For First-in-human Research Articles

Developing a mechanistic translational PK/PD model for a trifunctional NK cell engager to predict the first-in-human dose for acute myeloid leukemia.

Natural killer cell engagers (NKCEs), a treatment that stimulates innate immunity, have lately gained attention owing to their favorable safety profile, and their efficacy. Natural killer (NK) cell activation is driven by immune synapse formation between drugs, NK cells, and tumor cells. However, no clear translational modeling approach has been reported for first-in-human (FIH) dose estimation of humanized NKCEs. We developed the first translational mechanistic synapse-driven pharmacokinetic/pharmacodynamic (PK/PD) model for a trifunctional NKp46/CD16a-CD123 (CD123-NKCE) by integrating (i) invitro target cell cytotoxicity in MOLM-13 tumor cell lines at varying effector-to-tumor cell ratios and incubation intervals; (ii) nonhuman primate PK and profiles of CD123+ cells and NKP46+ NK cells; and (iii) healthy human or patients with acute myeloid leukemia system-specific parameters. To depict direct tumor cell killing by the innate immunity, no transit compartment was included in PK/PD model structures. Model predictions suggested an intrapatient dose escalation of 10/30/100 μg/kg twice weekly to be selected as the starting dose in the FIH trial. However, sensitivity analyses revealed that CD123+ cell growth rate constant and maximal tumor killing rate constant were the key uncertainties to the recommended active dose. This novel translational model structure can be used as the basis to predict clinical PK/PD data for CD123-NKCE, and the translational strategy may serve as a foundation for future advancements of NKCEs.

Abstract A138: Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody

Abstract Background: CD147 is a member of the immunoglobulin superfamily that is highly expressed in various cancers and is involved in growth, metastasis, and activation of inflammatory signals in cancer cells. DS-1471a is a novel humanized anti-human CD147 monoclonal antibody under development as an anticancer agent. In this study, pharmacokinetic (PK)-pharmacodynamic (PD) analysis of DS-1471a was conducted to set the dose and dosing regimen for first-in-human (FIH) study. The safety profile of DS-1471a was also assessed in cynomolgus monkeys. Methods: Preclinical pharmacological study was conducted in xenograft model mice transplanted with MIA PaCa-2 cells by intravenous (IV) administration of DS-1471a, and receptor occupancy (RO) of CD147 in tumor was measured. Monkey PK and RO in blood were measured after the IV administration of DS-1471a. The expression levels of CD147 in hepatocytes and erythrocytes in monkeys and humans were measured to estimate the species differences. Using monkey PK, RO, and CD147 expression data, a minimal physiologically based pharmacokinetic (PBPK) model was constructed. Subsequently, PK and RO profiles in humans were predicted by replacing physiological parameters and CD147 expression levels with human values. For the safety assessment, DS-1471a was intravenously administered to monkeys every 2 weeks for 1 month. Results: In xenograft model mice, DS-1471a exhibited partial and potent antitumor activity at 1 and 3 mg/kg, respectively. At those doses, RO in tumor the day after dosing was 18% (1 mg/kg) and 89% (3 mg/kg). In monkeys, non-linear PK was observed, owing to high expression of CD147 in erythrocytes, resulting in target-mediated drug disposition. Compared to the findings in monkeys, the human expression level of CD147 was lower in erythrocytes and higher in hepatocytes. PBPK modeling, incorporating species differences in CD147 expression levels, projected that RO in tumor after the IV administration of DS-1471a to humans would reach 20%, 50%, and 90% at 2 day after injection at 0.3, 1, and 3 mg/kg, respectively. In the monkey toxicity study, DS-1471a was well tolerated at up to 158.4 mg/kg (human equivalent dose of 51 mg/kg). Conclusions: Based on preclinical PK-PD analysis and safety study of DS-1471a, the starting dose in FIH study was set to 1 mg/kg as a safe and efficacious dose. Citation Format: Miki Yokoyama, Masataka Oitate, Ken Sakurai, Takuma Iguchi, Katja Damme, Kayoko Nanai, Keisuke Fukuchi. Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A138.

Improving oncology first-in-human and Window of opportunity informed consent forms through participant feedback

BackgroundAlthough patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation of important information in consent forms for these trials.MethodsThe study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial’s consent form. The location of information in the consent forms was compared to the participants’ suggestions for placement.Results34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the “Risks” section. 3/5(60%) consents did this.ConclusionsDesigning consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.

