Celine Pitou

A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

A phase I dose-escalation study to a predefined dose of a transforming growth factor-β1 monoclonal antibody (TβM1) in patients with metastatic cancer

Transforming growth factor β (TGF-β) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-β ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TβM1 is a humanized mAb optimized for neutralizing activity against TGF-β1. The objective of this clinical trial was to assess the safety and tolerability of TβM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤2 on the ECOG scale were administered TβM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TβM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TβM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-β1 expression signature in patients’ whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study

A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma

Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naïve and previously hedgehog (Hh)-inhibitor–treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n = 25; dose confirmation, n = 19; and BCC dose expansion, n = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%–61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment–naïve (11/16) patients. Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment–naïve patients. Clin Cancer Res; 24(9); 2082–91. ©2018 AACR.

Characterizing Gemcitabine Effects Administered as Single Agent or Combined with Carboplatin in Mice Pancreatic and Ovarian Cancer Xenografts: A Semimechanistic Pharmacokinetic/Pharmacodynamics Tumor Growth-Response Model.

In this work, a semimechanistic tumor growth-response model for gemcitabine in pancreatic (administered as single agent) and ovarian (given as single agent and in combination with carboplatin) cancer in mice was developed. Tumor profiles were obtained from nude mice, previously inoculated with KP4, ASPC1, MIA PACA2, PANC1 (pancreas), A2780, or SKOV3×luc (ovarian) cell lines, and then treated with different dosing schedules of gemcitabine and/or carboplatin. Data were fitted using the population approach with Nonlinear Mixed Effect Models 7.2. In addition to cell proliferation, the tumor progression model for both types of cancer incorporates a carrying capacity representing metabolite pool for DNA synthesis required to tumor growth. Analysis of data from the treated groups revealed that gemcitabine exerted its tumor effects by promoting apoptosis as well as decreasing the carrying capacity compartment. Pharmacodynamic parameters were cell-specific and overall had similar range values between cancer types. In pancreas, a linear model was used to describe both gemcitabine effects with parameter values between 3.26 × 10−2 and 4.2 × 10−1 L/(mg × d). In ovarian cancer, the apoptotic effect was driven by an EMAX model with an efficacy/potency ratio of 5.25–8.65 L/(mg × d). The contribution of carboplatin to tumor effects was lower than the response exerted by gemcitabine and was incorporated in the model as an inhibition of the carrying capacity. The model developed was consistent in its structure across different tumor cell lines and two tumor types where gemcitabine is approved. Simulation-based evaluation diagnostics showed that the model performed well in all experimental design scenarios, including dose, schedule, and tumor type.

Abstract B32: LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC)

