Search

303 Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]

Purpose To investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. Experimental Design The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU. Results The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg). Conclusions Single agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.

Pancreatic cancer remains one of the deadliest cancers with survival described in number of months and weeks. Recent advances in the treatment of pancreatic cancer led to the recent approval of a liposomal irinotecan (ONIVYDETM (irinotecan liposome injection), previously MM-398). Given the activity of taxanes in pancreatic cancer and the ability of nanoliposomes to deliver drugs, we developed a novel EphA2-targeted nanoliposomal docetaxel (MM-310) and evaluated its activity in patient derived xenograft (PDX) models of pancreatic cancer as a monotherapy, as well as in combination with gemcitabine. Additionally, we aimed to test the predictive potential of key biomarkers that are linked to the MM-310 mechanism of action. Several PDX models developed at Roswell Park Cancer Institute were screened for the expression of EphA2 (MM-310 target), CD31 (blood vessels), Massons Trichrome (fibrosis), CA XI (hypoxia), and E-Cadherin (adhesion molecule that can potentially inhibit target engagement). Eight EphA2+ PDX models were used to evaluate the activity of MM-310 and compare it to clinically relevant agents including nab-paclitaxel, liposomal irinotecan, oxaliplatin, and gemcitabine. We also tested the combination potential of MM-310 and gemcitabine. MM-310 was able to statistically significantly control tumor growth in all tested models with tumor regression in more than 85% of the models. When compared with standard of care agents in tumor models, at equitoxic dosing, MM-310 demonstrated greater activity to nab-paclitaxel in 80% (4/5), gemcitabine in 100% (5/5), and oxaliplatin in100% (5/5), and liposomal irinotecan in 80% (4/5). Gemcitabine is currently considered a standard of care in pancreatic cancer in combination with nab-paclitaxel, thus we conducted a study to evaluate the potential combination benefits of gemcitabine with MM-310. The combination of suboptimal doses of MM-310 and gemcitabine led to significant tumor growth control which was greater to either arm alone. Additionally, at equitoxic dosing of 50% maximum tolerated dose, MM310 + gemcitabine showed greater effect than ABRAXANE (paclitaxel protein-bound particles for injectable suspension) + gemcitabine. Although we have excluded EphA2 negative models from these studies, biomarker analysis showed that MM-310 effects are not correlated with the EphA2 expression level, suggesting that a low level EphA2 might be sufficient to mediate activity and that liposome delivery might be the rate limiting step. Additional biomarker analysis will be conducted. In conclusion, we found that MM-310 is highly active in several patient derived models of pancreatic cancer and that it was equal or greater to most standard of care agents. Future studies will aim at identifying markers for differentiating response to MM-310 (EphA2 targeted nanoliposomal docetaxel) and ONIVYDE (irinotecan liposome injection). Citation Format: Daryl C. Drummond, Ninfa L. Straubinger, Tista Roy Chaudhuri, Michael Moser, Walid S. Kamoun, Lia Luus, Zhaohua Richard Huang, Suresh Tipparaju, Bryan Gillard, Carl Morrison, Elizabeth Repasky, Dmitri B. Kirpotin, Robert M. Straubinger. Activity of an EphA2-targeted docetaxel nanoliposome in pancreatic patient-derived models as monotherapy and in combination with gemcitabine. [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 2069.

Objectives Liposomal delivery of irinotecan could provide protection against drug hydrolysis, deliver more active lactone form to tumours and prolong irinotecan exposure time. Nevertheless, conventional drug-loading technologies have typically resulted in undesired drug retention properties. To resolve the problem, a modified gradient loading method was developed and the resulting formulations were evaluated in a systemic manner. Methods Irinotecan was loaded into liposomes using a novel sulfobutyl ether beta-cyclodextrin (sbe-CD) gradient. The effect of drug-to-lipid ratio (D/L) and polyethylene glycol (PEG) grafting density were investigated. Drug release experiments were performed in ammonium-containing medium based on the fluorescence dequenching phenomenon of irinotecan. Pharmacokinetic studies were performed in normal balb/c mice treated with different formulations. To compare the anti-tumour effect of different formulations, an RM-1 prostate cancer model was used. Acute toxicity studies were performed in healthy female c57 mice. Key findings Irinotecan could be encapsulated into liposomes with > 90% loading efficiency at a high drug-to-lipid mass ratio (> 0.5). In-vitro release experiments revealed that sbe-CD anion was more able to retain irinotecan than sulfate. Moreover, the elevated D/L ratio elicited decreased drug release kinetics. Both trends had also been observed when the effects of anions and D/L ratio on half-life of irinotecan were assessed. Pegylated liposomal irinotecan loaded with sbe-CD/triethylammonium gradient had irinotecan half-life values ranging from 9.4 to 13.1 h, surpassing vesicles prepared by the triethylammonium sulfate method (∼4.5 h). In the RM-1 tumour model, all the liposomal irinotecan formulations were more therapeutically active than free irinotecan and the formulation with a high D/L ratio was the most efficacious. Moreover, the high D/L formulation might be less toxic than free irinotecan based on acute toxicity studies. Conclusions The novel sbe-CD gradient could mediate effective irinotecan loading and improve irinotecan retention, thus resulting in highly active liposomal irinotecan formulations. The improvement in drug retention might be associated with the formation of complicated aggregates inside vesicles.

