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Methodology Results Background First-in-Human Studies of Monoclonal Antibodies in Oncology: An Overview of Study Designs and Stopping Criteria Man Qing LIANGa, Nathalie H GOSSELINb, Jean-François MARIERb 7th FIP Pharmaceutical a Université de Montréal, Montréal, Canada b Certara, Princeton, NJ Sciences World Congress [email protected]; [email protected]; [email protected] (PSWC 2020) Background Methodology Results 4 PK profile of lumretuzumab 1 First-in-human studies of monoclonal antibodies in oncology included in review Ideal Study Design Part I – Literature Review AUC/dose vs dose Cmax/dose vs dose ‣ Minimize the number of patients treated at • Keywords 18 12 2 Plateau: Linear elimination doses lower than the optimal dose o Phase I Anticancer monoclonal FDA approved PK population ‣ o antibody phase I studies anticancer mAb studies extracted for ) 2000 Minimize the risk of toxicity Dose finding / dose escalation trials / study design 400 1 400 simulations 2000 - extracted for review (part II) 300 300 ‣ Minimize accrual suspension (suspension of o Monoclonal antibody / molecular targeted agents 200 200 Rapid clearance patient recruitment) • Search method 6 1 100 at smaller doses /dose (L o Manually screened references from previous literature review (binding to max C receptors) = at: Oncology Phase I Trials o Database: SCOPUS Anticancer mAb PK population study considerably 100 extracted for (h/L) AUC/dose under investigation 10 smaller AUC Presented Population Characteristics o TITLE((phase i) OR (phase 1) OR (phase one)) AND ((study) OR simulations (part II) 10 (studies) OR (trial) OR (trials)) AND ((name of the molecule) OR Few anticancer monoclonal ‣ Open-label, single-arm, very few patients (code of the molecule)) 2 Characteristics of the studied anticancer Dose (mg) Dose (mg) mAbs in first-in-human phase I clinical trials antibodies trials reached the MTD ‣ Trial drug used when standard of care did not o First-in-human studies work • Collected data for each mAb: Monoclonal Year Type Target Reason for stopping trial Was MTD “[…] the PK profile showed linearity at doses of 400 mg and 95% antibody reached? target saturation was achieved from 400 mg over the entire ‣ Toxic effects are difficult to capture in phase I o Type (human, humanized, chimeric, etc.), target dosing interval. Hence, the optimal biologic dose was because patients with advanced cancers do o Phase I study: Year of publication, dose escalation method, % dose Rituximab * 1994 Chimeric CD20 Predetermined doses No determined to be 400 mg.“ (Meulendijks et al. 2016) not stay for long periods of time (disease increments, reason for stopping trial, maximum tolerated dose Cetuximab * 1999 Chimeric EGFR PK No progression) (MTD) reached or not, number of patients and dose levels, study Gemtuzumab 1999 Humanized CD33 Target inhibition No objectives ozogamicin * antibody-drug Monoclonal Antibodies conjugate 5 PK profile of panitumumab AUC/dose vs dose (mAbs) Used in Cancer Part II – Pharmacokinetic Simulations Trastuzumab * 1999 Humanized HER2 PK No Cmax/dose vs dose Bevacizumab * 2001 Humanized VEGF Target inhibition and PK No • Parameters extracted from PK population studies of the drug Ipilimumab * 2005 Human CTLA-4 Toxicity Yes ‣ ) MAbs have a different PK profile than 1 o Distribution parameters: V, V2, Q Pertuzumab * 2005 Humanized HER2 PK No - traditional cytotoxic molecules (Target mediated drug disposition, or TMDD) o Elimination parameters: CL, Vmax, Km Panitumumab * 2008 Human EGFR PK No 2 mg QW ‣ MAbs have a limited toxicity profile • Tested at phase I doses, duration of infusion and frequencies Nivolumab * 2010 Human PD-1 Predetermined doses No /dose (L 2 mg QW max ‣ Efficacy can be observed when the receptor Ramucirumab * 2010 Human VEGFR2 Toxicity Yes C 1.5 mg AUC/dose (h/L) AUC/dose occupancy is full • Pharmacokinetic simulations performed using Certara’s Phoenix™ Durvalumab * 2014 Human PD-1 Response No 1.5 mg QW QW Pre-Phoenix: Buildup dataset with several dose levels using population MEDI-575 2014 Human PDFGRa PK, optimal biologic No First-in-Human Study Designs PK parameters from the literature concentration Dose (mg/kg) Dose (mg/kg) Step 1: Implement model in Phoenix Pembrolizumab * 2014 Humanized PD-1 Predetermined doses from No No prior assumption on ”In the terminal phase of the weekly dose concentration profile, there was a rapid the dose-toxicity curve pharmacologic models Requires Step 2: Graph the rich profile decline in levels for doses 0.75 to 1.5 mg/kg weekly, whereas at