was 3.5 mg/kg (=1.03 mg/kg MMC-equivalents) in a cohort of 6 patients. Although no DLT was observed for single dose Promitil, the occurrence of several cases of delayed thrombocytopenia grade 2-3 after 3 or more cycles of Promitil in patients treated at lower dose levels (2-3 mg/kg) led us to terminate dose escalation. The 1st cycle MTD of Promitil is 3 mg/kg and the recommended dose for additional cycles is 2 mg/kg at intervals of 28 days. PK analysis indicates MLP has a slow, nearly mono-exponential clearance, with a half-life of 20-24 hours and a small volume of distribution similar to blood volume. Conclusions: The single dose MTD and the 12-week maximal cumulative dose of Promitil in MMC-equivalents are ∼3-fold greater than for MMC. Thrombocytopenia is cumulative dose limiting. The PK is characteristically Stealth-like as with other pegylated liposomes. Final results of safety, complement activation, PK, and tumor responses will be presented. Disclosure: A.A. Gabizon: is founder, director, and chief scientist of Lipomedix Pharmaceuticals, the company developing the product Promitil; Y. Amitay: works as a Senior Scientist in Lipomedix Pharmaceuticals; P. Ohana: is Director of Medical Affairs for Lipomedix Pharmaceuticals. All other authors have declared no conflicts of interest.

Background: PLD is a pegylated liposomal formulation of doxorubicin approved for the treatment of ovarian cancer, Kaposi's sarcoma, and multiple myeloma. We have reported that age, gender, and monocyte count may affect the clearance (CL) of PLD. In multiple myeloma, PLD is used with bortezomib, a proteosome inhibitor which can affect monocyte count. The purpose of this cross study comparison was to assess the effects of bortezomib on the CL of PLD. Methods: This was a cross trial comparison of patients with solid tumors who received PLD alone and PLD + bortezomib. The PLD alone group (n = 34) received PLD at 10 to 60 mg/m2 IV every 28 days. The PLD + bortezomib group (n = 25) received bortezomib at 0.90 to 1.50 mg/m2 IV on days 1, 4, 8, and 11, and PLD at 30 mg/m2 IV on day 4, every 21 days. PK studies of PLD were performed for cycle 1, after administration of PLD alone and PLD + bortezomib. Serial blood samples were obtained from 0 to 96 h and from 7 to 28 days after administration of PLD. Plasma samples were processed to measure sum total (encapsulated + released) doxorubicin via HPLC and the clearance (CL) was calculated with WinNonlin using noncompartmental methods. Results: In patients < 60 years old, the mean (± standard deviation) PLD CL after administration of PLD alone and in combination with bortezomib was 63.4 (± 46.1) and 23.3 (± 7.6) mL/h, respectively (P=0.017). In patients >= 60 years old, the PLD CL after administration of PLD alone and in combination with bortezomib was 39.1 (± 18.5) and 38.0 (± 15.5) mL/h, respectively (P>0.05). In male patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 65.4 (± 33.4) and 38.4 (± 9.7) mL/h respectively (p>0.05). In female patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 40.1 (± 33.4) and 24.6 (± 11.2) mL/h respectively (P>0.05). Conclusion: This cross study comparison suggests that bortezomib decreases PLD CL in younger patients and in male patients. Although the underlying mechanism for this effect on PLD CL is not known, it may be related to bortezomib inhibition of mononuclear phagocyte activity in certain patient populations, which is responsible for the CL of PLD. There is a need to further investigate this in a prospective drug interaction study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3768. doi:1538-7445.AM2012-3768

e13003 Background: Peglyated liposomal (PL) anticancer agents are nanoparticles that may improve antitumor efficacy by enhancing tumor drug delivery while limiting exposure in normal tissues. Howev...

