Non-liposomal Irinotecan Research Articles

A phase II study of neoadjuvant liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in pancreatic adenocarcinoma.

For patients with localized pancreatic cancer with minimal vascular involvement, optimal survivability requires a multidisciplinary approach of surgical resection and systemic chemotherapy. FOLFIRINOX is a combination chemotherapy regimen that offers promising results in the perioperative and metastatic settings; however, it can cause significant adverse effects. Such toxicity can negatively impact some patients, resulting in chemotherapy discontinuation or surgical unsuitability. In an effort to reduce toxicities and optimize outcomes, this investigation explores the safety and feasibility of substituting liposomal irinotecan (nal-IRI) for nonliposomal irinotecan to improve tumor drug delivery and potentially reduce toxicity. This regimen, NALIRIFOX, has the potential to be both safer and more effective when administered in the preoperative setting.

Second-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer: a single-center experience and review of literature.

Prognosis of patients with pancreatic cancer is still extremely poor. First-line palliative therapies with FOLFIRINOX or gemcitabine/nab-paclitaxel have been established in the last decade. In the second-line, 5-FU/LV in combination with nanoliposomal irinotecan (nal-IRI) after gemcitabine has been shown to be effective. However, the use of nal-IRI as third-line therapy after FOLFIRINOX and gemcitabine-based chemotherapies is still controversial. In this study, we report about the use of 5-FU/LV + nal-IRI in a daily practice and analyze whether nal-IRI is an option as third-line therapy after FOLFIRINOX and gemcitabine/nab-paclitaxel. This is a single center retrospective analysis of patients with irresectable pancreatic cancer who were treated with 5-FU/LV and nal-IRI from 2017 to 2021 as second- or third-line palliative treatment. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed, and multivariate analysis was used to identify independent prognostic factors. Twenty-nine patients receiving 5-FU/LV and nal-IRI were included in the analysis. The majority of patients (n=19) received 5-FU/nal-IRI as third-line therapy after pre-exposition to FOLFIRINOX and gemcitabine/nab-paclitaxel. Median OS and PFS were 9.33 months (95% CI: 3.37, 15.30) and 2.90 months (95% CI: 1.64, 4.16), respectively. Furthermore, patients receiving nal-IRI + 5-FU/LV as third-line treatment also showed some benefits, with no OS difference compared to second-line patients (9.33 vs. 10.27 months; HR: 1.85; 95% CI: 0.64, 5.41; P=0.253). Adverse effects were similar to reported trials. In our study, the use of 5-FU/nal-IRI in unselected patients with advanced pancreatic cancer showed similar OS, PFS and tolerance as randomized prospective phase II/III trials. Interestingly, the use of 5-FU/nal-IRI seemed to be beneficial in third-line therapy, despite a pre-exposure to non-liposomal irinotecan.

Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50mg/kg/week) or non-liposomal irinotecan (10, 25, 50mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50mg/kg/week. Using the selected IM-PAN-001 model at the MTD (both treatments, 50mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.

Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs.

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first‐line treatment in several countries. However, irinotecan has not been successfully introduced as a second‐line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal‐IRI) combined with 5‐fluorouracil and leucovorin (5‐FU/LV) was reported in the phase III NAPOLI‐1 trial in metastatic PDAC following failure of gemcitabine‐based therapy. Several features of nal‐IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN‐38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN‐38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half‐life and higher area under the concentration‐time curve (0–∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal‐IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small‐cell lung cancer.

Differentiation of liposomal irinotecan from dose-dense non-liposomal irinotecan in patient-derived pancreatic cancer xenograft tumor models.

