Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma (MPM)
Condition: Mesothelioma, Malignant
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: Placebo; Amatuximab; Pemetrexed; Cisplatin
Intervention description: 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.; 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.; Combination Phase - Pemetrexed 500 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.; Combination Phase - Cisplatin 75 mg/m^2 will be administered IV on Day 1 of each 21-day cycle for 6 cycles.
Intervention MeSH terms: Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 124.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Amatuximab; Pemetrexed; Cisplatin; Unresectable Malignant Pleural Mesothelioma; ARTEMIS

Summary:

      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.
    

Eligibility criteria:

        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