Background: PLD is a nanoparticle approved for treatment of refractory ovarian cancer. The reticuloendothelial system (RES), which includes monocytes (MO), may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes such as PLD, though factors affecting the CL of liposomes are unclear. Previously we reported that the CL of liposomes is associated with age and monocyte counts. This study's objective was to characterize the function of MO and granulocytes with and without ex vivo PLD exposure in the blood of healthy volunteers. Methods: Blood samples were obtained from six (4 males, 2 females) healthy human volunteers, immediately placed on ice and processed. Blood samples were incubated with PLD 10 mcg/mL or 5% dextrose solution (control) for 1 hour (h) at 37°C with 5% CO2. After incubation, PHAGOTEST® and PHAGOBURST® (Orpegen Pharma) tests were performed to evaluate phagocytic activity and respiratory burst activity. PHAGOBURST® tests were performed after fMLP and PMA stimulation. Samples were analyzed using Dako CyAn Flow Cytometer with Summit software. Comparisons were made between samples with and without PLD exposure, gender, and age >60 and Results: The mean + SD age of healthy volunteers was 45.9 + 14.9 yo. The mean fluorescence per cell, grouped by functional test and age, gender, and with or without PLD exposure are summarized in Table 1.Table 1.Mean Fluorescence Phagocytic ActivityRespiratory Burst Activity with fMLPRespiratory Burst Activity with PMA GranulocytesMonocytesGranulocytesMonocytesGranulocytesMonocytesAge >60 (n=2)447.6323.383.757.7377.789.4Age Conclusions: Differences in phagocytic and respiratory burst activity in granulocytes and MO of healthy volunteers were observed. There is variability in activity based on the type of assay used. There appears to be both age and gender differences in activity. A 1 h ex vivo exposure to PLD does not seem to significantly alter cell function. Future studies will characterize MO and granulocyte function, PLD uptake, and viability with and without PLD exposure in additional healthy subjects and ovarian and breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3697.

Introduction: S-CKD602 is a pegylated liposomal formulation of CKD-602, a camptothecin analogue. Optisomal Topotecan (TLI) is a sphingomyelin stabilized liposomal formulation of topotecan. The cytotoxicity of CKD-602, topotecan and other camptothecin analogues is related to the duration of exposure. Pegylated and sphingomyelin liposomal formulations have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. The pharmacokinetics (PK) of liposomal agents is highly variable in patients. Moreover, the factors associated with this variability are unknown. Thus, we evaluated the plasma PK disposition of TLI and S-CKD602 in male and female rats. Methods: TLI was administered at 0.93mg/kg IV x1 and S-CKD602 at 0.6 mg/kg IV x1 to male and female Sprague-Dawley rats via a bilateral jugular vein cannula. Plasma samples for TLI were obtained in 6 cohorts (n= 3 rats per cohort, total = 18 rats per gender): 1) pre, 1, and 3 min; 2) 5, 10, and 20 min; 3) 0.5, 1, and 2 h; 4) 4, 8, and 12 h; 5) 24, 36, and 48 h; 6) 60 and 72 h post dose. Plasma samples (n= 3 rats per time point per gender) for S-CKD602 were obtained prior to the end of the infusion, and at 4, 8, 24, 48, and 72 h after administration. Total (lactone and hydroxyl acid) form of sum total (encapsulated and released) CKD-602 and topotecan were measured via LC/MS. The clearance (CL) was estimated using noncompartmental PK analysis. Results: For TLI, the CL in male and female rats were 0.026 ± 0.0038 and 0.021 ± 0.0015 L/h/kg, respectively. For S-CKD602, the CL in male and female rats were 0.0037 ± 0.0004 and 0.0027 ± 0.0001 L/h/kg, respectively. For TLI and S-CKD602, CL was 1.2-fold (p=0.14) and 1.4-fold (p=0.009) lower in female rats compared with male rats, respectively. Conclusions: The CL of TLI and S-CKD602 was lower in female rats as compared with male rats. These studies suggest that gender may affect the disposition of liposomal formulations of drugs and may play a role in the high PK variability reported in patients treated with liposomal formulations of anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3700.