e16724 Background: Liposomal irinotecan (ONIVYDE) is approved with 5-fluorouracil/leucovorin for metastatic pancreatic ductal adenocarcinoma (PDAC) post progression on gemcitabine-based therapy. The liposomal formulation prolongs payload residence time in the circulation and tumor lesions, where local conversion to the active metabolite SN-38 is thought to occur. The effect of the liposomal formulation on therapeutic index (TI) was assessed in patient-derived xenograft PDAC models (IM-PAN-001 [untreated tumor] and SA-PAN-077) in severe combined immunodeficiency mice. Methods: Liposomal (2.5, 10 or 50 mg/kg, intravenous [IV] 1 x weekly) and non-liposomal irinotecan (2, 5 or 10 mg/kg, IV 5 x weekly) were administered for 3 weeks (n = 8/group). Maximum tolerated dose (MTD) and clinically-relevant weekly doses (10 mg/kg, liposomal; 33 mg/kg, non-liposomal) of irinotecan were evaluated. TI was the ratio of MTD/lowest dose with anti-tumoral activity; time to reach tumor volume of 600 mm3 (TTV600) was a proxy for overall survival. Tumor, plasma, gut and bone marrow were sampled for pharmacokinetics and safety assessment; DNA damage was evaluated via pH2AX and 53BP1 IHC. Results: The Table reports results of the more sensitive IM-PAN-001 model: TI of weekly liposomal irinotecan was 4-fold higher than for 5 x weekly non-liposomal irinotecan (TI was narrower for SA-PAN-077). For liposomal vs non-liposomal irinotecan in IM-PAN-001, TTV600 was longer at both MTD and clinically equivalent doses, and tumoral irinotecan levels were higher at MTD. High levels of DNA damage were present in most cancer cells in IM-PAN-001 compared to SA-PAN-077 one week after the last liposomal treatment cycle. Conclusions: In both PDAC models, TI was higher for weekly liposomal vs 5 x weekly non-liposomal irinotecan, suggesting potential benefits of the liposomal formulation in a clinical setting. [Table: see text]

Influence of liposomal irinotecan (nal-IRI) and non-liposomal irinotecan, alone and in combination, on tumor growth and angiogenesis in colorectal cancer (CRC) models.

711 Background: The long circulating liposomal irinotecan nal-IRI (MM-398/PEP02, Onivyde) is approved for treatment of metastatic pancreatic cancer after disease progression with gemcitabine-based therapy. Besides their direct cytotoxic activity, camptothecins are thought to inhibit tumor angiogenesis via downregulating hypoxia-inducible factor 1 leading to attenuation of VEGF expression. Due to different deposition kinetics, irinotecan HCl and nal-IRI are likely to show different activities in vivo suggesting that a combination of the two agents may optimize intratumoral exposure and improve treatment efficacy. Methods: The activities of nal-IRI, irinotecan and their combination were compared in three human CRC xenograft models with different sensitivity to SN-38, the active metabolite of irinotecan, in vitro. Nal-IRI was dosed at 5 mg/kg q7d, while irinotecan HCl was dosed at 25 mg/kg at days 1 and 2 q7d. The activity of different regimens on tumor cell viability, hypoxia markers and the microvascular density was determined by quantitative biomarker analysis. Results: The relative antitumor activity of nal-IRI was most pronounced in tumor models with natural or acquired irinotecan resistance. Combinations of nal-IRI with irinotecan HCl was significantly better than irinotecan HCl alone in all tumor models although nal-IRI only provided 10% additional irinotecan. The antitumor activity of nal-IRI and Irintecan HCl in combination was accompanied by up to two times more tumor cell death and a marked 3-7 fold reduction of the microvessel density. Despite the strong antiangiogenic effect resulting in tumor hypoxia, the increase in HIF1α and, to lesser degree, HIF2α, was relatively modest and VEGF signal intensity remained at 85-115% of control values. Conclusions: Our results suggest that both irinotecan HCl and nal-IRI can counteract the hypoxia-mediated increase of HIF1α in vivo as previously reported in vitro. Furthermore, the combination of the two formulations demonstrated significant efficacy benefits. A combination of irinotecan HCl and nal-IRI merits further clinical investigation.

Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts.

335 Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.

Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.

The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect. Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated. Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle. Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.

