A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer

AH, Ko; Ma, Tempero; Ys, Shan; Su, Wu Chou; Lin, Yulin; Dito, Elizabeth; A, Ong; Wang, Y-W; Cg, Yeh; Lt, Chen

doi:10.1038/bjc.2013.408

Cited by 146 publications

(101 citation statements)

References 18 publications

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“…A three-arm phase II study of nal-IRI versus irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma demonstrated an objective response rate comparable with docetaxel (17). A nal-IRI phase II study in patients with metastatic, gemcitabine-refractory pancreatic cancer achieved a one-year survival rate of 25% (18). Nal-IRI combined with 5-FU and leucovorin demonstrated significantly improved overall survival for gemcitabine-refractory pancreatic cancer patients compared with 5-FU/leucovorin alone in a recently completed phase III pivotal trial (NAPOLI-1; ref.…”

Section: Introductionmentioning

confidence: 99%

Activity of MM-398, Nanoliposomal Irinotecan (nal-IRI), in Ewing's Family Tumor Xenografts Is Associated with High Exposure of Tumor to Drug and High SLFN11 Expression

Kang

Wang

Makena

et al. 2015

Clinical Cancer Research

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Purpose: To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI).Experimental Design: Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting.Results: Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/ dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines.Conclusions: In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.

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Section: Introductionmentioning

confidence: 99%

Activity of MM-398, Nanoliposomal Irinotecan (nal-IRI), in Ewing's Family Tumor Xenografts Is Associated with High Exposure of Tumor to Drug and High SLFN11 Expression

Kang

Wang

Makena

et al. 2015

Clinical Cancer Research

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“…The preclinical data could be somewhat confirmed by a phase II and III study of nal-IRI in advanced gemcitabine-refractory PDAC [62,63]. After failure of first-line therapy with gemcitabine, nal-IRI treatment achieved a mPFS of 2.4 months and a mOS of 5.2 months, with a disease control rate of 50% in the phase II trial [62]. These data were confirmed by the so far not fully published NAPOLI-1 trial (phase III) [63].…”

Section: Metastatic Pancreatic Cancermentioning

confidence: 93%

“…The formulation of nanoliposomal irinotecan (nal-IRI) yielded increased intratumoral levels of CPT-11 and its active metabolite SN-38 compared to standard irinotecan in a mouse xenograft of human colon carcinoma and pancreatic cancer [60,61]. The preclinical data could be somewhat confirmed by a phase II and III study of nal-IRI in advanced gemcitabine-refractory PDAC [62,63]. After failure of first-line therapy with gemcitabine, nal-IRI treatment achieved a mPFS of 2.4 months and a mOS of 5.2 months, with a disease control rate of 50% in the phase II trial [62].…”

Section: Metastatic Pancreatic Cancermentioning

confidence: 99%

Pancreatic Cancer: Progress in Systemic Therapy

Perkhofer

Ettrich

Seufferlein

2014

Gastrointest Tumors

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the Western world. Due to lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in the identification of only 15-20% of patients with potentially curable disease. The major limiting factor is an already locally advanced or metastatic disease at the time of diagnosis. Consequently, systemic therapy forms the backbone of treatment strategy for the majority of patients. Summary: A deeper understanding of the molecular characteristics of pancreatic cancer has led to the identification of several potential therapeutic targets. A variety of targeted therapies are currently under clinical evaluation as single agents or in combination with chemotherapy for PDAC. This review highlights the current state of chemotherapy in pancreatic cancer and provides an outlook on its future perspectives. Key Message: This review focuses on the current chemotherapy regimens for the systemic treatment of PDAC. Practical Implications: Various neoadjuvant approaches have been explored, including chemoradiation, chemotherapy followed by chemoradiation or intensified chemotherapy without defining a standard of care so far. The standard of care is gemcitabine or 5-fluorouracil. The oral fluoropyrimidine S-1 may be a promising new agent in this setting. For first-line treatment of metastatic pancreatic cancer, no targeted therapy has yet demonstrated clinical benefit apart from the combination of the tyrosine kinase inhibitor erlotinib plus gemcitabine. Recently, novel chemotherapeutic regimens such as FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound paclitaxel have been introduced. Both combinations have proved to be superior to the standard gemcitabine regimen. For second-line treatment the combination of 5-fluorouracil/leucovorin and oxaliplatin yields improved results compared to best supportive care.

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“…MM-398 is a liposomal sphere encapsulating irinotecan developed by Merrimack pharma. MM-398 is being evaluated in the clinical trials for its ability to treat various cancers, which are resistant to chemotherapy such as pancreatic, colorectal, lung and glioma (Ko et al 2013;Roy et al 2013;Saif 2014). Another liposomal formulation developed by Merrimack pharma is MM-302, which encapsulates doxorubicin.…”

Section: Applications Of Liposomes In Cancermentioning

confidence: 99%