Phase 1 and dosefinding study of patritumab U31

Authors: Hiroshi Wakui Noboru Yamamoto Shinji Nakamichi Yousuke Tamura Hiroshi Nokihara Yasuhide Yamada Tomohide Tamura

Publish Date: 2014/01/18

Volume: 73, Issue: 3, Pages: 511-516

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Abstract

Patritumab U31287 is a human epidermal growth factor receptor3 HER3targeted antibody that blocks ligandassociated activation of HER3 This openlabel phase 1 and dosefinding study ClinicalTrialsjp Identifier JapicCTI101262 aimed to assess the safety pharmacokinetics incidence of antipatritumab antibody recommended dose for subsequent clinical studies preliminary efficacy and patritumabrelated biomarkers in Japanese patients with advanced solid tumorsPatients received patritumab 9 or 18 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity occurred Adverse events AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE version 40 Doselimiting toxicities DLTs were evaluated from the initial dose to Cycle 1 Day 21 Tumor response was assessed with Response Evaluation Criteria in Solid Tumors RECIST version 11Nine patients received patritumab 9 mg/kg n = 3 or 18 mg/kg n = 6 Five patients were male all patients had Eastern Cooperative Oncology Group performance status PS ≤ 1 and median range age of 67 50–69 years No DLTs were reported Patritumabrelated AEs reported in ≥2 patients were ALT increase three patients thrombocytopenia diarrhea stomatitis cheilitis rash maculopapular and AST increase two each Pharmacokinetics profile was similar to the preceding US phase 1 study Soluble HER3 concentration in serum unexpectedly increased in all patients These changes did not correlate with clinical response Four patients had a best response of stable disease All patients tested had negative for antipatritumab antibody formationThe human epidermal growth factor receptor3 HER3 is expressed in many normal tissues and in a variety of solid tumors 1 2 Unlike other HER family members HER3 lacks intrinsic kinase activity 3 However the cytoplasmic tail of HER3 contains six docking sites for the p85 regulatory subunit of phosphatidylinositol3kinase PI3K and serves as a scaffold for PI3K/protein kinase B signaling for the HER family via heterodimeric interactions with other HER family members 4 5 6 Increased levels of HER3 have been associated with a negative clinical prognosis including survival in several tumor types 7 8 9 10 11 Recent data suggest that HER3 is involved in resistance to other HER receptortargeted therapeutics eg trastuzumab lapatinib cetuximab gefitinib and erlotinib 12 13 14 15 16Patritumab U31287 is a fully human monoclonal immunoglobulin G1 IgG1 antibody directed against HER3 Patritumab inhibits ligand binding heregulin alpha and heregulin beta and receptor activation and induces HER3 downregulation Functionally patritumab inhibits tumor cell proliferation survival and anchorageindependent growth in vitro and inhibits growth of HER3 expressing xenograft tumor models in vivo 17 18 19 20In a preceding US Phase 1 study ClinicalTrialsgov Identifier NCT00730470 21 the tolerability of patritumab was evaluated up to the dose of 20 mg/kg without doselimiting toxicities DLTs The most frequently reported patritumabrelated adverse events AEs were fatigue 12/57 211  diarrhea 7/57 123  and nausea 6/57 105  The majority of patritumabrelated AEs were Grade 1 or 2 This was an openlabel phase 1 and dosefinding study to evaluate the safety pharmacokinetics PK of repeated administration of patritumab and preliminary efficacy in Japanese patients with advanced solid tumorsEligible patients had histologically or cytologically confirmed advanced solid tumors that were refractory to standard treatment and were well known to express HER3 eg lung breast colorectal cervical esophageal and sarcoma Eligibility criteria also included the following age 20–75 years at informed consent Eastern Cooperative Oncology Group ECOG performance status PS 0–1 life expectancy greater than 3 months no previous chemotherapy radiation therapy hormonal therapy or surgery within 4 weeks before treatment with patritumab 6 weeks for previous treatment with nitrosoureas or mitomycin C and adequate hematologic hepatic and renal function Any toxicity related to prior therapy must have recovered Exclusion criteria included previous treatment with other antiHER3targeted therapy symptomatic brain metastasis pleural effusion and ascites that required drainage a history of thromboembolic disease or bleeding diatheses serious preexisting medical conditions such as uncontrolled infections severe cardiovascular or cerebrovascular disease uncontrolled hypertension or diabetes mellitus chronic diarrhea inflammatory bowel disease partial ileus and psychiatric disorders a history of hypersensitivity reactions to any drugs a history of serious hypersensitivity to drug containing polysorbate 20 hepatic B or C virus or human immunodeficiency virus infection pregnancy or lactation and not willing to use contraception during and after 6 months of the study

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