Molecule Anticancer Agents

Published OnlineFirst April 25, 2013; DOI: 10.1158/1078-0432.CCR-12-3649

Clinical Cancer Cancer Therapy: Clinical Research

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small- Molecule Anticancer Agents

Whitney P. Caron1, Katherine P. Morgan1, Beth A. Zamboni6, and William C. Zamboni1,2,3,4,5

Abstract Purpose: Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. Experimental design: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. Results: The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 10.8) compared with small molecules (2.1 1.1; P ¼ 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 2.9) compared with small molecules (4.1 1.5; P ¼ 0.008). Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity. Clin Cancer Res; 19(12); 1–7. 2013 AACR.

Introduction remains encapsulated within nanoparticles, (generally > Nanoparticles or carrier-mediated agents used to deliver 95%) or linked to a conjugate or polymer is an inactive anticancer therapies have many unique advantages over prodrug, and thus the drug must be released from the carrier their traditional small-molecule counterparts, including to be active. After the drug is released from the carrier, the improved solubility, longer circulation time, greater plasma pharmacokinetic disposition of the drug will be the same as exposure (AUC), tumor-selective delivery, increased anti- that following administration of the noncarrier form of the tumor response, and reduced toxicity (1, 2). The pharma- drug (3, 4, 6). There is signiﬁcant interpatient variability cokinetics of nanoparticles is dependent upon the carrier seen in the pharmacokinetics of nanoparticles, such as and not the drug encapsulated within the carrier until the PEGylated liposomes, and the observed differences between drug gets released from the carrier (2–5). The drug that patients could be attributed to heterogeneity in the mono- nuclear phagocyte system (MPS; refs. 7, 8). The MPS is composed of circulating monocytes and dendritic cells, as Authors' Afﬁliations: 1Division of Pharmacotherapy and Experimental well as phagocytic cells in the liver and spleen (8). Therapeutics, University of North Carolina (UNC) Eshelman School of The relationship between MPS and nanoparticle clear- Pharmacy; 2UNC Lineberger Comprehensive Cancer Center; 3UNC Insti- tute for Pharmacogenomics and Individualized Therapy; 4Carolina Center ance (CL) was shown in a clinical phase I study using of Cancer Nanotechnology Excellence; 5North Carolina Biomedical Inno- S-CKD602, a PEGylated liposomal camptothecin analog, vation Network; and 6Department of Mathematics, Carlow University, Pittsburgh, Pennsylvania in patients with refractory solid tumors (9). After administration of S-CKD602 there was a greater percentage decrease W.P. Caron and K.P. Morgan contributed equally to this work. in monocytes (58 34) versus absolute neurophil count Corresponding Author: William C. Zamboni, Division of Pharmacotherapy (42 30) on 1 cycle of treatment (P ¼ 0.001; ref. 9). There and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB was also a linear relationship between percentage decrease 7361, Chapel Hill, NC 27599. Phone: 919-843-6665; Fax: 919-966-5863; in monocytes and the CL of encapsulated drug (R2 ¼ 0.75) E-mail: [email protected] and release of drug from the liposome (R2 ¼ 0.51; ref. 9). doi: 10.1158/1078-0432.CCR-12-3649 This relationship was not observed with the small-molecule 2013 American Association for Cancer Research. formulation CKD-602. Therefore, unlike small molecules,

