Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, 2-Part, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Proof-of-concept, Dose-finding Study Evaluating the Efficacy and Safety of CNTO 136 Administered Subcutaneously in Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy
Brief Summary: The purpose of this study is to evaluate the effectiveness and safety of subcutaneous (under the skin) administration of anti-interleukin-6 monoclonal antibody (CNTO 136) in reducing signs and symptoms of participants with active rheumatoid arthritis (RA) with methotrexate (MTX) therapy.


Options:
A: Inclusion Criteria:

* Diagnosed with rheumatoid arthritis (RA) for at least 4 months prior to screening
* Have been treated and having an inadequate response with the tolerated dose of methotrexate (MTX) (at least 15mg/week) for at least 4 months prior to screening. MTX doses of 10 or 12.5 mg/week are allowed if participant had intolerance of 15 mg/week
* MTX route of administration and dose (not to exceed 25 mg/week) should be stable for at least 6 weeks prior to the start of the study medication
* Have active RA as defined by persistent disease activity with at least 6 swollen and 6 tender joints, at the time of screening and baseline, and either anti-cyclic citrullinated peptide antibody-positive or rheumatoid factor positive at screening
* C-reactive protein greater than or equal to 1.0 mg/dL (10 mg/L)
* Agree to use one of the contraception methods defined in the protocol

Exclusion Criteria:

* Have inflammatory diseases other than RA that might confound the evaluation of the benefit of CNTO 136 therapy in arthritis
* Family history of/ have long QT syndrome; or a history of second or third-degree heart block
* Received systemic immunosuppressives or disease modifying antirheumatic drug other than MTX, sulfasalazine, hydroxychloroquine or chloroquine within 4 weeks prior to the start of study medication
* Received intra articular (into joints), intramuscular, or intravenous corticosteroids within 4 weeks prior to the start of study medication
* Positive human immunodeficiency virus test, hepatitis B or hepatitis C
* History of / have chronic or recurrent infectious disease, history of / active tuberculosis
* Have serious infection within 2 months prior to start of study medication
B: Inclusion Criteria:

* Histologically or cytologically confirmed MM
* Have received only one prior systemic chemotherapy platinum-based regimen for advanced MM
* Measurable disease, defined at least 1 unidimensionally measurable lesion \> 20 mm by conventional techniques or \> 10 mm by spiral CT scan (modified RECIST criteria)
* Disease not amenable to curative surgery
* No known brain metastasis
* Age 18 and over
* Performance status 0-2
* Life expectancy \> 12 weeks
* Adequate hematologic, hepatic and renal function
* Platelet count \> 75000/mm3
* Absolute granulocyte count \> 1000/mm3
* Hemoglobin \> 9 g/dL
* Bilirubin total \< 1.5 x ULN (Upper limited normal), except patients with documented Gilbert's syndrome, who must have a total bilirubin \< 3.0 mg/dl
* AST and ALT \< 2.5 x ULN ( \< 5 x ULN if documented liver metastasis are present)
* Creatinine level \< 2mg/dl or calculated creatinine clearance \> 60 mL/min as determined by the Cockcroft Gault equation.
* Not pregnant or nursing
* Fertile patients must use effective contraception
* Patient must be willing and able to provide written informed consent, and the trial have to be approved by the institutional review board at each institution

Exclusion Criteria:

* Symptomatic chronic inflammatory or autoimmune disease
* Active hepatitis B or C
* Prior treatment with tremelimumab or other anti-CTLA-4 antibody or anti-PD1, anti-PDL-1 agents
* Clinically relevant cardiovascular disease
* History of psychiatric disabilities, potentially interfering with the capability of giving adequate informed consent
* Uncontrolled active infections
* Other concurrent chemotherapy, immunotherapy, radiotherapy or investigational agents
* History of other malignancies except for adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma of cervix, unless the patient has been disease-free for at least 5 years
C: Inclusion Criteria:

