TAK-580 In Gliomas and Other Tumors

Status: Recruiting
Phase:
DFCI Protocol ID: 17-589

This research study is studying a drug TAK-580 (MLN2480) as a possible treatment a low-grade glioma that has not responded to other treatments. The name of the study drug involved in this study is: • TAK-580 (MLN2480)

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

Inclusion Criteria:

  -  Participants must meet the following criteria on screening examination to be eligible
     to participate in the study:

       -  Phase I

    -  Pediatric patients with radiographically recurrent or radiographically
       progressive non-hematologic malignancies (CNS or solid tumors) associated
       with activation of the RAS/RAF/MEK/ERK pathway will be eligible.

    -  Mutational status requires a pathology report, genomic sequencing, or
       immunohistochemical report of a mutation or activation of the
       RAS/RAF/MEK/ERK pathway.

       -  Phase II

    -  Mutational status requires a pathology report, genomic sequencing, or
       immunohistochemical report of a mutation or activation of the
       RAS/RAF/MEK/ERK pathway.

    -  Patients with measurable radiographically recurrent or radiographically
       progressive disease that is measureable in at least two dimensions on
       imaging after standard up-front therapy as defined in the following three
       strata below will be eligible:

 -  Stratum 1: Patients with radiographically recurrent or radiographically
    progressive low-grade gliomas with a BRAF KIAA1549 (or similar)
    truncated fusion duplication not previously treated with a BRAF or MEK
    inhibitor

 -  Stratum 2: Patients with NF1 and radiographically recurrent or
    radiographically progressive LGG (NF1 may be defined clinically - see
    Appendix S - OR genetically) not previously treated with a BRAF or MEK
    inhibitor

 -  Stratum 3: Patients with radiographically recurrent or radiographically
    progressive tumors thought to involve the RAS/RAF/MEK/ERK pathway but
    not included in Stratum 1 or 2. This includes any radiographically
    recurrent or radiographically progressive LGG not included in Stratum 1
    or 2 (i.e., any LGG without a BRAF truncated fusion in a patient
    without NF1), any CNS tumor other than LGG in a patient with NF1, and
    any other CNS or solid tumor (regardless of grade) with a documented
    activating BRAF, NRAS, or KRAS mutation

    -  Tumor tissue for correlative studies is required for all patients except
       those with NF1 and LGG (stratum 2) unless surgery was performed prior to
       enrollment or any patient with optic pathway glioma (stratum 2 or 3), for
       whom tumor tissue is optional

    -  Patients must have received at least one prior chemotherapy or radiation
       regimen prior to radiographic progression.

    -  Patients for whom tumor biopsy and/or resection is clinically indicated and
       who are eligible for and enrolled on the phase II component (any stratum)
       will also be eligible for the optional target validation stratum.

    -  Tumor must be measurable in at least two dimensions on imaging.

       -  The remaining criteria apply for all phases:

    -  Patients must be >1 year and <18 years old.

    -  Patients must have adequate performance status:

 -  Karnofsky ≥ 50 for patients ≥ 16 years of age (See Appendix A).

 -  Lansky ≥ 50 for patients < 16 years of age (See Appendix A).

    -  Patients who are unable to walk because of paralysis, but who are up in a
       wheelchair, will be considered ambulatory for the purpose of assessing the
       performance score (See Appendix A).

    -  A patient with low grade glioma who has failed standard therapy.

    -  At least 1 measurable lesion that can be reproducibly measured in 2
       dimensions

    -  Previous chemotherapy and hormone therapy (excluding physiologic
       replacement) must be completed at least 4 weeks or 4 half-lives, whichever
       is longer, prior to administration of TAK-580.

    -  Previous immunotherapy/ monoclonal antibody use must be completed at least 4
       weeks or 4 half lives, whichever is longer prior to administration of
       TAK-580. In addition, radiation therapy to the target lesion must be
       completed at least 6 months prior to administration of TAK-580. All
       associated toxicity from previous therapies must be resolved to ≤ Grade 1 or
       considered baseline prior to administration of TAK-580.