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trials of nanoparticles and equivalent small molecules to Translational Relevance evaluate whether significant differences existed in study The degree of dose escalation from starting dose to design, progression, and outcomes between nanoparticles MTD is significantly greater for nanoparticle compared and small molecules. Nanoparticles comprise carrier-medi- with small-molecule anticancer drugs. This is associated ated platforms of anticancer agents, including liposomes with a significantly greater number of dose levels, time and conjugates, which contain an active small molecule, required to complete phase I studies, and costs to con- whereas the small molecule includes cytotoxics and any duct phase I studies of nanoparticles. These findings non–nano anticancer agent excluding targeted therapies. necessitate the need to optimize the design of phase I studies of nanoparticle agents, particularly the identifi- Materials and Methods cation of the most appropriate preclinical animal model Study design to use when evaluating nanoparticle toxicity. We evaluated differences in how phase I studies of nanoparticles and small molecules were designed and conducted. We evaluated the following factors related to phase I study designs for nanoparticles and small molecules: (i) there is a bidirectional interaction between nanoparticles ratio of MTD to starting dose; (ii) the number of dose and cells of the MPS where the MPS cells are involved in escalations; (iii) the number of patients enrolled; (iv) time the uptake and clearance of nanoparticles, which results required to complete the study; and (v) total estimated cost in pharmacologic effects of nanoparticles on MPS cells. of the study. Conversely, small molecules are cleared from circulation Using databases such as PubMed, Medline, and American by more traditional mechanisms such as liver metabolism Society of Clinical Oncology Proceedings, searches for peer and renal excretion (10). reviewed phase I studies of nanoparticles and small mole- Preclinical trials of anticancer drugs require a rodent and cules were conducted using the search terms: MTD, preclin- nonrodent model for toxicokinetic and toxicologic studies ical, phase I, pharmacokinetics, and toxicity. Data was (11). The nonrodent model most commonly selected is a collected for 9 nanoparticles and matching small-molecule canine (11). The toxicologic and toxicokinetic data are used anticancer agents. The nanoparticles were Abraxane (albu- to determine the starting dose in phase I trials based on one- min-bound paclitaxel), NKTR-102 (PEGylated irinotecan), tenth of the rodent LD10 (lethal dose for 10% of population liposomal vincristine, OSI-211 (liposomal lurotecan), tested) or one-third of the dose associated with the dose- liposomal vinorelbine, NK-105 (PEGylated paclitaxel), limiting toxicity (DLT; side effects of a drug or other treat- S-CKD602 (PEGylated liposomal CKD-602), IHL-305 ment are serious enough to prevent an increase in dose or (PEGylated liposomal irinotecan), MBP-426 (PEGylated level of that treatment) in dogs (11, 12). The starting dose in liposomal oxaliplatin; refs. 16–24). The small molecules the first inhuman phase I study of anticancer agents is then were paclitaxel, irinotecan, lurtotecan, vinorelbine, CKD- based on dose in the most sensitive species (11). 602, and oxaliplatin (25–28). The nanoparticle and small- The most predictive animal model for toxicology and molecule preclinical toxicology data was collected when pharmacology studies of nanoparticles is unclear (13, 14). available to determine the animal model used in defining The CL of PEGylated liposomes in preclinical species has starting dose in phase I clinical trials. been assessed through allometric scaling (15). Pharmaco- For preclinical studies, the MTD found in rats and dogs kinetic studies were conducted at the maximum tolerated were recorded. For phase I studies in patients with advanced dose (MTD) of PEGylated liposomal doxorubicin (Doxil; solid tumors, the starting dose, the number of dose escala- PLD), CKD-602 (S-CKD602), and cisplatin (SPI-077) in tions from starting dose to MTD, number of patients, and mice, rats, and dogs, and as part of phase I studies in patients the ratio of MTD to starting dose were recorded for each with refractory solid tumors (12, 15). Dogs had the fastest nanoparticle and small molecule. The MTD reported in all CL of the 3 different PEGylated liposomes evaluated when studies was defined as 1 dose below the dose associated with compared with mice, rats, and humans (15). As these the DLT. The DLT was defined as a grade 4 hematologic or studies were conducted at the MTD, dogs also had the grade 3/4 nonhematologic toxicity in all studies. The dose- lowest exposure associated with toxicity, which suggests escalation strategy for all of the reviewed phase I studies that dogs may not be appropriate models for nanoparticle were conducted using the conventional 3þ3 modified toxicology or pharmacology studies (15). Fibonacci design (29). The methods used to determine the It has been observed that the starting doses in phase I starting dose in the phase I study of the nanoparticles and trials for nanoparticles are considerably lower and more small molecules were the same. As per standard methods, dose escalations are required to reach the first signs of toxicology studies were conducted in rats and dogs. If rats toxicity and eventually DLT compared with small molecules were the most sensitive species, the starting dose in the (10, 15). When developing therapeutic agents that are phase I study was equal to one-tenth of the dose that was associated with potential high costs and adverse events, it severely toxic to 10% of the animals on a mg/m2 basis. If is critical to optimize the preclinical and clinical study dogs were the most sensitive species, the starting dose in the designs of these drugs. Therefore, the objective of the phase I trial was equal to one-sixth of the highest nontoxic current study was to conduct a review of clinical phase I dose in the dog on a mg/m2 basis."