1. Histologically confirmed diagnosis of soft tissue sarcoma of high or intermediate grade with one of the following histological subtypes:

   * Adipocytic sarcoma, including:
   * Dedifferentiated
   * Myxoid
   * Round Cell
   * Pleomorphic - Leiomyosarcoma
2. Documented evidence of advanced (locally recurrent, locally advanced and/or metastatic) adipocytic (restricted to subtypes listed in Inclusion 1) or leiomyosarcoma, incurable by surgery and/or radiotherapy.
3. Subjects should have received at least two standard systematic regimens for advanced soft tissue sarcoma one of which must have included an anthracycline (unless contraindicated).
4. Radiographic evidence of disease progression by RECIST criteria on or after the last anti-cancer therapy within the 6 months prior to randomization.
5. Presence of measurable disease meeting the following criteria:

   * At least one lesion of greater than or equal to 1.0 cm in long-axis diameter for non lymph nodes or greater than or equal to 1.5 cm in short-axis diameter for lymph nodes which is serially measurable according to RECIST 1.1 using either computerized tomography or magnetic resonance imaging or panoramic and close-up color photography.
   * Lesions that have had radiotherapy must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
6. Eastern Cooperative Oncology Group, performance status of 0, 1 or 2.
7. Adequate renal function defined as calculated creatinine clearance greater than 50 mL/min per the Cockroft and Gault formula.
8. Adequate bone marrow function, defined as:

   * Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 or greater than or equal to 1.5 x 10\^9/L.
   * Platelet count greater than or equal to 100,000/mm3 or greater than or equal to 100 x 10\^9/L.
   * Hemoglobin (Hb) greater than or equal to 10g/dL at baseline (blood transfusions,hematopoietic growth factors and hematinics are allowed during the Prerandomization Phase to correct Hb values less than 10g/dL).
9. Adequate liver function, defined as:

   * Bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
   * Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN. For total ALP greater than 3 times ULN, the ALP liver isoenzyme must be less than or equal to 3 times ULN.
10. All female subjects will be considered to be of child-bearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically (i.e., bilateral tubal ligation greater than or equal to 1 menstrual cycle prior to randomization, or have undergone a hysterectomy and/or bilateral oophorectomy).

    Female subjects of child-bearing potential must agree to use two forms of highly effective contraception from the last menstrual period prior to randomization (or use a double barrier method as described below until they are on two forms of highly effective contraception for at least one menstrual cycle), during the study treatment, and for 3 months after the final dose of study treatment. Female subjects exempt from this requirement are subjects who practice total abstinence. If currently abstinent, the subject must agree to use a double barrier method of contraception, i.e., condom and occlusive cap (diaphragm or cervical/vault caps) with spermicide or until they are on two forms of highly effective contraception for at least one menstrual cycle if they become sexually active during the study treatment and for 3 months after the final dose of study treatment. Highly effective contraception includes:
    * Placement of intrauterine device or system,
    * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) with spermicide,
    * Established hormonal contraceptive methods: oral, injectable or implant. Female subjects who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product from the last menstrual period prior to randomization, and must continue to use the same hormonal contraceptive product during study treatment, and for 3 months after the first dose of study treatment.
    * Vasectomized partner with confirmed azoospermia.
11. Male subjects and their female partner who are of child-bearing potential (as defined in Inclusion 10), and are not practicing total abstinence, must agree to use two forms of highly effective contraception from the last menstrual period of their female partner prior to randomization (or use a double barrier method as described above until they are on two forms of highly effective contraception for at least one menstrual cycle), during study treatment, and for 3 months (or 6 months if they received dacarbazine) after the final dose of study treatment. If currently abstinent, must agree to use a double barrier method of contraception if they become sexually active, or until they are on two forms of highly effective contraception as described above.
12. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
13. Males or females aged greater than or equal to 18 years at the time of informed consent.

