Kenneth T. Luu

Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

PURPOSE Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. RESULTS In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m(2)) was confirmed to be the same as that for single-agent INO (1.8 mg/m(2)). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. CONCLUSION R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20(+)/CD22(+) B-cell NHL.

A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition

In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (kon and koff), internalization of the drug-target complex (kint), target degradation rate (kdeg), and target abundance (R0), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1- to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic–pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.

Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure-Lowering Effect of the EP4 Agonist 5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate (PF-04475270)

Developing a population-based pharmacokinetic-pharmacodynamic (PKPD) model is a challenge in ophthalmology due to the difficulty of obtaining adequate pharmacokinetic (PK) samples from ocular tissues to inform the pharmacodynamic (PD) model. Using limited PK data, we developed a preclinical population-based PD model suitable for capturing the time course of dog intraocular pressure (IOP) that exhibited time-dependent sensitization after topical administration of PF-04475270 [5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate]. A physiologically relevant PK model was chosen to simultaneously capture the concentration profiles of CP-734432, a potent EP4 agonist and the active metabolite of PF-04475270, sampled from three ocular tissues of the anterior chamber: cornea, aqueous humor, and iris-ciliary body. Two population-based PD models were developed to characterize the IOP lowering profiles: model I, a standard indirect-response model (IRM); and model II, an extension of a standard IRM that empirically incorporated a response-driven positive feedback loop to account for the observed PD sensitization. The PK model reasonably described the PK profiles in all three ocular tissues. As for the PD, model I failed to capture the overall trend in the population IOP data, and model II more adequately characterized the overall data set. This integrated PKPD model may have general utility when PD sensitization is observed and is not a result of time-dependent PK. In addition, the model is applicable in the ophthalmology drug development setting in which PK information is limited but a population-based PD model could reasonably be established.1 TITLE PAGE Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure Lowering Effect of the EP4 Agonist, PF-04475270 Kenneth T. Luu, Eric Y. Zhang, Ganesh Prasanna, Cathie Xiang, Scott Anderson, Jay Fortner, Paolo Vicini Departments of Pharmacokinetics, Dynamics and Metabolism (K.T.L., E.Y.Z., C.X., P.V.), Ocular Biology (G.P., S.A.), Comparative Medicine (J.F.), Pfizer Global Research and Development, La Jolla, California, USA 92121 JPET Fast Forward. Published on August 18, 2009 as DOI:10.1124/jpet.109.157800

Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure Lowering Effect of the EP4 Agonist, PF-04475270

Developing a population-based pharmacokinetic-pharmacodynamic (PKPD) model is a challenge in ophthalmology due to the difficulty of obtaining adequate pharmacokinetic (PK) samples from ocular tissues to inform the pharmacodynamic (PD) model. Using limited PK data, we developed a preclinical population-based PD model suitable for capturing the time course of dog intraocular pressure (IOP) that exhibited time-dependent sensitization after topical administration of PF-04475270 [5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate]. A physiologically relevant PK model was chosen to simultaneously capture the concentration profiles of CP-734432, a potent EP4 agonist and the active metabolite of PF-04475270, sampled from three ocular tissues of the anterior chamber: cornea, aqueous humor, and iris-ciliary body. Two population-based PD models were developed to characterize the IOP lowering profiles: model I, a standard indirect-response model (IRM); and model II, an extension of a standard IRM that empirically incorporated a response-driven positive feedback loop to account for the observed PD sensitization. The PK model reasonably described the PK profiles in all three ocular tissues. As for the PD, model I failed to capture the overall trend in the population IOP data, and model II more adequately characterized the overall data set. This integrated PKPD model may have general utility when PD sensitization is observed and is not a result of time-dependent PK. In addition, the model is applicable in the ophthalmology drug development setting in which PK information is limited but a population-based PD model could reasonably be established.1 TITLE PAGE Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure Lowering Effect of the EP4 Agonist, PF-04475270 Kenneth T. Luu, Eric Y. Zhang, Ganesh Prasanna, Cathie Xiang, Scott Anderson, Jay Fortner, Paolo Vicini Departments of Pharmacokinetics, Dynamics and Metabolism (K.T.L., E.Y.Z., C.X., P.V.), Ocular Biology (G.P., S.A.), Comparative Medicine (J.F.), Pfizer Global Research and Development, La Jolla, California, USA 92121 JPET Fast Forward. Published on August 18, 2009 as DOI:10.1124/jpet.109.157800

