Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors

Our plain-English summary of Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors, by Y. Fujisaka, T. Kurata, K. Tanaka, et al (Investigational New Drugs, 2015).

The study

• Authors: Y. Fujisaka, T. Kurata, K. Tanaka, T. Kudo, K. Okamoto, J. Tsurutani, H. Kaneda, I. Okamoto, M. Namiki, C. Kitamura, K. Nakagawa
• Journal: Investigational New Drugs
• Published: 2015;33(2):380-8
• Cited by: 39 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

In plain English

This phase I dose-escalation study tested amatuximab, an antibody drug aimed at mesothelin, a protein found on mesothelioma and some other cancer cells. It did not study asbestos exposure. Seventeen Japanese patients with advanced solid tumors, treated at Kinki University Faculty of Medicine between November 2009 and March 2012, received weekly infusions at 50, 100 or 200 mg/m2 (milligrams per square meter of body surface). Most had colorectal cancer (seven) or pancreatic adenocarcinoma (six), and two had mesothelioma. Thirteen of 17 patients (76.5%) had treatment-related side effects, most often fatigue and fever. Two patients had dose-limiting side effects. One had a grade 3 cytokine release syndrome at 50 mg/m2. The other, a patient with pleural mesothelioma at 200 mg/m2, developed interstitial lung disease and died; this was judged probably related to the drug. There were no objective tumor responses, and three patients (17.6%) had stable disease. The authors concluded the drug was generally well tolerated up to 200 mg/m2. They found its behavior in the body similar to that in US patients. They noted that higher doses were not tested and that the stable-disease numbers were too small to be meaningful.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I dose-escalation drug trial (standard 3+3 design)
• Who was studied: 17 Japanese patients with advanced solid tumors (7 colorectal cancer, 6 pancreatic adenocarcinoma, 2 head and neck cancer, 2 mesothelioma), enrolled from 58 screened patients at Kinki University Faculty of Medicine, Japan, November 2009 to March 2012
• Exposure: Not an asbestos exposure study. The exposure was the drug amatuximab, given as a weekly intravenous infusion in 4-week cycles: 7 patients at 50 mg/m2, 3 at 100 mg/m2 and 7 at 200 mg/m2
• Main results:
  • 13 of 17 treated patients (76.5%) had a treatment-related adverse event
  • The most common treatment-related adverse events among the 17 patients were fatigue (5 patients, 29.4%) and pyrexia (fever) (4 patients, 23.5%)
  • One dose-limiting toxicity occurred at 50 mg/m2 (grade 3 cytokine release syndrome) and one at 200 mg/m2 (grade 5 interstitial lung disease). The maximum tolerated dose in this study was set at 200 mg/m2
  • One patient at 200 mg/m2, who had pleural mesothelioma, died of interstitial lung disease on day 60. This was considered probably related to amatuximab
  • 8 of 17 patients (47.1%) developed antibodies against the drug (HACA). This fell to 4 of 13 patients (30.8%) after premedication with antihistamines and acetaminophen became mandatory
  • There were no objective tumor responses. 3 of 17 patients (17.6%) had stable disease and 14 (82.4%) had progressive disease as best overall response
  • Drug levels (Cmax and AUC) rose almost in proportion to dose from 50 to 200 mg/m2. The drug's behavior in the body was similar in Japanese patients and US patients
  • Of 53 screened patients whose tumor tissue was tested, 24 (45.3%) were mesothelin positive, including 2 of 2 with mesothelioma
• The authors' conclusion: The authors concluded that amatuximab was generally well tolerated at 50, 100 or 200 mg/m2 in patients with solid tumors. They also concluded that its pharmacokinetic profile in Japanese patients was similar to that in US patients.
• Limitations the authors state:
  • Doses above 200 mg/m2 were not tested, so the true maximum tolerated dose might be higher
  • The numbers of patients with durable stable disease were too small to be meaningful
  • The relationship between efficacy and mesothelin expression could not be determined because no tumor regression was seen

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelin, Mesothelioma, Adenocarcinoma, Clinical Trial.

Related studies

• Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma — M. Takeda, Y. Ohe, et al. (2019)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells — K. Kobayashi, T. Sasaki, et al. (2015)
• Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection — A. Gupta, Z. Hussein, et al. (2016)
• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors — E. Hatterer, X. Chauchet, et al. (2020)

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