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A cost estimation analysis was conducted to appraise the particles are listed in Tables 1 and 2, respectively. The mean costs associated with a nanoparticles compared with a small SD (range) number of dose levels in a phase I clinical molecule phase I study. Cost estimates were obtained from study for nanoparticles and small molecules were 7.8 2.9 the literature and were based on the class (nanoparticles or (4–13) and 4.1 1.5 (3–7), respectively (P ¼ 0.008). A small molecules) of agent, number of treatment levels, and summary of mean SD (range) of MTD to starting dose, patients (30). number of dose levels, and number of patients enrolled is provided in Table 3. There was a higher but not statistically Statistics different number of patients enrolled in a clinical phase I The null hypothesis was that there was no difference in study of nanoparticles and small molecules (31.0 9.3 and the ratio of MTD to starting dose, dose escalations, and 25.1 11.2, respectively; P ¼ 0.16) patients enrolled in a phase I clinical study between nanoparticles and small molecules. This was tested using a Cost estimation Student t test with a set at 0.05. The average cost per patient to complete a phase I clinical trial is approximately $35,000 (30). Assuming 3 patients per Results dose level based on the conventional 3þ3 modified Fibo- Ratio of MTD to starting dose nacci design, the cost of a small molecule or nanoparticle The starting doses, MTD, and ratios of MTD to starting phase I clinical study would be $430,500 and $819,000, dose for each small molecule are shown in Table 1. For small respectively. Excluding the nanoparticle agents that did not molecules, the mean SD (range) of the ratio of MTD to require an increased number of dose levels compared with starting dose was 2.1 1.1 (1.3–4.0). The starting doses, their small-molecule counterpart brings the cost of a clinical MTD, and ratios of MTD to starting dose for each nano- phase I study of a nanoparticles to approximately $966,000. particles are shown in Table 2. For nanoparticles, the mean The rationale and justification of the removal is detailed SD (range) of the ratio of MTD to starting dose was 13.9 within the Discussion section. Thus, a phase I clinical study 10.8 (2.2–37.7). The ratio of MTD to starting dose of of 2 identical chemical entities administered as a standard nanoparticles was approximately 7-fold higher than small small molecule or within a nanoparticle formulation results molecule (P ¼ 0.005). For the nanoparticles, including in an approximately 2-fold difference in the overall costs. NKTR-102 (PEGylated irinotecan), liposomal vincristine (Marqibo), liposomal vinorelbine, NK-105 (PEGylated Discussion paclitaxel), S-CKD602 (liposomal CKD-602), and IHL- This is the first study or review highlighting major 305 (PEGylated liposomal irinotecan), it was confirmed differences between nanoparticle and small molecule that the starting doses in clinical phase I studies were based phase I clinical study design and outcomes. There was on toxicology studies in dog (18–20, 22–24). a significantly greater number of dose levels, time required to complete phase I studies, patient-related Dose escalations and number of patients resources, and costs to conduct phase I studies of nano- The dose-escalation strategy for all of the reviewed phase I particles compared with small molecules. These results studies were conducted using the conventional 3þ3 mod- indicate the inefficiency in which phase I studies of ified Fibonacci design (29). There was an increase in the nanoparticles are designed and/or carried out relative to number of dose escalations and patients enrolled on phase I small molecules. The cause of observed differences in studies of nanoparticles compared with small molecules. clinical phase I studies may be due to differences in the The total number of dose escalations and patients enrolled pharmacokinetics and pharmacodynamics of nanoparti- in a clinical phase I study for small molecules and nano- cles, preclinical animal models used for toxicities of

Table 1. Summary of starting dose, MTD, and ratio of MTD to starting dose in patients with refractory solid tumors in phase I clinical trials of small-molecule anticancer agents

Starting dose MTD Ratio of MTD to Total number Total number Small molecule (mg/m2) (mg/m2) starting dose of dose levels of patients Vincristine 0.5 0.75 1.5 3 30 Irinotecan 240 320 1.3 4 34 CKD-602 0.5 0.7 1.4 3 16 Paclitaxel 70 100 1.4 4 20 Vinorelbine 35 40 1.1 3 13 Oxaliplatin 45 135 3.0 7 44 Lurtotecan 0.3 1.2 4.0 5 19 Mean SD (range) 2.0 1.1 (1.1–4) 4.1 1.5 (3–7) 25.1 11.2 (13–44)