Abstract 3776: Antitumor response to inotuzumab ozogamicin (INO) in patients with refractory or relapsed indolent B-cell non-Hodgkin's lymphomas (NHL): Pharmacokinetic-pharmacodynamic (PK-PD) modeling and interim results from a phase II study

Background: INO (CMC-544) is a novel antibody-drug conjugate composed of a CD22-directed IgG4 antibody linked to calicheamicin, a potent cytotoxin. In this phase II study, INO was administered 1.8 mg/m 2 intravenously once every 28 days for a planned 4 to 8 cycles to patients with indolent B-cell NHL who were refractory to rituximab. Objective: The aim of this analysis was to evaluate the antitumor activity of INO by performing PK-PD modeling of the INO concentrations and tumor size (as determined from the sum of products of diameters). Methods: Analysis was performed with a set of 28 patients with indolent NHL (24 follicular, 2 small lymphocytic lymphoma, 2 marginal zone) having evaluable data at the interim stage of the study. Population PK-PD modeling was conducted using NONMEM v. 7.1.2. Longitudinal tumor size data included measurements from the pre-screen time, during INO therapy, and up to 15 months of follow up. The PK of total calicheamicin was described by a linear 2-compartment model. Tumor size (T) was described by an exponential net growth (kgr) model with an inhibitory drug effect (slope) on kgr and drug concentration (C p ), such that dT/dt = kgr(1-slope x C p )T. Results: Of the 28 subjects evaluated, 18 exhibited tumor shrinkage (maximum reduction from baseline with a range of 12%-100% and a median of 68%), among which 10 were progression free/without tumor regrowth in the range of 10-18 months post first dose. Tumor shrinkage was seen as early as 54 days post treatment initiation, with peak tumor shrinkage as early as Day 103. The population estimates of clearance (CL), central (V1), peripheral (V2) volumes of distribution, and intercompartmental clearance (Q) were 2.69 (±0.41) L/day/m 2 , 30.4 (±1.79) L/m 2 , 90.9 (±19.8) L/m 2 and 5.50 (±1.29) L/day/m 2 , respectively. The population parameter estimates of the PD model were 9.41 x 10 −4 (±5.33 x 10 −4 ) day −1 for kgr and 0.396 (±0.178) ng/mL −1 for the slope. Simulations from the model using 1,000 virtual subjects (1.8 mg/m 2 every 28 days for a total of 4 cycles) showed that the median 10% tumor shrinkage can be seen as early as 35 days, with peak suppression occurring as early as 161 days. In addition, the duration of response was sustained beyond 1 year post treatment, and the tumor size does not return to baseline for up to 2 years after the first treatment. Conclusions: Antitumor response to INO in this study was characterized by a markedly long duration of response. PK-PD modeling improved the quantitative understanding of the time course of tumor size relative to inotuzumab treatment. The model, with updated data from the ongoing study, has utility in optimizing the dose and treatment regimen for subsequent follow-up studies in indolent lymphoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3776. doi:1538-7445.AM2012-3776

Abstract 4479: PF-04691502, a potent and selective PI3K/mTOR dual inhibitor with antitumor activity

