Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine for Mesothelin Expressing Lung Adenocarcinoma
Condition: Lung Neoplasms
MeSH terms: Adenocarcinoma; Lung Neoplasms; Adenocarcinoma of Lung
Intervention: Anetumab Ravtansine; Blood test
Intervention description: Administered intravenously (IV) every 3 weeks; Research blood test for eligibility
Intervention MeSH terms: Maytansine; Anetumab ravtansine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Lung Adenocarcinoma; Immunotoxin; Immunotherapy

Summary:

      Background:

      Anetumab ravtansine is a new drug. It kills cancer cells that carry mesothelin. That is a
      protein on the surface of tumor cells in many types of tumors, including most lung cancers.
      Researchers want to find a safe dose for the study drug for lung cancer. They want to see if
      it can shrink tumors in mesothelin-positive lung cancer.

      Objectives:

      To test the safety and effectiveness of anetumab ravtansine for lung cancer.

      Eligibility:

      Adults 18 years and older who have lung cancer that has gotten worse on other therapy

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Tumor tissue sample. This can be from a previous procedure.

      Blood and urine tests

      Heart tests

      Scans. For one scan, a small amount of radioactive substance is injected into the blood.

      Eye exam

      The study will have 21-day cycles.

      On day 1 of each cycle, participants will get the study drug through a tube inserted in a
      vein.

      Participants will repeat a heart test in cycles 1 and 2.

      They will have blood tests weekly in cycle 1, twice in all other cycles.

      They will have scans every 6 weeks for the first 6 months, every 9 weeks until the end of
      year 2, then every 12 weeks.

      Participants will have samples of tumor tissue taken twice.

      About 30 days after stopping the study drug, participants will have a follow-up visit. This
      will include medical history, physical exam, blood and pregnancy tests, and heart and eye
      tests.

      Some will be called a few times a year to discuss their health and treatment.
    

Eligibility criteria:

        -  INCLUISION CRITERIA:

        Subjects must have histologically or cytologically confirmed previously treated
        unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or IV) as
        confirmed by the Laboratory of Pathology, National Cancer Institute (NCI)

        Subjects must have positive mesothelin expression in the archival tumor tissue, defined as
        the mesothelin membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on the
        membrane of greater than or equal to 10% of tumor cells.

        Subjects must provide sample of archival tumor tissue (tissue block preferred, at least 5
        formalin-fixated, paraffin-embedded [FFPE] slides acceptable) collected any time before the
        general screening. A fresh biopsy will be collected if archival sample is unavailable or
        insufficient.

        Subjects must have measurable disease, defined as at least one lesion that can be
        accurately measured in at least one dimension (longest diameter to be recorded for nonnodal
        lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10
        mm with spiral computed tomography (CT) scan. See Section 6.3 for the evaluation of
        measurable disease.

        Subjects with resected primary tumors who have documented metastases are eligible.

        Subjects should have received at least one prior platinum based chemotherapy and an immune
        checkpoint targeted agent. Subjects with epidermal growth factor receptor [EGFR]-mutated
        and anaplastic lymphoma kinase [ALK]-translocated non-small cell lung cancer (NSCLC) should
        have received Food and Drug Administration (FDA)-approved targeted therapies as
        appropriate.

        Age >18 years. Because no dosing or adverse event data are currently available on the use
        of anetumab ravtansine in subjects <18 years of age, children are excluded from this study.

        Eastern Cooperative Oncology Group (ECOG) performance status < or equal to 2

        Subjects must have adequate bone marrow function as assessed by the following laboratory
        test results:

          -  Hemoglobin greater than or equal to 9.0 g/dL or greater than or equal to 5.6 mmol/L

          -  Absolute neutrophil count (ANC) greater than or equal to 1,500/mm^3 or greater than or
             equal to 1.5 x 10^9/L

          -  Platelet count greater than or equal to 100,000/mm^3 or greater than or equal to 100 x
             10^9/L

        Subjects must have adequate kidney function, with serum creatinine <1.5 x ULN or calculated
        glomerular filtration rate (GFR) of > 45/mL/min/1.73 m^2

        Subjects must have adequate liver function as assessed by the following laboratory test
        results:

          -  Total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3.0 times upper
             limit of normal (ULN) in subjects without liver metastases or 5.0 times ULN in
             subjects with liver metastases

        Subjects must have adequate coagulation, as assessed by the following laboratory test
        results:

          -  International normalized ratio (INR) or prothrombin time (PT) less than or equal to
             1.5 x ULN

          -  Partial thromboplastin time (PTT) less than or equal to 1.5 x ULN

        Due to the lack of adequate reproductive toxicity data on anetumab ravtansine, subjects
        must use 2 forms of highly effective contraception concomitantly from the initiation of
        study therapy until 6 months after the last dose of study therapy. Additionally, the use of
        condoms is required. It should also be noted that, where 2 forms of effective contraception
        are required, a subject may choose to use a double-barrier method consisting of condom and
        cervical occlusive cap / diaphragm with spermicide

        Ability of subject to understand and the willingness to sign a written informed consent
        document.

        Subjects must provide a signed informed consent before any screening procedures.

        EXCLUSION CRITERIA:

        Subjects who have a previous or concurrent cancer that is distinct in primary site or
        histology from lung adenocarcinoma, except cervical carcinoma in situ, treated basal cell
        carcinoma, superficial noninvasive bladder tumors or any previous cancer curatively treated
        <2 years before the start of study treatment.

