Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma (MPM) (ARTEMIS)

A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma

This study was originally designed as a multicenter, double-blind, randomized, parallel-group study, using a placebo control or amatuximab 5 milligrams per kilogram (mg/kg), administered weekly, designed to evaluate the safety and efficacy of amatuximab in combination with pemetrexed and cisplatin in participants with unresectable Malignant Pleural Mesothelioma (MPM) who have not received prior systemic therapy.

Per a business decision made by the Sponsor, participants who were randomized to amatuximab and were still on active treatment at the time of the protocol amendment may have consented to continue to receive weekly treatment with amatuximab until disease progression or intolerable toxicity at the discretion of the principal investigator. Participants randomized to placebo or who were in follow-up at the time of the amendment have been discontinued from the study.

Study Overview

• Status: Terminated
• Conditions: Mesothelioma, Malignant
• Intervention / Treatment: Drug: Amatuximab; Drug: Pemetrexed; Drug: Cisplatin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
  • Queensland
    • Auchenflower, Queensland, Australia
  • Victoria
    • Richmond, Victoria, Australia, 3121
  • Western Australia
    • Perth, Western Australia, Australia
• France
  • Caen, France
  • Creteil, France
  • La Tronche, France
  • Lille, France
  • Lyon Cedex, France
  • Marseille, France
  • Rennes, France
  • Toulouse, France
• Germany
  • Berlin, Germany
  • Esslingen, Germany
  • Frankfurt am Main, Germany
  • Gauting, Germany
  • Hamburg, Germany
  • Hanover, Germany
  • Löwenstein, Germany
  • Ulm, Germany
  • Wöhrendamm, Germany
• Italy
  • Alessandria, Italy
  • Aviano, Italy
  • Bari, Italy
  • Bergamo, Italy
  • Genoa, Italy
  • Genova, Italy
  • Monza, Italy
  • Orbassano, Italy
  • Parma, Italy
  • Milano
    • Rozzano, Milano, Italy
  • Paradisa 2
    • Pisa, Paradisa 2, Italy, 56124
• United Kingdom
  • Dundee, United Kingdom
  • Hereford, United Kingdom
  • Leicester, United Kingdom
  • London, United Kingdom
  • Middlesex, United Kingdom
  • Preston, United Kingdom
  • Southampton, United Kingdom
  • Swindon, United Kingdom
  • Taunton, United Kingdom
  • Kent
    • Maidstone, Kent, United Kingdom
• United States
  • California
    • La Jolla, California, United States
  • Delaware
    • Newark, Delaware, United States
  • Maryland
    • Bethesda, Maryland, United States
  • Minnesota
    • Rochester, Minnesota, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • Texas
    • Dallas, Texas, United States
  • Washington
    • Spokane, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Are at least 18 years of age at the time of informed consent

2. Have confirmed diagnosis of MPM with the following characteristics:

   • Unresectable disease (defined as the participant not being a candidate for curative surgery)
   • Epithelial type
   • Have an archived tissue sample to be submitted either as a formalin fixed paraffin-embedded (FFPE) tumor block, or 5 to 15 unstained slides
3. Have measurable disease at Screening by computed tomography (CT) (or magnetic resonance imaging [MRI]) as defined by at least 1 lesion of greater than or equal to 1.5 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to the modified RECIST criteria
4. Have other significant medical conditions well-controlled and stable in the opinion of the investigator for at least 30 days prior to Day 1
5. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 at Screening
6. Have a life expectancy of at least 3 months, as estimated by the investigator

7. Have adequate organ reserve as determined by laboratory test results obtained within 2 weeks prior to Study Day 1 as indicated below:

   • Absolute neutrophil count greater than or equal to 1.5 x 10^9/L
   • Platelet count greater than or equal to 100 x 10^9/L
   • Hemoglobin greater than or equal to 9 g/dL
   • Serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN) (Participants with serum bilirubin abnormalities greater than this specified limit are eligible only if they have known Gilberts disease)
   • Aspartate aminotransferase less than or equal to 3 x ULN
   • Alanine aminotransferase less than or equal to 3 x ULN
   • Alkaline phosphatase less than or equal to 3 x ULN
8. Have a calculated serum creatinine clearance greater than or equal to 45 mL/min using the Cockcroft-Gault equation
9. Participants of childbearing potential must be surgically sterile or consent to use a highly effective method of contraception throughout the study period. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). If a participant of childbearing potential is neither surgically sterile nor postmenopausal, highly effective contraceptive measures must start either prior to or at Screening and continue throughout the entire study period and for at least 6 months after the last dose of chemotherapy and at least 30 days after the last dose of Test Article (amatuximab or placebo) is administered (whichever is later). A highly effective method of contraception is defined as one that results in a low failure rate (that is, less than 1% per year) when used consistently and correctly. Periodic abstinence, the rhythm method, the withdrawal method, condoms, and diaphragms are not acceptable methods of contraception. Women of childbearing potential must also refrain from egg cell donation for 6 months after the final dose of investigational product
10. Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period and for 6 months after discontinuation of chemotherapy and for 5 weeks after Test Article (amatuximab or placebo) discontinuation (whichever is later). No sperm donation is allowed during the study period and for 90 days after Test Article discontinuation
11. Be willing and able to provide written informed consent
12. Be willing and able to comply with all aspects of the protocol
13. Participants who were enrolled in the study and randomized to the amatuximab treatment arm may, at the discretion of the principle investigator (PI), consent to continue to receive amatuximab therapy until disease progression, intolerable toxicity, or withdraw of consent