Improving first-in-human and window-of-opportunity informed consent forms through participant feedback.

1562 Background: Although patient advocates have created templates for standard consent forms, assessing patient preferences for First in Human (FIH) and Window of Opportunity (WO) trials consents is important given their unique risks. FIH trials are the first time a drug is tested in humans. In WO trials, treatment naïve patients receive a therapeutic agent in the window of time between diagnosis and standard of care (SOC) surgery. Our goal was to determine patient-preferred presentation of important information in FIH and WO consent forms. Methods: The study consisted of two phases: (1) analysis of consents for FIH and WO oncology trials open at a cancer center between 2019 and 2022; (2) interview patients who had reviewed consents for FIH or WO trials during the consent process. FIH consents were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH info). The WO consents were analyzed for the location(s) of information stating the risk that trial may delay SOC surgery (WO info). Participants were asked about their preferred placement of the information in their own trial’s consent form and whether the consent was clear. Interviews were audio-recorded and double coded. Consent form analysis was compared to patients’ preferences. Results: 25 consents [20 FIH; 5 WO] were analyzed. 19/20 FIH consent forms included FIH info, and 4/5 WO consent forms included WO info. 42 patients were approached [19 FIH; 23 WO]; 34 [17 FIH; 17 WO] participated. 12/17 (71%) WO participants thought that the trial explanation in the consent form was clear. Conversely, only 9/17 (53%) FIH participants found it clear. Conclusions: Patients preferred that the important FIH and WO information be placed early in the consent, though exactly where varied. 82% of FIH participants wanted FIH information in the purpose, while only 19% of WO participants clearly preferred that WO information be in the purpose, and 41% preferred WO information to remain in the risks section. Using consent templates that reflect patient preferences accurately is essential for ethical informed consent; however, a one-size fits all approach may not accurately capture patient preferences, so multiple templates may be necessary. [Table: see text]

ID:15963 Athena: An Implantable Stimulation and Sensing Platform for Early Clinical Investigation of Advanced Neuromodulation Therapies

IRIS Biomedical’s mission is to provide breakthrough technology solutions for the neuromodulation market. To this end, we have developed ATHENA, an implantable 32-channel stimulating and sensing platform that supports a wide range of novel closed-loop therapies for First in Human (FIH) studies.

Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab

We present a novel approach for first-in-human (FIH) dose selection of the CD20xCD3 bispecific antibody, glofitamab, based on pharmacokinetic/pharmacodynamic (PKPD) assessment in cynomolgus monkeys to select a high, safe starting dose, with cytokine release (CR) as the PD endpoint. Glofitamab pharmacokinetics were studied in mice and cynomolgus monkeys; PKPD of IL-6, TNF-α and interferon-γ release following glofitamab, with/without obinutuzumab pretreatment (Gpt) was studied in cynomolgus monkeys. Potency differences for CR between cynomolgus monkeys and humans were determined by glofitamab incubation in whole blood of both species. The PKPD model for CR was translated to humans to project a starting dose that did not induce CR exceeding a clinically-predefined threshold. In cynomolgus monkeys, glofitamab showed a species-specific atypical high clearance, with and without B-cell debulking by Gpt. CR was related to glofitamab serum levels and B-cell counts. B-cell reduction by Gpt led to a marked decrease in CR. FIH starting dose (5 µg) was selected based on IL-6 release considering the markedly higher glofitamab in vitro potency in human vs monkey blood. This is a novel PKPD-based approach for selection of FIH starting dose for a CD20xCD3 bispecific antibody in B-cell lymphoma, evidenced in the glofitamab study, NP30179 (NCT03075696).