        Subjects who have a history or current evidence of bleeding disorder, i.e. any
        hemorrhage/bleeding event of Common Terminology Criteria in Adverse Events (CTCAE) Grade
        greater than or equal to 2 within 4 weeks before the start of study treatment.

        History of symptomatic metastatic brain or meningeal tumors unless the subject is > 3
        months from definitive therapy and has no evidence of tumor growth on an imaging study
        within 2 weeks prior to study entry. Subjects with brain metastases must not be undergoing
        acute corticosteroid therapy or steroid taper. Chronic steroid therapy is acceptable
        provided that the dose is stable for one month prior to screening.

        Subjects who have a history or current evidence of uncontrolled cardiovascular disease
        including but not limited to the following conditions:

          -  Congestive heart failure of New York Heart Association (NYHA) Class III or IV

          -  Unstable angina (symptoms of angina at rest) or new-onset angina within <3 months
             before the start of study treatment.

          -  Arterial thrombosis, deep vein thrombosis, or pulmonary embolism within <3 months
             before the start of study treatment.

          -  Myocardial infarction or stroke within <3 months before the start of study treatment.

          -  Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade greater than or
             equal to 2) or pleural effusion (CTCAE Grade greater than or equal to 2)

          -  Cardiac arrhythmia requiring anti-arrhythmic therapy. Subjects receiving digoxin,
             calcium channel blockers except verapamil, or beta-adrenergic blockers except
             propranolol are eligible at the investigators discretion if the dose has been stable
             for at least 2 weeks before the start of study treatment. Subjects with sinus
             arrhythmia and infrequent premature ventricular contractions are eligible at the
             investigators discretion.

        Subjects who have a left ventricular ejection fraction (LVEF) <50%, as assessed by
        echocardiogram performed at screening.

        Subjects who have a corrected Q wave, T wave (QT) (corrected QT interval by Fredericia
        (QTcF)) interval >480 ms (CTCAE Grade >1) determined by the electrocardiogram (ECG)
        recorders algorithm on the screening ECG.

        Subjects who have a history or current evidence of uncontrolled hypertension defined as
        systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg at screening despite
        optimal medical management. Subjects with a history of mild to moderate

        hypertension are eligible at the investigator s discretion if the hypertension is
        adequately controlled by antihypertensive treatment used at a stable dose for at least 2
        weeks before the start of study treatment.

        Subjects who have a heart rate greater than or equal to 100 beats per minute (bpm) or less
        than or equal to 45 bpm determined by the ECG recorder s algorithm on the screening ECG.

        Women who are pregnant or breast-feeding. Women of reproductive potential must have a
        negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test obtained within
        7 days before the start of study treatment.

        Subjects who have had a major surgery or significant trauma within 4 weeks before the start
        of study treatment.

        Subjects who have had solid organ or bone marrow transplantation.

        Subjects who have a history of hypersensitivity to any of the study drugs or their
        excipients, or a history of severe hypersensitivity to any other antigen.

        Subjects who have a history of human immunodeficiency virus (HIV) infection or subjects who
        have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring
        treatment due to a theoretical concern that the degree of immune suppression associated
        with the treatment may result in progression of HIV infection. Subjects with chronic HBV or
        HCV infection are eligible at the investigators discretion if the subject is considered
        non-infectious based on serological markers.

        Subjects who have an active clinically serious infection of CTCAE Grade greater than or
        equal to 2.

        Subjects with a non-healing serious wound, ulcer, or bone fracture unrelated to the primary
        tumor.

        Subjects with corneal epitheliopathy or any eye disorder that may predispose the subjects
        to drug-induced corneal epitheliopathy, or may interfere with diagnosis of
        treatment-emergent corneal epitheliopathy at the discretion of the investigator in
        consultation with the ophthalmologist/optometrist. Low grades of superficial punctate
        keratitis, within the range seen in the normal population, should not lead to the exclusion
        of the patient

        Subjects experiencing unresolved toxicity of previous antitumor therapy which is CTCAE
        Grade >1 before the start of study treatment, except for alopecia or hemoglobin greater
        than or equal to 9.0 g/dL or greater than or equal to 5.6 mmol/L.

        Subjects with any clinical condition that is considered unstable or might jeopardize the
        safety of the subject and/or influence the subjects compliance in the study.

        Subjects who have received systemic anticancer therapy within 3 weeks before the start of
        study treatment. Mitomycin C or nitrosoureas must be excluded within 6 weeks before the
        start of study treatment.

        Subjects who have received radiotherapy to tumor lesions that would be chosen as target
        lesions (measurable disease) within 4 weeks before the start of treatment, except if there
        is objective evidence of progression of the lesion by Response Evaluation Criteria in Solid
        Tumors (RECIST) 1.1 between the

        prior radiotherapy and the screening computed tomography (CT) or magnetic resonance imaging
        (MRI) scan. Palliative radiotherapy to nontarget lesions is allowed at the investigators
        discretion.

        Use of drugs that inhibit renal tubular secretion (e.g. probenecid and cimetidine) within 2
        weeks before the start of study treatment.

        Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 2
        weeks before the start of study treatment.

        Subjects who have previously received anetumab ravtansine.

        Subjects who are concurrently receiving any other investigational agents.