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A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal-IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment. Cancer Res; 74(23); 7003–13. ©2014 AACR.

Most anticancer therapies are unspecific and therefore inevitably lead to off-target toxicity. To overcome these shortcomings, targetable hybrid polymerization liposomal nanoparticles (HPLNs) have been invented. Multiple innovative and proprietary technologies have been developed to enable creation of this unique form of nanoparticle therapy with covalent attachment of targeting molecules such as tumor specific antibodies or peptides. Human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating irinotecan (CD99-HPLN/Ir) can efficiently reach implanted Ewing sarcoma tumors in xenograft mice and dramatically reduce and/or eliminate the tumor burden. Complete tumor ablation has been observed at doses as low as 1 mg irinotecan/kg, treated twice per week. In other cases, animals who failed untargeted (HPLN/Ir) treatment showed complete tumor ablation after ‘salvage’ treatment with CD99-HPLN/Ir. Our CD99 targeted HPLN/irinotecan formulation, termed NV103 showed much better efficacy than the commercial untargeted liposomal irinotecan (Onivyde™) and doxorubicin (Doxil™). Toxic side effects, normally associated with systemic administration of free irinotecan, were minimized or undetectable. Our nanoparticles showed excellent bioavailability. Even the untargeted HPLN/Ir improve drug bioavailability six-fold in a comparison experiment with the drug in liposome form (Onivyde™), with no discernable systemic toxicity. Experiments using human antiCD99 antibody targeted HPLNs demonstrated they can be used for delivery of therapeutic nucleic acids including siRNA, ASO or functional CRISPR-Cas9 systems against EWS-FLI1. Targeted HPLN/ siRNA and ASO against EWS-Fli1 reduced the protein expression of EWS-Fli1 by 35% and 65%, respectively. Our results of HPLN/CRISPR-Cas9 systems showed the high efficient delivery of CRISPR-Cas9 components and a 70% knockdown of EWS-FLI1 expression in vitro. In the initial animal study our work showed the systemic administration of human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating CRISPR-Cas9 against EWS-Fli1 could reduce the tumor growth of Ewing tumor successfully. In conclusion, our targeted HPLNs can be used as a clinically viable method for the targeted delivery of varied therapeutics including chemotherapeutic agents (Doxorubicin and Irinotecan), therapeutic nucleic acids (siRNA and ASO) and CRISPR-Cas9 systems. Ultimately, after development of other tumor-specific targeting agents and varied encapsulated therapeutics, this technology can be usefully adapted for the treatment of various cancers as well. Citation Format: HyungGyoo Kang, Jon Nagy, Sheetal Mitra, Triche Triche. Targeted therapy of Ewing’s sarcoma by human anti CD99 targeted hybrid polymerized liposomal nanoparticles (HPLNs) encapsulating anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2875.

Background: HER2-negative metastatic breast cancer (MBC) patients with central nervous system (CNS) involvement previously treated with a local therapy had very few possibilities of disease response with conventional systemic treatments. Liposomal irinotecan (nal-IRI) is a novel formulation of irinotecan. It has shown promising activity in patients with CNS involvement. The aim of this trial is to evaluate the efficacy of nal-IRI as single agent in HER2-negative MBC patients with CNS progression following local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy. Trial design: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive intravenous nal-IRI in a fixed dose of 60 mg/m2 expressed as irinotecan hydrochloride trihydrate salt on day 1 of a 14-day cycle until progression or unacceptable toxicity. The principal selection criteria are: (1) HER2-negative inoperable MBC with CNS involvement; (2) prior local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy; (3) prior treatment with taxanes; (4) at least one measurable brain lesion according to RECIST v1.1 criteria. The primary objective is to evaluate the efficacy of naI-IRI monotherapy. Primary endpoint is the CNS overall response rate (ORR), defined as the percentage of patients who experienced complete (CR) and partial response (PR) (as best response). It will be assessed in accordance with the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CNS ORR ≤5% while targeting an improvement of the CNS ORR to ≥15% would be an optimal approach for evaluating the study strategy. At least 2 responders among 23 patients will be necessary to proceed to the second stage. At the study end, ≥6 responders out of 56 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 63 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. The secondary objectives include safety-related outcomes and efficacy measures: CNS clinical benefit rate (CR, PR and stable disease [SD] ≥12 weeks), ORR according to a CNS volumetric parameter (CR, PR and >65% reduction of CNS lesion), clinical benefit rate (CR, PR and SD ≥24 weeks), progression-free survival and overall survival. Trial registration: NCT03328884. Date of registration: November 1st, 2017. First patient included: July, 05th 2017. Citation Format: Javier Cortés, David Paez, José Manuel Pérez García, Salvador Blanch Tormo, Kepa Amillano Parraga, Manuel Ruiz Borrego, Antonio Antón Torres, María Fernández, Emilio Alba Conejo, Miguel Ángel Seguí Palmer, Joan Dorca Ribugent, Rafael López López, Mireia Margelí Vila, Elena Aguirre, Antonio Llombart. Multicenter open-label, phase II trial, to evaluate the efficacy and safety of liposomal irinotecan (nal-IRI) for progressing brain metastases in patients with HER2-negative breast cancer (The Phenomenal Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT154.