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Table 2. Summary of starting dose, MTD, and ratio of MTD to starting dose in patients with refractory solid tumors in phase I clinical trials of nanoparticle anticancer agents

Starting dose MTD Ratio of MTD to Total number Total number Carrier-mediated agent (NP) (mg/m2) (mg/m2) starting dose of dose levels of patients Albumin-bound paclitaxel 135 300 2.2 4 19 NKTR-102 (PEGylated irinotecan)a 58 144 2.5 5 27 Liposomal vincristinea 0.5 2.4 4.8 6 28 OSI-211 (liposomal lurtotecan) 0.15 1.8 12.0 7 37 Liposomal vinorelbinea 2 28 14.0 7 30 NK-105 (PEGylated paclitaxel)a 10 180 18.0 7 19 S-CKD602 (PEGylated liposomal CKD-602)a 0.1 2.1 21.0 13 45 IHL-305 (PEGylated liposomal irinotecan)a 7 160 22.9 10 42 MBP-426 (PEGylated liposomal oxaliplatin) 6 226 37.7 11 39 Mean SD (range) 13.9 10.8 (2.2–37.7) 7.8 2.9 (4–13) 31.8 9.5 (19–45)

aConﬁrmed starting doses in clinical phase I studies were based on toxicology studies in dog.

nanoparticles, or study design issues of nanoparticles scaling was used to compare the pharmacokinetic disposi- compared with small molecules. tion of three different PEGylated liposomes (S-CKD602, The pharmacokinetics of nanoparticles is more variable Doxil, SPI-077) across species (mice, rats, dogs, and than small molecules. A meta-analysis compared differ- humans) at the MTD, the pharmacokinetic disposition in ences in AUC CV% as a measure of variability between dogs was a consistent outlier from other animal models liposomal and nonliposomal anticancer agents (31). For (15). In addition, when a Dedrick Time Equivalent model liposomal agents, the mean SD of CV% of AUC was 65.6 was used, dogs had the highest CL and thus the lowest 18.6. For nonliposomal agents, the mean SD of CV% of exposure of all 3 liposomal agents at the MTD (15). This AUC was 30.7 16.0. The ratio of liposomal to nonlipo- suggests that dogs clear PEGylated liposomes faster than somal CV% of AUC for each pair was 2.7 (P < 0.001; Eq 1). other species which results in a lower plasma exposure but Similarly, the mean SD ratio of AUCmax to AUCmin at the are the more sensitive to nanoparticles toxicity at this lower MTD was 34.1 41.9 for liposomes and 3.6 1.8 for non- exposure. Thus, using dogs to determine starting dose in liposomal drugs. The ratio of liposomal to non-liposomal man results in a dose that is lower than needed and ratio of AUCmax to AUCmin for each pair was 16.7 (P < 0.13). consequently creates exposures that have a low probability The signiﬁcantly higher and clinically relevant pharmaco- of achieving response and/or inducing toxicity. This results kinetic variability of nanoparticles compared with small in an increase in the number of dose levels, number of molecules may be affecting the design and progression of patients, and ratio of MTD to starting dose for nanoparticles phase I studies of nanoparticles agents. Thus, studies need to compared with small molecules. Physiologically based be coducted and methods developed to evaluate and predict pharmacokinetic modeling and allometric scaling have the factors inducing the high pharmacokinetics and phar- been previously used for many small-molecule agents to macodynamic variability of nanoparticles (32–34). predict human pharmacokinetics from animal data. Mah- A potential reason for the discrepancy between nanopar- mood reported on the MTD of 25 small-molecule antican- ticles and small molecules in human phase I studies could cer drugs that could be used to predict the proper starting be model selection in preclinical studies. When allometric dose in humans (35). He concluded that the approach saves

Table 3. Comparison of ratio of MTD to starting dose, number of dose levels, and number of patients enrolled on study for clinical phase I studies of nanoparticle and small-molecule anticancer agents

Ratio of MTD to Number of Total number starting dose dose levels of patients NP Mean SD (range) 13.9 10.8 7.8 2.9 31.8 9.5 SM Mean SD (range) 2.0 1.1 4.1 1.5 25.1 11.2 Comparison of NP vs. SM; 2 sample t test P ¼ 0.005 P ¼ 0.008 P ¼ 0.16

Abbreviations: NP, nanoparticle; SM, small molecule.

