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

Primary Outcome

• • Overall Survival (OS) [ Time Frame: Until date of death or up to 60 months ]
    [ Designated as safety issue: No ] OS is defined as the time from the date of randomization to the date of death, regardless of cause.

Secondary Outcome Measures

• • • Progression Free Survival (PFS) [ Time Frame: First observation of disease progression or until date of death or up to 60 months ] [ Designated as safety issue: No ]
      PFS is defined as the time (in weeks) from the date of randomization to the date of the first observation of progression as determined by the independent radiologic assessment using the modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria or the date of death, whichever comes first, regardless of the cause.
    • Objective Response Rate [ORR] [ Time Frame: Until date of death or up to 60 months ] [ Designated as safety issue: No ]
      ORR (the proportion of subjects with complete response [CR] and partial response [PR]) as defined by the modified RECIST criteria using an independent radiologic review of computed tomography (CT)/Magnetic resonance imaging (MRI) scan. Objective response will be assessed at select visits during the Combination Treatment Phase as well as the Maintenance Treatment Phase.
    • Duration of response (DR) [ Time Frame: First documentation of objective tumor progression or until date of death or up to 60 months ] [ Designated as safety issue: No ]
      DR is defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death on study (ie, within 30 days after the last dose of Test Article).
    • Disease control rates (DCR) [ Time Frame: Until date of death or up to 60 months ] [ Designated as safety issue: No ]
      DCR is the proportion of subjects with CR, PR, or stable disease (SD) as defined by the modified RECIST criteria using an independent radiologic review of CT/MRI scan.
    • Duration of disease control (DDC) [ Time Frame: First documentation of objective tumor progression or until date of death or up to 60 months ] [ Designated as safety issue: No ]
      DDC is defined as the time from the first documentation of objective tumor response or SD to the first documentation of objective tumor progression or to death.
    • Health related quality of life (QOL) [ Time Frame: Until date of death or up to 60 months ] [ Designated as safety issue: No ]
      QOL as measured by the Lung Cancer Symptom Scale for mesothelioma (LCSS-Meso; Hollen, et al., 2006) as the treatment population average across the duration of the trial for 9 items.
    • Duration of Performance Status Maintenance (DPSM) [ Time Frame: Until date of death or up to 60 months ] [ Designated as safety issue: No ]
      DPSM is defined as the time from randomization until the last time the performance status was no worse than at baseline or to death on study.
    • Safety and tolerability as a measure of number of participants with Adverse Events (AEs)/Serious Adverse Events (SAEs) [ Time Frame: Until date of death or up to 60 months ] [ Designated as safety issue: No ]
      Safety assessments will consist of monitoring and recording all adverse events, including adverse events of interest, hypersensitivity adverse events and serious adverse events; regular monitoring of hematology, blood chemistry, and urine values; regular monitoring of electrocardiograms (ECGs); periodic measurement of vital signs; and performance of physical examinations.
    • Pharmacokinetic (PK) and pharmacodynamic (PD) profile [ Time Frame: Serum samples of amatuximab at Day 1 of every Cycle during the combination treatment phase and every third cycle during the maintenance treatment phase until first evidence of disease progression or up to 60 ] [ Designated as safety issue: No ]
      PK and PD profile is analyzed to study exposure-response relationships for effects of amatuximab on OS, PFS, ORR, DR, DCR, DDC and DPSM and hypersensitivity adverse events.

Eligibility

Inclusion Criteria

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

Have confirmed diagnosis of MPM with the following characteristics:

1. Unresectable disease (defined as the participant not being a candidate for curative surgery)
2. Epithelial type
3. Have an archived tissue sample to be submitted either as a formalin fixed paraffin-embedded (FFPE) tumor block, or 5 to 15 unstained slides

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

Have other significant medical conditions well-controlled and stable in the opinion of the investigator for at least 30 days prior to Day 1

Have an ECOG Performance Status 0 or 1 at Screening

Have a life expectancy of at least 3 months, as estimated by the investigator

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

1. Absolute neutrophil count greater than or equal to 1.5 x 109/L
2. Platelet count greater than or equal to 100 x 109/L
3. Hemoglobin greater than or equal to 9 g/dL
4. 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.)
5. Aspartate aminotransferase less than or equal to 3 x ULN
6. Alanine aminotransferase less than or equal to 3 x ULN
7. Alkaline phosphatase less than or equal to 3 x ULN

Have a calculated serum creatinine clearance greater than or equal to 45 mL/min using the Cockcroft-Gault equation

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 (ie, 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.

Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (ie, 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.

Be willing and able to provide written informed consent

Be willing and able to comply with all aspects of the protocol

Exlcusion Criteria

Have any history of the following:

1. 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
2. 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

Currently have mesothelioma of the sarcomatous type, mixed histologic disease, or have malignant peritoneal mesothelioma

Have confirmed presence of central nervous system metastases

Active viral hepatitis or active human immunodeficiency virus infection

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

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)

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).

Have known intolerance to the Test Article (ie, documented hypersensitivity AE to prior monoclonal antibody therapy, or to amatuximab or any of its excipients)

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

Have any medical or other condition that in the opinion of the investigator(s) would preclude the participant’s participation in a clinical study

Are scheduled for debulking surgery during the study

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