228P - Subgroup analysis by prior non-liposomal irinotecan therapy in NAPOLI-1: a phase 3 study of nal-IRI±5-fluorouracil/leucovorin in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy

Background: In the global, randomized phase 3 NAPOLI-1 study, liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) significantly increased median OS vs. 5-FU/LV by 45% (6.1 vs. 4.2 mo; unstratified HR = 0.67 [0.49–0.92]; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have progressed following gemcitabine-based therapy. Here, we present a subgroup analysis by prior non-liposomal irinotecan (NLI). Methods: Study methodology has been published (Wang-Gillam; Lancet 2016). Robustness of overall treatment effect was assessed by prospectively-defined subgroups, including prior NLI, based on primary survival analysis data (cut-off February 2014) of the ITT population. Results: OS, PFS and CA19-9 response rates in patients with (n = 29) and without (n = 207) prior NLI are shown (see Table). In patients without prior NLI, nal-IRI+5-FU/LV (n = 105) improved median OS vs. 5-FU/LV (n = 102) by 2.5 mo to 6.7 mo (HR = 0.62; P < 0.01). Most frequent TEAEs were GI disorders (diarrhea, vomiting, nausea), regardless of prior NLI. ≥Grade 3 TEAEs and TEAEs leading to dose modification were similar in patients with (9 [75%]; 6 [50%]) and without (81 [77%]; 77 [73%]) prior NLI in the nal-IRI+5-FU/LV arm.Table: 228PPrior NLInal-IRI+5-FU/LV (n = 12 [10.3%])5-FU/LV (n = 17 [14.3%])Unstratified HR (95%CI); p-valueMedian OS, mo (95%CI)4.57 (0.99–6.44)4.83 (1.94–NR)1.25 (0.49–3.19); P=0.64Median PFS, mo (95%CI)1.51 (0.92–4.53)1.43 (1.18–4.40)0.83 (0.34–2.02); P=0.66CA19-9 response rates, n/N (%)0/10 (0)0/10 (0)N/ANo prior NLInal-IRI+5-FU/LV (n = 105 [89.7%])5-FU/LV (n = 102 [85.7%])Median OS, mo (95%CI)6.67 (5.26–8.97)4.17 (3.15–5.82)0.62 (0.44–0.86); P<0.01Median PFS, mo (95%CI)3.45 (2.76–4.24)1.48 (1.41–1.87)0.52 (0.37–0.71); P<0.0001CA19-9 response rates, n/N (%)28/87 (32.2)7/71 (9.9)P<0.001 Open table in a new tab Conclusions: This post-hoc subgroup analysis shows significant increases for nal-IRI+5-FU/LV vs. 5-FU/LV in OS, PFS and CA19-9 response rates in patients without prior NLI. Outcomes were similar in both arms in patients with prior NLI. The low number of patients with prior NLI preclude firm conclusions from being drawn and further research is needed to explore the impact of prior NLI. Clinical trial indentification: NCT01494506 Legal entity responsible for the study: This study was sponsored by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA; rights for nal-IRI now reside with Ipsen in the US (April 2017); PharmaEngine, Inc. holds the rights in Taiwan; Shire holds rights in the rest of the world through a licensing agreement with Ipsen. Funding: This study by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA; editorial assistance was funded by Shire (previously Baxalta), Zug, Switzerland. Disclosure: J.F. Blanc: Honoraria received from Bayer Sp, Merrimack; Consultant/Advisor for Bristol-Myers Squibb, Novartis, Lilly Oncology; Travel/Accommodation/Expenses received from Bayer Sp. R. Hubner: Consultant/Advisor for Celgene, BTG, Baxalta (now part of Shire); Speakers’ Bureau for Abbott, Ipsen; Travel/Accommodation/Expenses received from Celgene. A. Wang-Gillam: Consultant/Advisor for Merrimack, Pfizer, Newlink Genetics; Research funding from Newlink Genetics, AstraZeneca, BioMed Valley Discoveries, Lilly, AbbVie, Verastem, Precision Biologics. G. Bodoky: Honoraria received from Servier, Roche, Bayer, Pfizer, Janssen, Novartis, Lilly; Advisory boards for Bayer, Roche, Pfizer, Janssen, Novartis, Lilly, Taiho, Nordic. A. Dean: Honoraria received from Specialised Therapeutics Australia; Consultant/Advisor for Baxalta (now part of Shire), Celgene. G. Jameson: Honoria received from Celgene; Speakers’ Bureau for Celgene. D. Cunningham: Research funding from Amgen, AstraZeneca, Bayer, Celgene, Merrimack, Medimmune, Merck Serono, Sanofi. F. Braiteh: Relevant to this publication: Consultant fees received from Ipsen and Merrimack; Honoraria from Ipsen: Travel/Accommodation fees from Ipsen and Merrimack; Speaker’s Bureau for Ipsen and Merrimack. D. von Hoff: Relevant to this publication: Research funding from Merrimack; Consultant for Alphamed Consulting and Baxalta (now part of Shire). L-T. Chen: Consultant/Advisor for ONO, Eli Lilly, MSD, PharmaEngine, Merrimack, TTY Biopharm, SynCore Biotechnology, Five Prime Therapeutics, Novartis; Research funding from Novartis, GSK, Merck Serono, TTY Biopharm, Polaris; Patents/Royalties/Intellectual property with HuniLife Biotechnology. K. Mamlouk: Employment – Ipsen; former Merrimack employee Stock and Other Ownership Interests - Blueprint Medicines; Merrimack, F. de Jong: Shire employee and stockholder. J. Siveke: Consultant/advisor: Celgene, Merrimack, Baxalta, Boehringer-Ingelheim, Lilly; Honoraria: Celgene, Merrimack, Baxalta, Lilly; Research funding: Novartis, Boehringer-Ingelheim, Celgene, BMS. All other authors have declared no conflicts of interest.