Ethics of First-in-Human Transplantation Trials of Bioartificial Organs

"The most effective treatment for type 1 diabetes is transplantation of either a whole pancreas from a deceased donor or islet cells derived from multiple deceased donors. However, transplantation has several limitations, including shortage of post-mortem donors and the need for post-transplant patients to use life-long immunosuppressive medication. In the last decade, the field of regenerative medicine has combined engineering and biological technologies in the attempt to regenerate organs. The European VANGUARD project aims to develop immune-protected bioartificial pancreases for transplantation into non-immunosuppressed type 1 diabetic patients. This project is creating a ‘combination product’ using cells and tissue from a variety of sources, including placentas and deceased donors. The clinical development of this complex product raises ethical questions for first-in-human (FIH) clinical trials. Under what conditions can bio-artificial organs safely are transplanted in humans for the first time? How can patients be selected, recruited and informed responsibly? In this presentation, we investigate the ethical conditions for clinical trials of bio-engineered organs, focusing inter alia on study design, subject selection, risk-benefit assessment, and informed consent. We present the results of a review of the literature on the ethics of clinical trials in regenerative medicine, cell and gene therapy and transplantation, and specify existing ethical guidance in the context of FIH transplantation trials of bioartificial organs. We conclude that this new and innovative area at the intersection of regenerative medicine, cell and gene therapy and transplantation requires adequate consideration of the ethical issues in order to guide responsible research and clinical implementation. "

LIPOPHILICITY, AQUEOUS SOLUBILITY, AND DEGREE OF IONIZATION OF ATRACTYLODIN AND β-EUDESMOL, THE BIOACTIVE COMPOUNDS ISOLATED FROM ATRACTYLODES LANCEA

Objective: The study aimed to evaluate the critical physicochemical properties (lipophilicity, aqueous solubility, and degree of ionization) of atractylodin and β-eudesmol using in vitro testing.
 Methods: Lipophilicity (Log P and Log D) was determined using the shake-flask method (n-octanol/water partition). Aqueous solubility was determined using kinetic solubility assay in media with pH ranging from 1.2 to 7.4. The degree of ionization (pKa) was determined using the potentiometric titration method.
 Results: Log P and Log D values of 3.0-5.0 suggested moderate lipophilicity of both compounds. Both exhibited low aqueous solubility over the investigated pH range (0.08-0.93 and 1.97-32.48 μg/ml for atractylodin and β-eudesmol, respectively). Based on the pKa values of 9.63 (atractylodin) and 9.12 (b-eudesmol), both are classified as basidic compounds.
 Conclusion: Atractylodin and β-eudesmol are classified as BCS class II drugs. The physicochemical parameters of both compounds obtained from the current study will be further applied for in silico prediction of their ADME (absorption, distribution, metabolism, and excretion) properties. In addition, PBPK modeling will be used for the prediction of optimal dose regimens of the capsule formulation of the standardized extract of Atractylodes lancea for first-in-human (FIH) and phase II studies in patients with cholangiocarcinoma.

Abstract 2273: Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach

Abstract Following the clinical success of checkpoint inhibitors, cancer immunotherapy is rapidly expanding into combination treatments to enhance response rates and duration. Engagement of co-stimulatory molecules from the tumor necrosis factor receptor (TNFR) superfamily, including 4-1BB, may be a promising approach to enhance the benefits of cancer immunotherapy. Agonistic antibodies against the costimulatory receptor 4-1BB (CD137) have been shown to effectively enhance the anti-tumor activity of checkpoint inhibitors and other agents in preclinical animal models. However, the clinical development of 4-1BB agonistic antibodies has met with limited success thus far. Anti-4-1BB monoclonal antibodies have either been reported to cause significant dose-limiting hepatotoxicity or demonstrated limited efficacy as single agent therapeutics. We generated a DARPin® therapeutic candidate, MP0310 (AMG 506), which comprises domains binding to 4-1BB and fibroblast activation protein (FAP). MP0310 triggers 4-1BB activation only if bound and clustered via FAP which is abundantly expressed by cancer associated fibroblasts present in many solid tumors. In vitro functional assays indicate that MP0310 is a potent T cell co-stimulator in the presence of FAP-expressing cells. In vivo activity of tumor-targeted 4-1BB agonism was assessed in the HT-29 colon carcinoma xenograft model in PBMC humanized mice in combination with a T cell engager. Consistent with tumor targeting, MP0310 enhanced intra-tumoral CD8 T cell expansion while showing only limited systemic activity. We used a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to integrate in vitro and in vivo data to support the estimation of a minimal anticipated biological effect level (MABEL) and the relevant dose range for first in human (FIH) studies. In addition to a PK model describing the MP0310 concentrations over time in mouse and monkey, direct and indirect response models were used to describe receptor occupancy (RO), intra-tumoral CD8 T cell infiltration and peripheral CD8 count kinetics. Predictions from the combined PK and PD models using average intra-tumoral and peripheral drug concentrations (Cav) provide a MABEL dose with minimal expected systemic PD effects at 20% RO as well as the anticipated therapeutic dose range in humans. In conclusion, our PK/PD-modeling approach provides support for the selection of a safe starting dose for MP0310 (AMG506) in patients. It provides a rationale for selecting the maximum tested dose, and may help reduce the number of cancer patients receiving sub-therapeutic doses. MP0310 (AMG 506) is currently being evaluated in a Ph1 clinical study. Citation Format: Alexander Link, Laurent Juglair, Heïdi Poulet, Guy Lemaillet, Christian Reichen, Patricia Schildknecht, Ivana Tosevski, Joanna Robinson, Niina Veitonmäki, Jörg Herbst, Keith Dawson, Christof Zitt, Camila de Almeida, Rik de Greef, Victor Levitsky, Michael T. Stumpp, Hong Ji, Elmar Vom Baur. Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2273.