Exclusion Criteria:

1. Subjects who have received any anti-cancer therapy, including radiotherapy, cytotoxic, hormonal, biological (including humanized antibodies) and targeted agents within 21 days, or five half-lives of the drug (whichever is longer) prior to randomization.
2. Subjects who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than or equal to Grade 1, according to Common Terminology Criteria for Adverse Events (CTCAE), except for peripheral neuropathy (see Exclusion 6) and alopecia.
3. Subjects that have previously been treated with dacarbazine or its analogue temozolomide or eribulin.
4. Major surgery within 21 days prior to randomization.
5. Pre-existing peripheral neuropathy greater than CTCAE Grade 2.
6. Significant cardiovascular impairment, defined as:

   * Cardiac failure, New York Heart Association (NYHA) Class II according to the NYHA Functional Classification,
   * Unstable angina or myocardial infarction within 6 months of enrolment,
   * Serious and potentially life-threatening arrhythmia.
7. Subjects with a high probability of Long QT Syndrome or QTc interval prolongation of more than or equal to 501 msec on at least two separate ECGs, following correction of any electrolyte imbalance.
8. Subjects with known central nervous system metastases.
9. Any serious concomitant illness or infectious disease requiring treatment, or infectious disease not requiring treatment, but with significant risks for myelosuppressive complications associated with chemotherapy.
10. Any malignancy that required treatment, or has shown evidence of recurrence (except for soft tissue sarcoma, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to randomization.
11. Female subjects must not be pregnant as documented by a negative beta-human chorionic gonadotropin (beta-hCG) test with a minimum sensitivity 25 IU/L or equivalent unit of beta-hCG at Screening and Baseline, or breastfeeding.
12. Hypersensitivity to the active substance, or any of the excipients of the eribulin drug product, or dacarbazine, (please refer to the dacarbazine prescribing information).
13. Any medical or other condition which, in the opinion of the PI or designee, will preclude participation in a clinical trial.
D: DISEASE CHARACTERISTICS:

* Histologically confirmed localized Ewing's sarcoma or peripheral primitive neuroectodermal tumor (PNET) of the bone or soft tissues

  * Diagnostic biopsy of primary tumor within 30 days of study
* Paraspinal or bony skull tumors of extradural origin allowed

  * No intradural soft tissue tumors
* Askin's tumor of the chest wall allowed

  * Chest wall tumors with ipsilateral pleural effusions or ipsilateral pleural-based secondary tumor nodules allowed
  * No contralateral pleural effusions
* No metastatic disease or distant node involvement

  * One pulmonary or pleural nodule greater than 1 cm in diameter OR more than 1 nodule greater than 0.5 cm in diameter are considered pulmonary metastasis
  * Solitary lung nodules of 0.5-1 cm OR multiple nodules of 0.3-0.5 cm allowed unless biopsy positive for tumor
* Light microscopic appearance (hematoxylin and eosin stained) consistent with Ewing's sarcoma or peripheral PNET
* No immunohistochemical or ultrastructural evidence of rhabdomyosarcoma
* No esthesioneuroblastoma
* Clinically or pathologically involved regional lymph nodes allowed
* No CNS involvement

PATIENT CHARACTERISTICS:

Age:

* 50 and under at diagnosis

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* Not specified

Hepatic:

* Bilirubin no greater than 1.5 mg/dL

Renal:

* Creatinine normal for age
* Creatinine clearance or isotope glomerular filtration rate at least 75 mL/min

Cardiovascular:

* Shortening fraction at least 28% by echocardiography OR
* Ejection fraction at least 55% by radionuclide angiogram

Other:

* Not pregnant or nursing
* Fertile patients must use effective contraception
* No other prior malignancy except skin cancer diagnosed at least 5 years ago and currently in remission

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior immunotherapy for skin cancer
* No concurrent sargramostim (GM-CSF)
* No concurrent pegfilgrastim

Chemotherapy:

* No prior chemotherapy

Endocrine therapy:

* Not specified

Radiotherapy:

* No prior radiotherapy

Surgery:

* Prior complete or partial excision of primary tumor allowed

Answer: A