Abstract CT146: 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 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

Abstract 5151: Nanoliposomal irinotecan (nal-IRI, MM-398) has greater anti-tumor activity than topotecan and irinotecan in mouse models of small cell lung cancer

Abstract Nal-IRI, a liposomal formulation of irinotecan, is designed for extended circulation relative to non-liposomal irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 (TOP1) by extended SN-38 exposure is hypothesized to enable superior anti-tumor activity compared to traditional TOP1 inhibitors. Topotecan, another TOP1 inhibitor, is an approved second-line treatment option for small cell lung cancer (SCLC). Here, we evaluate the anti-tumor activity of nal-IRI compared to irinotecan and topotecan in preclinical models of SCLC including those that have been pre-treated with therapeutics used clinically to treat SCLC. Anti-tumor activity of nal-IRI, irinotecan, or topotecan was evaluated based on tumor volume assessments in DMS-53, DMS-114 and NCI-H1048 subcutaneous xenograft models in NOD-SCID mice, as well as in a patient-derived xenograft (PDX) model in nu/nu mice. To approximate clinical dosing: Nal-IRI was dosed at 16 mg/kg (irinotecan HCl basis), q1w, equivalent to a proposed clinical dose of 90 mg/m2 free base, q2w; irinotecan was dosed at 33 mg/kg q1w, equivalent to a clinical dose of 180 mg/m2 q2w; and topotecan was dosed at 0.83 mg/kg/week, day 1-2 every 7 days, which approximates a clinical dose intensity of 1.5 mg/m2 (days 1-5 every 21 days). Additionally, the activity of these agents was evaluated after tumors progressed following prior treatment with either topotecan, irinotecan or the combination of weekly carboplatin (30 mg/kg) plus etoposide (25 mg/kg), a standard first line regimen. Nal-IRI demonstrated anti-tumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, NCI-H1048 and a PDX model in comparison with irinotecan or topotecan, which each had limited tumor growth control. Furthermore, Nal-IRI demonstrated anti-tumor activity in tumors that progressed following treatment with topotecan, and demonstrated significantly greater anti-tumor activity than both topotecan (p&amp;lt;0.0001) and irinotecan (p&amp;lt;0.0001) in NCI-H1048 tumors (8/8 complete responses) that had progressed on prior carboplatin plus etoposide treatment. These results support the further clinical development of nal-IRI versus IV topotecan in patients with SCLC that progressed on or after prior platinum containing therapy. Citation Format: Shannon C. Leonard, Daniel Gaddy, Helen Lee, Stephan Klinz, Jonathan Fitzgerald, Bart Hendriks. Nanoliposomal irinotecan (nal-IRI, MM-398) has greater anti-tumor activity than topotecan and irinotecan in mouse models of small cell lung cancer [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 5151. doi:10.1158/1538-7445.AM2017-5151

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer.

Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (C max) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 C max and diarrhea with tIRI C max. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2 (free‐base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

PD-018 - Subgroup analysis by prior non-liposomal irinotecan therapy in NAPOLI-1: A phase 3 study of nal-IRI±5-fluorouracil/leucovorin in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy

PD-018 - Subgroup analysis by prior non-liposomal irinotecan therapy in NAPOLI-1: A phase 3 study of nal-IRI±5-fluorouracil/leucovorin in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy

Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarcinoma.