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time and avoids many unnecessary steps in attaining the in contrast to preclinical and clinical in vivo data of other MTD in humans. This information is in contrast to nano- liposomal anticancer agents which have a much greaterper- particles, which are not extensively metabolized, have centage of (i.e., 90%–95%) drug retention during the first greater pharmacokinetic variability compared with small 24 hours and beyond (22, 41). One of the most compelling molecules, and the pharmacokinetics in animal models is examples of low vincristine retention in liposomes comes not directly extrapolated to humans. (15). Although animal from a study conducted by Sapra and colleagues, whose models have successfully predicted small-molecule phar- objective was to find an effective strategy for treating B-cell macokinetics in humans in prior studies, the ability to malignancies in a murine model of human B-cell lympho- predict nanoparticle pharmacokinetics in humans based ma (42). Long-circulating sterically stabilized immunolipo- on results in animal models seems to be more problematic. some formulations of vincristine and doxorubicin were The inability to extrapolate nanoparticle pharmacokinetics given to these mice. The liposomal vincristine formulation to patients from animal models is most likely due to had a much faster drug release rate from the liposomes than differences in the MPS across species. Thus, the standard liposomal doxorubicin. In addition, after normalization of models and methods used for small molecules cannot be drug load to lipid amount, the drug to lipid ratio was several used for nanoparticles. Future studies are needed to deter- fold higher for liposomal doxorubicin than for liposomal mine the most appropriate animal model and scaling vincristine over a 48-hour period (42). Thus, the liposomal methods for nanoparticles. vincristine included in this review seems to have rapid CL Another potential reason for an increased number of dose and release of drug from the carrier and thus does not levels could be that nanoparticles have a lower toxicity than exhibit classic nanoparticle properties of prolonged circu- small molecules and therefore the dose of nanoparticles can lation of encapsulated drug that is cleared by the MPS. be escalated to higher levels than small molecules. In vitro Instead, the vincristine is rapidly released from the lipo- and preclinical studies have shown that the toxicity of some and cleared via hepatic metabolism and thus acts PEGylated liposomal agents and other nontargeted nano- more like a small-molecule agent than the other nanopar- particles carriers is less than the comparative small molecule ticles included in this review. (3, 36, 37). For example, the cytotoxicity of mitomycin C The pharmacokinetics and pharmacodynamics of IHL- was drastically reduced when prepared in PEGylated lipo- 305 were also different than other nanoparticless. IHL-305 somes (38). It also has been clinically noted that the is a PEGylated liposome formulation of CPT-11. CPT-11 is a biodistribution pattern of liposomes can lead to a relative prodrug that must be converted to the active moiety SN-38 reduction of drug concentrations in tissues that are known by carboxylesterase enzymes in vivo (43). The complexity of to be sensitive to the drug (39). The biodistribution pattern CPT-11 metabolism goes further, to include active lactone is due to the unique pharmacokinetic profile that is and inactive carboxylate forms of both the CPT-11 and SN- obtained after administration of nanoparticles, such as 38, which exist at an equilibrium dependent upon pH and increased plasma exposure (AUC) and reduced CL of the binding proteins (44). The complexity of metabolism inactive-encapsulated drug (3, 22). Generally, stable nano- increases with the involvement of genetic polymorphisms particles carriers have minimal drug release in the circula- in uridine diphosphate glucuronosyltransferases (UGT) tion which reduces toxicities in normal organs (3, 22). isoform 1A1, (UGT1A1), which is responsible for glucur- Of the nanoparticles 9 agents reviewed, 4 studies stated onidation of SN-38 (45). Therefore, it is unclear whether that the starting dose was based on dogs within the clinical differences in phase I outcomes are observed due to IHL-305 phase I study. One study (Abraxane) stated that dogs had a formulation, or due to the dosing of a prodrug that is hypersensitivity reaction to the nanoparticles and the in the dependent upon many factors for metabolism. remaining 4 studies, no information was provided on the The phase I starting dose of albumin-bound paclitaxel starting dose. There were 3 nanoparticless that did not was not based on the dog toxicology studies because dogs follow the trend of greater resources and time to complete had a hypersensitivity reaction to human albumin which the phase I study (e.g., greater ratio of MTD to starting dose) lead to an early termination of toxicologic studies in compared with small molecule. Those were nanoparticles dogs (46). Therefore, the starting dose of albumin-bound were liposomal vincristine, albumin-bound paclitaxel paclitaxel was based on toxicology studies in nonhuman (Abraxane), and liposomal irinotecan. These agents all primates. Dogs seem to be inherently sensitive to the exhibit "nonclassical" nanoparticles properties and inter- toxicologic effects of nanoparticles, as evidenced through esting aspects of their preclinical and clinical results provide toxicology studies as well as allometric scaling (15). The rationale for why they can be removed from the analysis. starting dose of albumin-bound paclitaxel based on toxicity A study conducted by Zhigaltsev and colleagues, com- studies in nonhuman primates was most likely higher than pared drug loading and retention among liposome-encap- would have been determined on the basis of toxicology sulated vinca alkaloids: vincristine, vinblastine, and vinor- studies in dogs. Thus, the number of dose levels from the elbine (40). While vincristine had the greatest percentage of higher starting dose to the MTD of albumin-bound pacli- drug retention after a single dose of the 3 tested vinca taxel was less than other nanoparticles in the review. This alkaloids, it had only approximately 56% or 78% drug highlights the potential benefits of conducting toxicologic retention after 24 hours for the 0.1 w/wt and 0.3 wt/wt and pharmacologic studies of nanoparticles in nonhuman drug-to-lipid ratio formulations, respectively. This finding is primates instead of dogs as the nonrodent species of choice.