Readiness for First-In-Human Neuromodulatory Interventions.

Novel neurointerventions present innovative therapeutic approaches to a range of treatment-refractory disorders. We sought to characterize factors that inform and define translational readiness for first-in-human (FIH) neuromodulatory trials. We used a two-part methodology involving a scoping review of the biomedical literature on the readiness of FIH trials for both neurological and non-neurological applications, and semi-structured interviews with stakeholders about decision-making for neuromodulation using magnetic resonance-guided focused ultrasound as a case example. One hundred and thirty factors relevant to FIH readiness were identified in the scoping review. Trial design, adequacy of preclinical evidence, and risk were ubiquitous across biotechnologies. Target organ, target function, and inadequacy of animal models were dominant in the neurointervention literature. Interview results on the relative importance of these factors reveal divergent values, priorities, and understandings both between patients and clinicians and between patients affected by different conditions. Readiness of neurotechnology for FIH trials is defined by a multitude of interacting factors that pertain to clinical and nonclinical priorities, perceptions, and values.

The New First-in-Human EMA Guideline: Disruptive or Constructive? Outcomes From the First EUFEMED Discussion Forum.

The European Federation for Exploratory Medicines Development (EUFEMED) organized a meeting in Leuven, Belgium entitled ‘The new FIH EMA guideline: Disruptive or constructive?’ to provide a forum for stakeholders to discuss the guideline’s operational impact. The revised EMA Guideline on strategies to identify and mitigate risks for first-in-human (FIH) and early clinical trials with investigational products was published on 20 July 2017. The revision gave guidance on sentinel dosing/staggering of subjects within a multiple-ascending dose (MAD) clinical trial, permissible maximum exposure/investigation of supra-therapeutic doses and dose escalations above the no-observed adverse effect level. As the guidelines came into operation on 1 February, 2018 it was assumed that by the date of the meeting many early phase stakeholders had gathered sufficient first-hand experience of working within the guideline to discuss their thoughts on its impact. The concluding part of the meeting focused on the possible differences between European countries in handling the revised FIH guideline and ways of achieving harmonization. Information on current industry practice was gathered by online polling during the meeting, where perception of the revised guideline as either ‘disruptive’ or ‘constructive’ was explored at the start and at the end of the Forum along with recommendations on reducing future regulatory discordance. It was generally agreed that the necessary changes encompassed by new guidelines included both constructive and disruptive aspects. The final vote on whether the new FIH guideline is disruptive or constructive was taken by 69 delegates: 51% stated that it was both constructive and disruptive, 48% decided on constructive, none on disruptive and 1% were still undecided. It was generally accepted that stakeholders need to continue in a process of stakeholder engagement and discussion, particularly on critical safety issues. Such an approach allows partners to adopt a proactive approach to sharing best practice. For example, attendees agreed that a ‘Question and Answer’ document harmonized between the European agencies is required for the sentinel approach and for the selection of supratherapeutic doses.