Intravenous liposomal irinotecan injection (Onivyde®) is approved for use in combination with 5-fluorouracil and leucovorin (5-FU/LV) in patients with metastatic pancreatic adenocarcinoma that has progressed following gemcitabine-based therapy. Liposomal irinotecan is a liposome-encapsulated formulation of the topoisomerase-1 inhibitor irinotecan, developed to overcome the pharmacological and clinical limitations of non-liposomal irinotecan. In the pivotal multinational, phase III NAPOLI-1 trial in patients with metastatic pancreatic adenocarcinoma that had progressed following gemcitabine-based therapy, liposomal irinotecan in combination with 5-FU/LV significantly prolonged median overall survival (OS; primary endpoint) and median progression-free survival (PFS) at the time of the primary analysis (after 313 events) and final analysis (after 382 events) compared with 5-FU/LV control therapy. The objective response rate was also significantly higher in the liposomal irinotecan plus 5-FU/LV group than in the control group. Liposomal irinotecan-based combination therapy had a manageable safety profile; the most common treatment-emergent adverse events (TEAEs) of grade ≥3 severity were haematological or gastrointestinal in nature. The incidence of neutropenic sepsis was low. In a setting where there is a paucity of second-line treatment options, liposomal irinotecan in combination with 5-FU/LV is an important emerging treatment option for metastatic adenocarcinoma of the pancreas that has progressed following gemcitabine-based therapy.

P1.07-006 Preclinical Support for Evaluation of Irinotecan Liposome Injection (nal-IRI, MM-398) in Small Cell Lung Cancer

Nal-IRI (irinotecan liposome injection, MM-398, ONIVYDE®), in combination with 5-fluorouracil and leucovorin, is currently approved by the FDA for treatment of patients with advanced pancreatic cancer who have progressed on gemcitabine-based therapies. Nal-IRI is designed for extended circulation relative to non-liposomal irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite SN-38 in the tumors. Sustained inhibition of topoisomerase 1 (TOP1) by extended SN-38 delivery is hypothesized to enable superior anti-tumor activity compared to traditional TOP1 inhibitors. Topotecan, a TOP1 inhibitor, is currently a standard of care for second-line treatment of small cell lung cancer (SCLC). Here, we evaluate nal-IRI compared to topotecan in preclinical models of SCLC. Anti-tumor activity of nal-IRI as a monotherapy was evaluated in DMS-53 and NCI-H1048 xenograft models. Cells were implanted subcutaneously into right flanks of NOD-SCID mice; treatments were initiated when tumors had reached approximately 280 mm3. Nal-IRI was dosed at 16 mg/kg salt, q1w, which is equivalent to a proposed clinical dose of 90 mg/m2 free base, q2w. Topotecan was dosed at 0.83 mg/kg/week, Day 1-2 every 7 days, which approximates a clinical dose intensity of 1.5 mg/m2 (Day 1-5 every 21 days). Tumor metabolite levels were compared in mice treated with nal-IRI or non-liposomal irinotecan at 24 hours post-injection, using previously established high performance liquid chromatography methods. Carboxylesterase activity and sensitivity to SN-38 in mouse SCLC models were comparable to those measured in tumor types where either nal-IRI or irinotecan HCl has proven to be efficacious clinically (e.g. pancreatic cancer, colorectal cancer). Nal-IRI delivered irinotecan to SCLC tumors to a similar or greater extent than other tumor types including pancreatic tumors. The tumor irinotecan and SN-38 levels of nal-IRI (16 mg/kg salt) were 12 to 57-fold and 5 to 20-fold higher than non-liposomal irinotecan (30 mg/kg salt), respectively. Nal-IRI demonstrated anti-tumor activity in both xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses after 4 cycles in NCI-H1048 or DMS-53 models, respectively, compared with topotecan which had limited tumor growth control. This study demonstrated that nal-IRI is more active than topotecan at clinically relevant doses in SCLC preclinical models, and thus support further clinical development of nal-IRI versus topotecan in patients with SCLC that have progressed on prior platinum-based therapy.