Most anticancer therapies are unspecific and therefore inevitably lead to off-target toxicity. To overcome these shortcomings, targetable hybrid polymerization liposomal nanoparticles (HPLNs) have been invented. Multiple innovative and proprietary technologies have been developed to enable creation of this unique form of nanoparticle therapy, including the use of cross linked lipids to improve both stability and bioavailability, modified polyethylene glycol (PEG) for both ‘stealthiness' (to prevent immune response to the nanoparticle) and for covalent attachment of targeting molecules such as tumor specific antibodies or peptides. Our present study showed the superior efficacy of human anti-CD99 targeted HPLNs in the treatment of Ewing sarcoma. Human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating irinotecan (CD99-HPLN/Ir) can efficiently reach implanted Ewing sarcoma tumors in xenograft mice and dramatically reduce and/or eliminate the tumor burden. Complete tumor ablation has been observed at doses as low as 1 mg irinotecan/kg, treated twice per week. In other cases, animals who failed untargeted (HPLN/Ir) treatment showed complete tumor ablation after ‘salvage' treatment with CD99-HPLN/Ir. Our CD99 targeted HPLN/irinotecan formulation, termed NV103 showed much better efficacy than the commercial untargeted liposomal irinotecan (Onivyde™) and doxorubicin (Doxil™). Toxic side effects, normally associated with systemic administration of free irinotecan, were minimized or undetectable. Our nanoparticles showed excellent bioavailability. Even the untargeted HPLN/Ir improve drug bioavailability six-fold in a comparison experiment with the drug in liposome form (Onivyde™), with no discernable systemic toxicity. Antibody targeting of the HPLN irinotecan formulation (NV103) improves the efficacy 12-fold, over the untargeted liposome form. In conclusion, this formulation may be effective for treatment of other CD99-expressing tumors like certain leukemias, lymphomas and glioma. Ultimately, after development of other tumor-specific targeting agents and varied encapsulated therapeutics, this technology can be usefully adapted for the treatment of other cancers as well. Citation Format: Hyunggyoo Kang, Jon Nagy, Timothy Triche. Targeted anticancer drug delivery to Ewing's sarcoma using human anti-CD99 targeted hybrid polymerization liposomal nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3705.

Background/Objectives: Children with relapsed or refractory solid tumors have a poor prognosis. Irinotecan is active in some pediatric solid tumors and synergizes with alkylating agents. nal-IRI encapsulates irinotecan into long-circulating, liposome-based nanoparticles. In adults, nal-IRI demonstrated extended plasma exposure compared with non-liposomal irinotecan. In pediatric solid tumor models, nal-IRI had robust preclinical activity and synergized with cyclophosphamide, and therefore merits testing in children with relapsed and refractory solid tumors. Herein we describe a phase 1 dose-escalation study of nal-IRI in combination with cyclophosphamide (NCT02013336) and preliminary pharmacokinetic and safety results. Methods: Cyclophosphamide was administered on days 1-5 of each cycle (250 mg/m2/d intravenously [IV]) with a single 90-min IV infusion of nal-IRI on day 3 of a Q3-week schedule, escalating from 60 mg/m2 to 210 mg/m2 (expressed as irinotecan HCL trihydrate salt), in a standard 3+3 dose-escalation design to determine the maximum tolerated dose. To date, the nal-IRI dose has been escalated from 60 mg/m2 to 150 mg/m2. Samples for pharmacokinetic analysis were collected during the first cycle of chemotherapy before infusion and at 4h, 24h, 48h, 120h, and 168h post-infusion. Plasma pharmacokinetics of total irinotecan and SN-38 were quantified using mixed effect modeling, and were compared with adult values from a population pharmacokinetic analysis of 6 clinical studies of nal-IRI.1 Results: To date, 10 males and 6 females with a median age of 12.8 years (range: 5-19) have been enrolled: 10 with Ewing sarcoma, 2 with neuroblastoma, 3 with osteosarcoma, and 1 with rhabdomyosarcoma. The estimated total irinotecan volume of distribution (Vd) was 1.9 L, clearance (CL) was 10.3 L/week, and half-life (t1/2) was 21.2 h, which were 42% (Vd and CL) of adult values and comparable to adult values (t1/2). The corresponding Cmax was 72% higher than that observed in adults. SN-38 clearance was 11.4 L/week (comparable to adults), t1/2 was 19.3 h (48% of adult values), and Cmax was 68% of adult values. Thrombocytopenia leading to treatment delay was a dose-limiting toxicity at 150 mg/m2 (n=1); other systemic toxicity attributed to chemotherapy within the 1st cycle was nausea/vomiting (n=1). Conclusions: Preliminary safety and pharmacokinetic data support continued investigation of nal-IRI in pediatric oncology. Clinical outcomes including safety of patients treated in this study will be reported once a maximum tolerated dose is achieved. 1. Adiwijaya B et al. Clin Pharmacol Ther. 2017. In press. Citation Format: Paul D. Harker-Murray, William H. Meyer, Patrick Leavey, Min H. Kang, Hwangeui Cho, Bambang S. Adiwijaya, Jonathan B. Fitzgerald, J Marc Pipas, Daryl C. Drummond, C. Patrick Reynolds. Plasma pharmacokinetics of liposomal irinotecan (nal-IRI) in pediatric oncology patients with recurrent or refractory solid tumors: South Plains Oncology Consortium Study 2012-001 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT146. doi:10.1158/1538-7445.AM2017-CT146

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.

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