Abstract LB-296: Discovery of ARN-3261 as a potent, selective, orally available SIK2 inhibitor for treating ovarian, endometrial, primary peritoneal, fallopian tube, and triple negative breast cancers

Abstract ARN-3261 is an orally bioavailable small molecule inhibitor of the Salt Inducible Kinase 2 (SIK2, 11 nM) and SIK3 (19 nM). Three isoforms of SIK (SIKs) proteins have been reported: SIK1 (SNF1LK), SIK2 (QIK), and SIK3 (QSK). They are the Ser/Thr centrosome kinase family members required for bipolar mitotic spindle formation. The overexpression of SIK2 kinase in 30% of ovarian cancer specimens allows a novel, clinically important new method of treating ovarian cancer by blocking SIK2 kinase activity. In addition to a role in ovarian cancer, SIK2 and SIK3 are prevalent in several other tumor types, including breast, prostate diffuse large B-cell lymphoma, and melanoma cancers. Inhibition of SIK2 has been reported to cause centrosome splitting in interphase, while SIK2 depletion blocked centrosome separation in mitosis and sensitized ovarian cancers to paclitaxel in culture and in vivo Xenograft models. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher levels of expression of SIK2 have been shown to be highly correlated with poor survival in patients with high-grade serous ovarian cancers. Using the homology structure of SIK2, fragment-based lead optimization strategies, and screening and structure-activity relationship efforts, we have discovered ARN-3261, a first-in-class novel, selective inhibitor of SIK2 that could prove useful in treating ovarian, endometrial, primary peritoneal, fallopian tube, and triple negative breast cancers. ARN-3261 specifically inhibited SIK2-expressed SKOv3 cells with an IC50 of 92 nM. ARN3261 was effective against ovarian, breast cancer cell lines alone and in combination with Paclitaxel and Cisplatin. ARN-3261 also inhibited ovarian tumor growth significantly at 70% in SKOv3 human ovarian cancer Xenografts in Ncr nu/nu mice in a dose dependent manner at 20, 40, 60, and 100 mg/kg orally. Moreover, ARN-3261 has exhibited excellent in vivo pharmacokinetic, pharmacodynamics, and correlative PK/PD and ADME characteristics. Preliminary in vitro and in vivo tumor up-take studies suggest that ARN-3261 blocks centrosome separation by inhibiting SIK2, thereby enhancing the sensitivity of Paclitaxel. Encouraged by these results, we initiated the IND enabling GLP-Toxicology and safety studies to bring ARN-3261 to the clinic for First-In-Human (FIH) Phase 1 trials. The non-clinical pharmacology data along with Phase 1 POC clinical trial plans will be presented. Citation Format: Hariprasad Vankayalapati, Venkatakrishnareddy Yerramreddy, Jinhua Zhou, Jeffrey A. Handler, Rajendra P. Appalaneni, Ramamohan R. Kancherla, Roy J. Wu, Hiroshi Takemori, Angelique Whitehurst, Amir Anthony Jazaeri, Robert L. Coleman, Zhen Lu, Robert C. Bast. Discovery of ARN-3261 as a potent, selective, orally available SIK2 inhibitor for treating ovarian, endometrial, primary peritoneal, fallopian tube, and triple negative breast cancers [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 LB-296. doi:10.1158/1538-7445.AM2017-LB-296

Stakeholder views on participant selection for first-in-human trials in cancer nanomedicine.

Participant selection for first-in-human (fih) trials involves complex decisions. The trial design makes it unlikely that participants will receive clinically relevant therapeutic benefit, but they are likely to experience risks of various magnitudes and types. The aim of the present paper was to describe and discuss the views of investigators and ethics committee members about the choice of trial participants for fih trials in cancer nanomedicine. We drew insights from an exploratory qualitative study involving thematic analysis of 46 in-depth interviews with key stakeholders in Europe and North America involved in fih nanomedicine trials. The present work draws on subset of 21 interviews with investigators and ethics committee members who have either conducted or reviewed a fih cancer nanomedicine trial or are planning one. Investigators and ethics committee members are aware of the ethics standards for recruiting patients with end-stage cancer into fih trials, but they nonetheless question the practice and provide reasons against it. Although it is a standard and ethically accepted practice to enrol patients with end-stage cancer and no treatment options into fih trials of investigational chemotherapeutic molecules, doing so can threaten the validity and generalizability of the trials, thereby weakening translational research. Another possibility is to stratify and include patients with less advanced disease who demonstrate certain biomarkers or cancer genotypes and who have a disease profile similar to that tested in preclinical studies. The latter approach could be a step toward personalized medical research and targeted drug development. Such a patient selection approach requires multi-stakeholder discussion to reach scientific and ethics consensus.