Exclusion Criteria:

1. Have any history of the following:

   • Prior systemic therapy or radiotherapy for MPM; local radiotherapy of noncurative intent (ie, for prevention of instrument-tract recurrence and/or symptom control) is permitted
   • Evidence of other active, invasive malignancy requiring treatment within the past 5 years; noninvasive cancer history (such as carcinoma-in-situ [CIS] that has been resected) is allowed
2. Currently have mesothelioma of the sarcomatous type, mixed histologic disease, or have malignant peritoneal mesothelioma
3. Have confirmed presence of central nervous system metastases
4. Active viral hepatitis or active human immunodeficiency virus infection
5. Have evidence of any other serious systemic disease, including active bacterial or fungal infection, or any medical condition that, in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
6. Clinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4, angina not well controlled by medication, or myocardial infarction within 6 months)
7. Electrocardiogram (ECG) demonstrating clinically significant arrhythmias (Note: participants with chronic atrial arrhythmia, ie, atrial fibrillation or paroxysmal supraventricular tachycardia, are eligible). A clinically significant ECG abnormality, including a marked prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval of greater than 500 ms)
8. Have known intolerance to the Test Article (ie, documented hypersensitivity AE to prior monoclonal antibody therapy, or to amatuximab or any of its excipients)
9. Pregnant and/or lactating females are excluded; a negative beta-human chorionic gonadotropin [B-hCG]) is required during Screening, and a separate local assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of Test Article
10. Have any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
11. Are scheduled for debulking surgery during the study
12. Are currently enrolled in another clinical study or used any investigational drug or device within 30 days (or 5 x the half-life of the investigational drug/device, whichever is longer) preceding informed consent
13. Participants previously randomized to placebo
14. Participants who have not signed the updated informed consent form associated with this amendment 2
15. Participants who have radiographic or clinical disease progression or intolerable toxicity such that ongoing amatuximab treatment through this study is not appropriate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1; Combination Phase - Amatuximab + Pemetrexed and Cisplatin Maintenance Phase - Amatuximab	Drug: Amatuximab; Combination Phase - Amatuximab 5mg/kg will be administered IV (intravenous infusion) once weekly for six 21-day cycles. Maintenance Phase - Amatuximab 5mg/kg will be administered IV (intravenous infusion) once weekly until disease progression.; Drug: Pemetrexed; Combination Phase - Pemetrexed 500 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.; Drug: Cisplatin; Combination Phase - Cisplatin 75 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.
EXPERIMENTAL: Arm 2; Combination Phase - Placebo + Pemetrexed and Cisplatin Maintenance Phase - Placebo	Drug: Pemetrexed; Combination Phase - Pemetrexed 500 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.; Drug: Cisplatin; Combination Phase - Cisplatin 75 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.; Drug: Placebo; Combination Phase - Placebo will be administered IV (intravenous infusion) once weekly for six 21-day cycles. Maintenance Phase - Placebo will be administered IV (intravenous infusion) once weekly until disease progression.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	AEs included both non-SAEs and SAEs and the same participant can have both SAEs and as well non-SAEs.	Baseline up to 3 years

Collaborators and Investigators

• Sponsor: Morphotek

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 3, 2015
• Primary Completion (ACTUAL): November 30, 2018
• Study Completion (ACTUAL): November 30, 2018

Study Registration Dates

• First Submitted: January 14, 2015
• First Submitted That Met QC Criteria: February 2, 2015
• First Posted (ESTIMATE): February 6, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 17, 2020
• Last Update Submitted That Met QC Criteria: March 4, 2020
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Cisplatin; Pemetrexed; ARTEMIS; Amatuximab; Unresectable Malignant Pleural Mesothelioma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Cisplatin; Pemetrexed
• Other Study ID Numbers: MORAb-009-201; 2014-004489-85 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No