A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of copper to complex irinotecan within the liposome. It is currently being evaluated for critical drug-loading parameters. Studies presented here were designed to determine the optimum copper concentration required for the effective encapsulation and retention of irinotecan into liposomes.Distearoylphosphatidylcholine/cholesterol liposomes were formulated using buffers containing various copper or manganese concentrations, and irinotecan loading was determined in the presence and absence of divalent metal ionophore A23187. The rate and extent of irinotecan encapsulation and the rate of irinotecan release from the liposomes were assessed. The amount of copper retained inside liposomes following irinotecan loading and the effect of copper on membrane permeability were determined.Efficient (98%) irinotecan loading was achieved using encapsulated copper concentrations of 50 mM. However, irinotecan release was copper concentration dependent, with a minimum 300 mM concentration required for optimal drug retention. The presence of copper increased liposomal membrane permeability.Results explain why irinotecan loading rates are enhanced in the presence of formulations prepared with copper, and we speculate that the Irinophore C formulation exhibits improved drug retention, due to generation of a complex between copper and irinotecan.

2029 Background: Treatment options for recurrent malignant glioma are limited. Preclinical activity of irinotecan has been seen in glioma models but only modest efficacy has been noted in clinical ...

Liposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with unprecedented drug loading efficiency and in vivo drug retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, either polymeric (polyphosphate) or nonpolymeric (sucrose octasulfate), liposomes were capable of entrapping CPT-11 at extremely high drug-to-lipid ratios (>800 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release in the circulation of 56.8 hours. CPT-11 was also protected from hydrolysis to the inactive carboxylate form and from metabolic conversion to SN-38 while circulating. The maximum tolerated dose in normal mice was determined to be 80 mg/kg for free CPT-11 and >320 mg/kg for nanoliposomal CPT-11. Nanoliposomal CPT-11 showed markedly superior efficacy when compared with free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models. This study shows that intraliposomal stabilization of CPT-11 using a polymeric or highly charged, nonpolymeric polyanionic trapping agent results in a markedly active antitumor agent with low toxicity. (Cancer Res 2006; 66(6): 3271-7)

Background: Liposomal anthracyclines (such as pegylated liposomal doxorubicin (PLD) or HER2-targeted liposomal doxorubicin (MM-302)) are being used and/or evaluated for the clinical management of breast cancer, but responses vary from patient to patient. It is hypothesized that variability in the deposition of liposomal therapeutics within tumors leads to differences in drug exposure, thereby directly influencing tumor response. We have developed MM-DX-929, a novel 64Cu-liposomal PET imaging agent, as a clinically-implementable tool to investigate whether image-based quantification of liposome deposition in tumors can predict treatment response to liposomal chemotherapeutics, including PLD, MM-302 and/or liposomal irinotecan (MM-398). Objectives: Our primary objective is to demonstrate that the extent of tumor uptake of MM-DX-929 is predictive of tumor response to MM-302 in preclinical breast cancer xenograft models. A secondary objective is to enable clinical translation of MM-DX-929 to enable incorporation into existing therapeutic trials. Methods: Mice bearing BT474-M3 mammary and subcutaneous tumors were injected intravenously with MM-DX-929 prior to dosing with MM-302. PET/CT imaging was performed at 16h post MM-DX-929 injection, and tumor uptake was determined. Response to treatment was quantified as tumor volume changes measured over a 2-month period by MRI. Results: Tumor deposition of MM-DX-929 administration correlated well with treatment response to MM-302 (Spearman correlation coefficient of −0.891 and a p-value of 0.0004). MM-DX-929 accumulation in tumors prior to the start of the MM-302 treatment successfully predicted improved tumor growth inhibition following MM-302 treatment. Conclusion: These findings support trials of MM-DX-929 as a predictive imaging agent to select patients who are most likely to respond to liposomal therapies. The clinical development of MM-DX-929 for identification of breast cancer patients likely to respond to liposomal therapeutics is currently being pursued. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-05.

Background: Irinotecan (CPT-11) is an antineoplastic prodrug, of which SN-38 is an active metabolite. Liposomal CPT-11 was developed to improve systemic and tumor exposure to CPT-11 and its active metabolite by reducing the exposure of CPT-11 to neutral and basic pH, in which CPT-11 is hydrolyzed into an inactive carboxylate form. The aims of the current study are 1) to compare the plasma and tissue/tumor pharmacokinetics of nanoliposomal CPT-11 (in clinical trials as PEP02 or MM-398) and conventional irinotecan in mice, and 2) to compare anti-tumor activity of the two formulations against Ewings Sarcoma murine xenografts. Methods: An assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to measure CPT-11 and SN-38 concentrations in plasma and tissue. Plasma and tissue pharmacokinetics of liposomal and conventional irinotecan were characterized in Balb/c mice (non-tumor bearing); pharmacokinetics and activity were assessed in athymic nu/nu mice xenografted with human Ewings sarcoma. Results: Following a 20 mg/kg dose of intravenous liposomal irinotecan, both plasma and tumor concentrations of CPT-11 and SN-38 were approximately 10-fold higher than conventional irinotecan. The Cmax and AUC were dose-proportionally increased after a single dose of liposomal irinotecan in non-tumor bearing mice. In mice xenografted with Ewings sarcoma (CHLA-258), liposomal irinotecan significantly extended event-free survival of mice compared with controls or conventional irinotecan (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5469. doi:10.1158/1538-7445.AM2011-5469

Purpose To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors. Methods Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg/m2, was given as a 90-min intravenous infusion, every 3 weeks. Results A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m2 (four patients). DLT was observed in three patients, one at 120 mg/m2 (grade 3 catheter-related infection) and two at 180 mg/m2 (grade 4 neutropenia lasting for >3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120 mg/m2. Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 (the active metabolite) after PEP02 was characterized by lower Cmax, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher Cmax and AUC levels of SN-38 than those of the other three patients at 180 mg/m2. Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6/*28. Two patients had objective tumor response. Conclusions PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg/m2, which will be the recommended dose for future studies.