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There are major differences between the design and toxicology studies must be identified. Identification of performance of phase I studies of nanoparticles compared the correct animal model may drastically decrease the with small molecules. There is a significant difference in the number of dose levels, patients, and costs associated with number of dose levels and ratio of MTD to starting dose as phase I clinical studies. In addition, there must be explo- well as increased number of patients enrolled and overall ration into new study designs for phase I studies of nano- costs associated with studies of nanoparticles versus small particles, as the unique pharmacology of nanoparticles molecules. These findings indicate that patients are being agents may not be amenable to trial designs established treated at doses that are very low and unlikely to produce for small molecules. toxicity and/or response. This undoubtedly leads to an inefficient use of patient resources, time, and funding. The Disclosure of Potential Conflicts of Interest potential primary cause of these issues in phase I studies of No potential conflicts of interest were disclosed. nanoparticles is that the low starting dose results from the Authors' Contributions use of an inappropriate toxicology model, which seems to Conception and design: K.P. Morgan be dogs or the ability to escalate the dose of nanoparticles Development of methodology: K.P. Morgan higher. An alternative nonrodent model such as nonhuman Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): W.P. Caron, K.P. Morgan, W. Zamboni primates may be more suitable. Analysis and interpretation of data (e.g., statistical analysis, biosta- There is preliminary evidence that suggests that factors tistics, computational analysis): W.P. Caron, K.P. Morgan, B.A. Zamboni, associated with the MPS may contribute to nanoparticles W. Zamboni Writing, review, and/or revision of the manuscript: W.P. Caron, K.P. pharmacokinetic and pharmacodynamic variability. Thus, Morgan, W. Zamboni there is a compelling need to identify the factors associated Administrative, technical, or material support (i.e., reporting or orga- with MPS function to improve the preclinical and clinical nizing data, constructing databases): K.P. Morgan studies of nanoparticles. It will be essential to further test The costs of publication of this article were defrayed in part by the whether the pharmacokinetics of nanoparticles can be payment of page charges. This article must therefore be hereby marked scaled across species using various measurements and advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. surrogates of the MPS, such as monocyte and macrophage activity or function, genetics, complement, or cytokines. In Received November 27, 2012; revised April 5, 2013; accepted April 12, addition, the most appropriate animal models for GLP 2013; published OnlineFirst April 25, 2013.

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www.aacrjournals.org Clin Cancer Res; 19(12) June 15, 2013 OF7

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

Whitney P. Caron, Katherine P. Morgan, Beth A. Zamboni, et al.

Clin Cancer Res Published OnlineFirst April 25, 2013.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-12-3649

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