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The PI3K pathway, which regulates cell growth, proliferation and survival, is activated in many types of human tumors by mutational activation of PI3Kα, loss of function of PTEN or activation of receptor tyrosine kinases. Inhibition of key signaling proteins in the pathway, such as PI3K, AKT and mTOR, therefore represents a high value targeting strategy for diverse cancers. PF-04691502 is a dual-specificity inhibitor of PI3K and mTOR which shows potent and selective activity in in vitro biochemical, cell and xenograft models. In in vitro biochemical assays PF-04691502 inhibited recombinant PI3Kα, β, γ and δ isoforms with Kis of 1.2-2.2 nM and recombinant mTOR with a Ki of 9.1 nM. PF-04691502 demonstrated a high degree of selectivity for inhibition of PI3K family kinases as shown by lack of activity against a panel of >75 protein kinases, including the Class III PI3K hVps34. PF-04691502 also inhibited transformation of avian fibroblasts mediated by PI3K γ, δ, mutant PI3Kα E545K or membrane-localized AKT with IC50s of ∼100nM. In cell assays PF-04691502 inhibited PI3K/mTOR signaling in SKOV3 ovarian cancer cells with PI3Kα mutations and in U87MG glioblastoma cells with PTEN alteration, as indicated by reduced levels of phosphorylation of AKT(T308), AKT(S473) and S6 ribosomal proteins. Functional studies for anti-proliferative effects suggest PF-04691502 has broad efficacy across tumor types. In SKOV3 and U87MG xenograft models PF-04691502 treatment resulted in dose-dependent tumor growth inhibition (TGI) with maximum TGI of ∼70% at the maximum tolerated dose of 10 mg/kg, by once daily oral dosing. Inhibition of AKT(S473) phosphorylation and S6RP(S235/236)/PRAS40(T246)/4EBP1(T37/46) phosphorylation were used as quantitative and qualitative pharmacodynamic (PD) endpoints, respectively; a clear pharmacokinetic (PK)/PD relationship was established in both models after multiple dose oral administration. In the U87MG xenograft model AKT(S473) phosphorylation was inhibited with an estimated EC50 of 5.7 nM (free plasma concentration) based on PK/PD modeling. The free plasma Area Under Curve was estimated to be 850 nM*hr for 70% TGI at 10mg/kg and was found to be similar in the SKOV3 model. The projected human efficacious dose of 10 mg once daily oral dosing provides Caverage steady state exposure of 22.4 nM (free plasma concentration) which is sufficient for 50-80% inhibition of pAKT S473, and corresponds to 74% TGI. Phase 1 clinical trials of PF-04691502 as a single agent are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4479.

Abstract 3224: Preclinical PKPD modeling and human dose projection of PF-04691502, a PI3K/mTOR dual inhibitor

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC PF-04691502 is a potent dual inhibitor of PI3K and mTOR, which are involved in regulating cell growth, proliferation and survival. The main objective of this work was to develop a preclinical pharmacokinetic-pharmacodynamic (PKPD) model for the compound and project the human efficacious dose. The PK of PF-04691502 in mouse obtained following oral dosing was described by a linear 2-compartment model which was used to drive two separate PD models: 1) an exponential growth model describing the tumor growth inhibition (TGI) and 2) an indirect-response model describing changes in intratumoral pAKT-S473/AKT in the U87MG xenograft mouse model. Based on the PK model, the half-life calculated from the linear elimination constant (k = 0.306 hr−1) was 2.3 hr and the plasma-compartment volume of distribution was 8.72 L/kg. The inter-compartmental distribution rate constants were 0.282 hr−1 and 0.212 hr−1 for k12 and k21, respectively. The model estimated in-vivo potency (IC50) for pAKT-S473/AKT suppression was 38.3 nM which was within the range of the IC50 (23 nM) for TGI (as parameterized by the model). The Imax estimated from the model was 0.975 (or 97.5%), which indicated nearly complete suppression of pAKT-S473/AKT production rate by PF-04691502. Based on the PKPD model and the scaled human PK, a clinical dose of 10 mg QD was determined to be adequate for maintaining the level of pAKT-S473/AKT below 50% of baseline. At steady-state PK this dose yielded a range of 50-80% human pAKT-S473/AKT suppression over the 24 hr dosing interval. In conclusion, PF-04691502 was determined to have a robust PKPD relationship in the preclinical animal model and was projected to have a clinically achievable efficacious dose of approximately 10 mg QD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3224.