We previously reported interim dose escalation results from this multi-center, open-label Phase 1 clinical trial (NCT01226485) (Bendell et al, EJC 2012). Here, we report the final aggregate safety results and the anti-tumor activity demonstrated by LY2940680, a novel Hh pathway inhibitor, in locally advanced (la) and metastatic (m) BCC. Methods: The primary objective of this study was to determine a recommended Phase 2 dose and regimen of LY2940680 that could be safely administered to patients with advanced cancer, including BCC. Patients deemed eligible for experimental therapy were enrolled in the study and dosed once daily (QD) for 28 day cycles until discontinuation. The maximum tolerated dose (MTD) was determined using a 3+3 dose escalation design. Based on initial anti-tumor activity, a cohort of la/m BCC patients was enrolled. Safety, PK/PD, and tumor response data were collected and analyzed. Results: A total of 84 advanced cancer patients were dosed, including 47 patients with la/m BCC. Median age was 62.5 years (range: 29-89). Advanced cancer patients received escalating doses ranging from 50 mg to 600 mg QD resulting in a MTD of 400 mg QD. The most commonly reported treatment-emergent adverse events (TEAE) possibly related to study drug (>20%) were dysgeusia (Gr 1-2: 46.4%, Gr 3: 2.4%), fatigue (Gr 1-2: 44.0%, Gr 3: 3.6%), nausea (Gr 1-2: 42.9%, Gr 3: 2.4%), muscle spasms (Gr 1-2: 35.7%, Gr 3: 4.8%), decreased appetite (Gr 1-2: 35.7%, Gr 3: 0%), vomiting (Gr 1-2: 29.7%, Gr 3: 2.4%), alopecia (Gr 1-2: 33.3%, Gr 3: 0%), and weight decrease (Gr 1-2: 26.2%, Gr 3: 1.2%). PK analysis showed no clear relationship between exposure (PK) and toxicity. PD marker analysis of Gli-1 mRNA from unaffected skin biopsies suggested all doses were biologically active (inhibition median of 91.7% with interquartile range (80.9-95.7%) in all patients with available pre- and post-treatment biopsies). The most common reasons for treatment discontinuation were progression of disease (n = 43), adverse event (n = 10) and withdrawal by subject (n = 10). All reported clinical responses (per RECIST 1.1) were in patients with la/m BCC. Overall response rate (ORR) for patients with la/m BCC (n = 47) was 46.8% (95% CI: 32.1-61.9%) and clinical benefit rate (CR+PR+SD) was 93.6% (95% CI: 82.5-98.7%). The median duration of response was estimated at 10.2 months (95% CI: 5.6- not estimable). Responses were observed in patients who were Hh treatment naive (11/16) but also in patients who previously failed Hh therapy (11/31). Conclusion: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced cancer including la/m BCC. Clinical responses were observed in la/m BCC patients naive to Hh inhibitor treatment and also in those who had failed treatment with other Hh inhibitor agents. This phase 1 study supports further clinical development of LY2940680 in advanced BCC and potentially in other malignancies Citation Information: Bendell J. et al. European Journal of Cancer (EJC) 2012 48(6 Suppl) Abstract 594. Citation Format: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff. LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B32.

Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms

BACKGROUND The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing. METHODS A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug. FINDINGS Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively. INTERPRETATIONS LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.

Systematic Modeling and Design Evaluation of Unperturbed Tumor Dynamics in Xenografts

Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterize tumor growth dynamics and also optimize upcoming experiments. To the best of our knowledge, this is the first report where unperturbed growth of a large set of tumor cell lines (n = 28) has been systematically analyzed using a previously proposed model of nonlinear mixed effects (NLME). Exponential growth was identified as the governing mechanism in the majority of the cell lines, with constant rate values ranging from 0.0204 to 0.203 day−1. No common patterns could be observed across tumor types, highlighting the importance of combining information from different cell lines when evaluating drug activity. Overall, typical model parameters were precisely estimated using designs in which tumor size measurements were taken every 2 days. Moreover, reducing the number of measurements to twice per week, or even once per week for cell lines with low growth rates, showed little impact on parameter precision. However, a sample size of at least 50 mice is needed to accurately characterize parameter variability (i.e., relative S.E. values below 50%). This work illustrates the feasibility of systematically applying NLME models to characterize tumor growth in drug discovery and development, and constitutes a valuable source of data to optimize experimental designs by providing an a priori sampling window and minimizing the number of samples required.

Predicting tumour growth and its impact on survival in gemcitabine-treated patients with advanced pancreatic cancer

Abstract The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi‐mechanistic joint TS‐OS model. TS and OS data were obtained from one phase II and one phase III study where gemcitabine was administered (1000‐1250 mg/kg over 30‐60 min i.v infusion) as single agent to patients (n = 285) with advanced pancreatic cancer. Drug exposure, TS and OS were linked using the population approach with NONMEM 7.3. Pancreatic tumour progression was characterized by exponential growth (doubling time = 67 weeks), and tumour response to treatment was described as a function of the weekly area under the gemcitabine triphosphate concentration vs time curve (AUC), including treatment‐related resistance development. The typical predicted percentage of tumour growth inhibition with respect to no treatment was 22.3% at the end of 6 chemotherapy cycles. Emerging resistance elicited a 57% decrease in drug effects during the 6th chemotherapy cycle. Predicted TS profile was identified as main prognostic factor of OS, with tumours responders’ profiles improving median OS by 30 weeks compared to stable‐disease TS profiles. Results of NCT00574275 trial were predicted using this modelling framework, thereby validating the approach as a prediction tool in clinical development. Our analyses show that despite the advanced stage of the disease in this patient population, the modelling framework herein can be used to predict the likelihood of treatment success using early clinical data. Graphical abstract Figure. No caption available.