    -  Female patients who:

 -  Are postmenopausal for at least 1 year before the screening visit, OR

 -  Are surgically sterile, OR

 -  If they are of childbearing potential, agree to practice 1 effective
    method of contraception and 1 additional effective (barrier) method, at
    the same time, from the time of signing the informed consent through 90
    days (or longer as mandated by local labeling [e.g., USPI, SmPC, etc,])
    after the last dose of study drug, OR

 -  Agree to practice true abstinence, when this is in line with the
    preferred and usual lifestyle of the patient. (Periodic abstinence
    [e.g., calendar, ovulation, symptothermal, postovulation methods],
    withdrawal, spermicides only, and lactational amenorrhea are not
    acceptable methods of contraception. Female and male condoms should not
    be used together.)

    -  Male patients, even if surgically sterilized (i.e., status post-vasectomy),
       who:

 -  Agree to practice highly effective barrier contraception during the
    entire study treatment period and through 120 days after the last dose
    of study drug, OR

 -  Agree to practice true abstinence, when this is in line with the
    preferred and usual lifestyle of the patient. (Periodic abstinence
    [e.g., calendar, ovulation, symptothermal, postovulation methods for
    the female partner], withdrawal, spermicides only, and lactational
    amenorrhea are not acceptable methods of contraception. Female and male
    condoms should not be used together.)

 -  Agree not to donate sperm during the course of this study or within 120
    days after receiving their last dose of study drug

    -  Patient must be able to swallow pills whole.

    -  Patient, parent, or legal guardian must be able to understand and be willing
       to provide informed consent.

    -  Thyroid function tests must be consistent with stable thyroid function.
       Patients on a stable dose of thyroid replacement therapy for a suggested
       minimum of 3 weeks before Cycle 1, Day 1 are eligible.

    -  Left ventricular ejection fraction (LVEF) of 50% or greater, as measured by
       echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan, within 28
       days before the first dose of TAK-580

    -  Inclusion of Women, Minorities, and Other Underrepresented Populations: This
       protocol is open to males and females of all races. See inclusion criteria
       above regarding specific eligibility requirements for female and male
       patients of child-bearing or child-fathering potential, respectively.

  -  Exclusion Criteria: Patients with any of the following characteristics will NOT be
     eligible:

       -  Patients with clinical progression but without radiographically recurrent or
  radiographically progressive disease.

       -  History of any major disease that might interfere with safe protocol
  participation, as determined by the investigator

       -  Patients with a history or current evidence of CSR (central serous retinopathy),
  RVO (retinal vein occlusion), or ophthalmopathy present at baseline that would be
  considered a risk factor for CSR or RVO

       -  Laboratory values:

    -  Absolute neutrophil count (ANC) ≤ 1000/μL

    -  Platelet count ≤ 75,000/μL (transfusion independent)

    -  Hemoglobin < 9 g/dL (hemoglobin may be supported by transfusion,
       erythropoietin, or other approved hematopoietic growth factors)

    -  Serum bilirubin ≥ 1.5 × upper limit of normal (ULN) or ³ 2 ´ ULN if patient
       is known to have Gilbert's Disease as the only underlying hepatic disorder

    -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 ×
       ULN. AST and ALT ≥ 5 × ULN for patients with liver metastasis

    -  Serum creatinine ≥ 2.0 mg/dL

       -  Current enrollment in any other investigational treatment study

       -  Evidence of current uncontrolled cardiovascular conditions, including but not
  limited to clinically significant cardiac arrhythmias, congestive heart failure,
  angina, or myocardial infarction, within the past 6 months

       -  Active hepatitis or human immunodeficiency virus infection

       -  Active bacterial or viral infection

       -  Female patients who are pregnant or currently breastfeeding. Female patients of
  childbearing potential must have a negative serum pregnancy test prior to
  enrollment.

       -  Major surgery within 28 days of Day 1 (does not include central venous access or
  shunts)

       -  Inability to comply with study requirements

       -  Refractory nausea and vomiting, malabsorption, or significant bowel or stomach
  resection that would preclude adequate absorption of TAK-580

       -  Treatment with any of the strong CYP2C inducers within 14 days before the first
  dose of TAK-580 (see Appendix H).

       -  Treatment with gemfibrozil (strong CYP2C8 inhibitor) within 14 days before the
  first dose of TAK-580.

       -  Other unspecified reasons that, in the opinion of the investigator, make the
  patient unsuitable for enrollment.

       -  Important note: The eligibility criteria listed above are interpreted literally
  and cannot be waived.

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