higher doses this beyond the assumption logistics Lumretuzumab 2015 Humanized HER3 Target inhibition and PK No that dose ∝ toxicity Study designs (expertise, Step 3: Non compartmental analysis (NCA) nonlinear decline was less apparent. Easier to implement software) PF-03446962 2015 Human ALK-1 Toxicity, PK, antitumor Yes Although the maximum tolerated dose was not reached, it is unlikely that increasing Step 4: Evaluation of non-linearity curve activity the dose beyond these doses would result in increased panitumumab activity Rule / algorithm because EGFR seems to be saturated at these dose levels, and no additional anti- Model-based based Vanucizumab 2017 Humanized VEGF-A Bayesian logistic regression No EGFR activity would be predicted at increased doses.” (Weiner et al, 2008) and Ang-2 model (BLRM) Traditional 3+3 Continual Escalation with Accelerated reassessment overdose control Elgemtumab 2017 Human HER3 BLRM (PK and PD) No & its variations titration method (CRM) (EWOC) References Bronctituzumab 2018 Humanized Notch1 Toxicity Yes 1. Agus DB, Gordon MS, Taylor C, et al: Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534-43, 2005 6 PK profile of cetuximab (+) Takes into 2. Ansell SM, Hurvitz SA, Koenig PA, et al: Phase I Study of Ipilimumab, an Anti–CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non–Hodgkin Lymphoma. Clinical Cancer (+) Less risk of (+) Simple (+) Less patients at Research, 1909 account all data overdose 3. Attarwala H: TGN1412: From Discovery to Disaster. Journal of Young Pharmacists : JYP 2:332-336, 2010 * FDA approved drugs (-) Many steps at subtherapeutic (-) Exposure to (-) Expertise 4. Attia P, Phan GQ, Maker AV, et al: Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043-53, Figure 10: AUC/dose vs dose Figure 11: Cmax/dose vs dose subtherapeutic dose doses 2005 unacceptably high required to (-) May mask doses 5. Bai S, Jorga K, Xin Y, et al: A Guide to Rational Dosing of Monoclonal Antibodies. Clinical Pharmacokinetics 51:119-135, 2012 cumulative effects determine the 6. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-14, 2000 Evolution of the choice of dose escalation method in phase I correct parameters 7. Becerra CR, Conkling P, Vogelzang N, et al: A phase I dose-escalation study of MEDI-575, a PDGFRalpha monoclonal antibody, in adults with advanced solid tumors. Cancer Chemother Pharmacol Pharmacologically Time-to-event 74:917-25, 2014 3 guided dose endpoints CRM 8. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic trials for anticancer monoclonal antibodies correlates. J Clin Oncol 28:3167-75, 2010 ) 1 escalation (PGDE) (TiTE-CRM) 9. Cook N, Hansen AR, Siu LL, et al: Early phase clinical trials to identify optimal dosing and safety. Molecular Oncology 9:997-1007, 2015 - 10. Dirks NL, Meibohm B: Population Pharmacokinetics of Therapeutic Monoclonal Antibodies. Clinical Pharmacokinetics 49:633-659, 2010 Dose escalation method used in phase I trial on monoclonal 11. Ferrarotto R, Eckhardt G, Patnaik A, et al: A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors. Ann Oncol 29:1561-1568, 2018 12. Food and Drug Administration CfBEaR. Guidance for Industry, Clinical Considerations for Therapeutic Cancer Vaccines In: Services USDoHaH, editor. 2011. p. 18. (+) Takes into account all data (+) Evaluates late / 13. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. New England Journal of Medicine 372:2018-2028, 2015 antibodies for cancer treatment (-) Exposure to unacceptably 14. Goff LW, Cohen RB, Berlin JD, et al: A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors. Clin Cancer Res cumulative toxicities 22:2146-54, 2016 high doses /dose (L (-) Many steps at 15. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 6 19:843-50, 2001 Pembrolizumab subtherapeutic doses max 16. Hansen AR, Cook N, Ricci MS, et al: Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials. Oncologist 20:653-9, 2015 400 17. Hibma J, Knight B: Population Pharmacokinetic Modeling of Gemtuzumab Ozogamicin in Adult Patients with Acute Myeloid Leukemia. Clin Pharmacokinet, 2018 et nivolumab 400 C (Le Tourneau et al, 2009 and Doussau et al, 2016) 18. Hidalgo M, Martinez-Garcia M, Le Tourneau C, et al: First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult 5 200 Patients with Advanced Solid Tumors. Clin Cancer Res 24:1536-1545, 2018 200 19. Hodi FS, Hwu W-J, Kefford R, et al: Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. Journal of Clinical New approaches Traditional 3+3 (h/L) AUC/dose Oncology 34:1510-1517, 2016 4 20.
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