Abstract B47: Nanoliposomal irinotecan (nal-IRI) is an active treatment and reduces hypoxia as measured through longitudinal imaging using [18F]FAZA-PET in an orthotopic patient-derived model of pancreatic cancer

Abstract Introduction: Tumor hypoxia has been strongly linked to aggressive disease progression and resistance to therapy, especially in pancreatic cancer where the desmoplastic reaction is thought to also interfere with deposition of both small molecule drugs and nanotherapeutics. [18F]fluoroazomycin arabinoside (FAZA) is a radioactive tracer that allows for non-invasive quantification of tumor hypoxia during treatment by positron emission tomography (PET). We have previously shown that in the HT-29 cell-line derived xenograft model of colorectal cancer, nanoliposomal irinotecan (nal-IRI) achieves improved tumor growth control and is able to maintain a significantly lower level of tumor hypoxia as compared to non-liposomal irinotecan. Here, we evaluate the effects of nal-IRI on the kinetics and magnitude of hypoxia changes in an orthotopic patient-derived tumorgraft model of a pancreatic cancer (OCIP51) that is highly hypoxic. Experimental Procedures: Tumor growth of orthotopically implanted OCIP51 tumors was monitored using magnetic resonance imaging. Longitudinal FAZA-PET imaging of tumor hypoxia changes was performed over a 21-day period following weekly administration of nal-IRI at 20 mg/kg (n = 10) and compared to untreated controls (n = 5). Mean tumor FAZA uptake (%ID/g) and hypoxic fractions were calculated. In addition [18F]-fluorothymidine (FLT-) PET was conducted before treatment initiation and after the 3rd dosing cycle to assess tumor cell proliferation. Tumor levels of irinotecan and its active metabolite SN-38 were evaluated using an HPLC method in samples harvested 24 h after the last administration of nal-IRI and in a separate pharmacodynamic study component (n = 10) at 24 h and 72 h after administration of a single dose of nal-IRI at 10 mg/kg. Nal-IRI induced DNA damage was assessed using γH2AX immunohistochemistry. Results: nal-IRI treatment resulted in tumor growth inhibition of 71.6% compared to controls at study end. Tumor growth control was observable at Day 5 post treatment initiation. FAZA uptake in treated tumors decreased by 36% within the first treatment cycle, while average FAZA levels in control tumors remained unchanged during this period. Nal-IRI treatment resulted in statistically significant decreases in the FLTmax and FLTmean values compared to pre-treatment values. 100% of nal-IRI treated mice survived to study end compared to only 40% of controls. Tumor weights at study end were almost 4 times smaller in nal-IRI-treated mice compared to the controls. Tumors from treated mice were fluid-filled and showed extensive blood pooling, while tumors from untreated mice appeared to be much less vascularized. Irinotecan levels detected in the OCIP51 tumors were 8 times lower at 72 h after nal-IRI administration, while SN-38 levels were ~28 times lower when compared to previous findings in HT-29 tumors. Treatment with nal-IRI in the OCIP51 tumors significantly increased the frequency and intensity of γH2AX staining across tumor cell areas compared to that observed in the untreated tumors, which were characterized by only a scattered and sporadic γH2AX staining. Importantly, the stromal areas did not show γH2AX staining in either the treated or the control group. Conclusions: This study demonstrated the feasibility of performing longitudinal tumor hypoxia and proliferation assessments using FAZA- and FLT-PET imaging in a highly hypoxic orthotopic model of pancreatic cancer. Although this model showed reduced levels of liposomal drug deposition compared to cell-line derived xenograft models, treatment with nal-IRI led to effective tumor growth control, as well as significant changes in the tumor microenvironment as measured by reduced hypoxia levels compared to baseline and control tumors. Results from this study support the utility of FAZA-PET for evaluation of tumor hypoxia after anti-cancer therapy with nal-IRI as a means to provide early assessment of treatment activity. Citation Format: Stephan Klinz, Jinzi Zheng, Raquel De Souza, Manuela Ventura, Nancy Paz, David Hedley, David Jaffray, Jonathan Fitzgerald.{Authors}. Nanoliposomal irinotecan (nal-IRI) is an active treatment and reduces hypoxia as measured through longitudinal imaging using [18F]FAZA-PET in an orthotopic patient-derived model of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B47.