title: MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: an open-label, phase 1 dose-escalation and expansion study.
abstract: BACKGROUND
  Inflammation is an important feature of the malignant phenotype and promotes angiogenesis, tumour invasiveness, metastases, and cachexia. We used a first-in-class, monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α, a mediator of chronic inflammation. We aimed to assess the safety and tolerability of MABp1 for interleukin-1α blockade in a refractory cancer population.
  
  
  METHODS
  We did an open-label, dose-escalation, and phase 1 study of MABp1 in adults with metastatic cancer at the MD Anderson Clinical Center for Targeted Therapy (Houston, TX, USA). We used a standard 3+3 design to identify the maximum tolerated dose. Patients received MABp1 intravenously once every 3 weeks through four dose levels: 0.25 mg/kg, 0.75 mg/kg, 1.25 mg/kg, and 3.75 mg/kg. After the dose-escalation phase, a second dosing arm was started with dosing every 2 weeks at the maximum tolerated dose. The primary objectives were safety, tolerability, characterisation of the pharmacokinetic profile, and identification of the recommended phase 2 dose. Secondary endpoints included pharmacodynamic effects and antitumour activity. All patients who received at least one dose of MABp1 were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT01021072.
  
  
  RESULTS
  Between March 15, 2010, and July 30, 2012, 52 patients with metastatic cancer (18 tumour types) received anti-interleukin-1α monotherapy in dose-escalation and expansion groups. MABp1 was well tolerated, with no dose-limiting toxicities or immunogenicity. Thus, the recommended phase 2 dose was concluded to be 3.75 mg/kg every 2 weeks. Pharmacokinetic data were consistent at all dose levels and showed no evidence of accumulation or increased clearance of MABp1 at increasing doses. For 42 assessable patients, median plasma interleukin-6 concentrations had decreased from baseline to week 8 by a median of 2.7 pg/mL (IQR -12.6 to 3.0; p=0.08). Of the 34 patients restaged, one patient had a partial response and ten had stable disease. 30 patients were assessable for change in lean body mass, which increased by a mean of 1.02 kg (SD 2.24; p=0.02) between baseline and week 8. The most common adverse events possibly related to the study drug were proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%). The most frequent grade 3-4 adverse events (regardless of relation to treatment) were fatigue (3; 6%), dyspnoea (2; 4%), and headache (2; 4%). Two patients (4%) had grade 5 events (death due to disease progression), which were unrelated to treatment.
  
  
  CONCLUSIONS
  MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted.
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA. Electronic address: dshong@mdanderson.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Palliative Care and Rehabilitation Medicine, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hui
authors.affiliation: Department of Palliative Care and Rehabilitation Medicine, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bruera
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: XBiotech USA, Austin, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Stecher
authors.affiliation: XBiotech USA, Austin, TX, USA.
authors.forename: Prasant
authors.initials: P
authors.lastname: Mohanty
authors.affiliation: XBiotech USA, Austin, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Simard
authors.affiliation: UC San Diego Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors*; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053582:Interleukin-1alpha; C000599944:MABp1 monoclonal antibody