The unique status of first-in-human studies: strengthening the social value requirement

For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials. Here, we provide some of necessary steps needed to assess the anticipated social value of the intervention.

Non-Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First-in-Human Dose Selection for CNTO 5825, an Anti-Interleukin-13 Monoclonal Antibody.

CNTO5825 is a human anti-interleukin-13 (IL-13) monoclonal antibody (mAb) that inhibits binding of human IL-13 to IL-13Rα1 and IL-13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non-clinical PK data in order to select the right and safe doses for first-in-human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98to 11.49ml/day/kg in rats and from 5.78 to 7.19ml/day/kg in cynomolgus monkeys. The volume of distribution at steady-state (Vss) in rats was large (151.52-155.64ml/kg) compared to cynomolgus monkey (49.77-61.10ml/kg). The terminal half-life (T1/2 ) ranged from 12.29 to 14.15days in rats and from 6.61 to 7.73days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1-10mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70kg) based on time-invariant method with combined PK data from rats and monkeys were 4.84±1.13ml/day/kg and 68.93±35.55ml/kg, respectively. The selected doses for the FIH study based on time-invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.

O1-14-5 - Syntactic Analysis for Single Agent Phase I Trials in Japan, From National Cancer Center Hospital (Ncch) Experience

Background: In Japan, most phase I (P-I) trials except for first in human (FIH) trials have been started from dosage provided evidence of safety, around 50% dosage of maximum tolerated doses (MTDs) or maximum administered doses (MADs) based on the initial P-I trials in the West. However, little has been well elucidated about actual status in P-I trials in Japan, such as dose limited toxicity (DLT) profiles, MTD or MAD levels, anti-tumor response, overall survival, and poor prognostic factors compared with those in the West.Methods: We retrospectively analyzed the data of patients enrolled in the single agent P-I trials at NCCH conducted between July 1995 and December 2012. The doses with anti-tumor response observed, DLT profiles, MTDs and MADs were compared with those in the West.Results: A total of 777 patients were enrolled in 54 single agent P-I trials including 5 FIH trials. The median age was 57 (range, 18-76) years and 57.9% were male. ECOG performance status (PS) of 0 and 1 were 38.6 and 61.1%. The common tumor types were lung (31.9%), colorectal (21.0%) and sarcoma (13.8%). DLTs were observed in 90 (11.6%) patients. The 85.2% of DLTs were observed in the similar dose ranges as compared with those in the West. The MTDs or MADs in the majority were also close, and 68.9% of agents were confirmed as the same dose levels in the West. The response rate was 6.2% (95% CI: 4.6-8.1). Median survival time was 11.5 (95% CI: 10.2-12.7) months. Male, PS of 1, body weight loss (> 5% within 3 months), liver metastasis, elevation of AST and LDH (> ULN), and hypoalbuminemia (< LLN) were independent poor prognostic factors for survival.Conclusion: The toxicity profiles including DLTs, MTDs or MADs and antitumor response in the single agent P-I trials in Japan were comparable to those in the West. We believe that the P-I trials in Japan could be carried out in the same time lines, such as the parallel or the global P-I settings, as in the West.

The Study Pathologist’s Role in GLP Studies

Results of early nonclinical "General Toxicology" studies are used to set a safe starting dose for first-in-human (FIH) clinical trials. In FIH trials, the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong. With that in mind, good laboratory practice regulations require that a standardized system be used for the conduct, documentation, and retention of study-related materials. The study pathologist, working within that system of standards, documentation, and oversight, is key to the identification of potential target organs of toxicity and other toxicologically significant findings.

Modeling and Simulation at the Interface of Nonclinical and Early Clinical Drug Development

The role of modeling and simulation (M&amp;S) in early drug development was discussed in a break out session of the European Medicines Agency/European Federation of Pharmaceutical Industries and Associations (EMA/EFPIA) M&amp;S workshop held in December 2011 in London, UK. The discussions were focused on two themes: (i) M&amp;S in nonclinical and early clinical drug development and (ii) M&amp;S for first‐in‐human (FIH) dose selection. Illustrative case studies were presented and links are listed in Table 1. Common objectives and next steps were identified, discussed, and agreed.CPT: Pharmacometrics &amp; Systems Pharmacology (2013) 2, e30; doi:10.1038/psp.2013.3; advance online publication 27 February 2013

Clinical pharmacology considerations in biologics development

Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.