TAK-580 In Gliomas and Other Tumors

• ClinicalTrials.gov Identifier: NCT03429803
• Recruitment Status: Active, not recruiting
• First Posted: February 12, 2018
• Last Update Posted: September 11, 2019
• Sponsor: Karen D. Wright MD
• Collaborators: PALGA foundation; Millennium Pharmaceuticals, Inc.; National Cancer Institute (NCI); Pacific Pediatric Neuro-Oncology Consortium; Team Jack Foundation
• Information provided by (Responsible Party): Karen D. Wright MD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

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)

Condition or disease	Intervention/treatment	Phase
Low-grade Glioma	Drug: TAK-580	Phase 1; Phase 2

Detailed Description:

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved TAK-580 as a treatment for any disease.

This is the first time that TAK-580 will be given to children. There is limited experience with TAK-580 in humans.

The purpose of this study is to test the safety TAK-580 in children and adolescent participants with brain tumors. The investigators want to find out what effects, good and/or bad, it has on participants and the participant's brain tumor, and find the dose of TAK-580 that is tolerated by participants without too many side effects to use in Phase II of the study.

Research in the laboratory has shown that TAK-580 may have activity against cancer cells. TAK-580 belongs to a group of drugs called type II BRAF inhibitors. BRAF abnormalities are found in cancer cells. There are no type II BRAF inhibitors approved by the FDA for humans at the time of this study's start. TAK-580 functions by locking the mutant BRAF molecule and the next molecule in the activation chain together so that the signal that tells the tumor cell to divide is blocked.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II and Target Validation Study of TAK-580 (MLN2480) for Children With Low-Grade Gliomas and Other RAS/RAF/MEK/ERK Pathway Activated Tumors
• Actual Study Start Date: February 27, 2018
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: TAK-580 (MLN2480); Phase I; Patients (< 18 years) with radiographically recurrent or radiographically progressive non-hematologic malignancies (Central Nervous System (CNS) or solid tumors) associated with activation of the RAS/RAF/MEK/ERK pathway will be eligible; Study treatment cycle lasts 28 days,oral, once a week	Drug: TAK-580; 28 day cycle, oral, once per week; Other Name: MLN2480
Experimental: TAK-580 (MLN2480) Stratum I; Phase II; Patients with radiographically recurrent or radiographically progressive low grade glioma (LGG) containing a BRAF truncated fusion lesion (KIAA1549 or similar translocations) not previously treated with a BRAF or MEK inhibitor; Study treatment cycle lasts 28 days,oral, once a week	Drug: TAK-580; 28 day cycle, oral, once per week; Other Name: MLN2480
Experimental: TAK-580 (MLN2480) Stratum II; Phase II; Patients with Neurofibromatosis 1(NF1) defined clinically OR genetically, and radiographically recurrent or radiographically progressive LGG not previously treated with a BRAF or MEK inhibitor; Study treatment cycle lasts 28 days,oral, once a week	Drug: TAK-580; 28 day cycle, oral, once per week; Other Name: MLN2480

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: Greater and equal 28 days ]
   A DLT is defined as an AE or abnormal laboratory value assessed as at least possibly related to the study medication, which occurs ≤ 28 days following the first dose of TAK-580 (Cycle 1)
2. Progression free survival [ Time Frame: 6 months ]
   Strata 1 and 2

Secondary Outcome Measures :

1. • Blood samples for TAK-580 concentration measurements (i.e. pharmacokinetic measures) [ Time Frame: cycle 1: pre-dose, 1, 2, 3, 4, 5, 6, 24 and 120 hours post Day 1 dose; cycle 1: day 15 pre-dose; all other cycles: day 1 pre-dose; end of therapy or at time of toxicity requiring patient be taken off study or dose held; time of surgery if applicable) ]
   measurement of phosphorylated ERK in peripheral blood mononuclear cells, will be performed on all patients in the phase I component of the trial
2. Tumor response [ Time Frame: 48 Weeks ]
   Tumor response as determined by measurement of the longest tumor dimension and its perpendicular for each central nervous system target lesion. Response Evaluation Criteria In Solid Tumors (RECIST) will be applied to solid tumors. Response criteria for identified lesions are then assigned complete, partial, stable or progressive designations.
3. Complete Response Rate (Stratum 1) [ Time Frame: 48 Weeks ]
   pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
4. Partial Response Rate (Stratum 1) [ Time Frame: 48 Weeks ]
   pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
5. Stable Disease Rate (Stratum 1) [ Time Frame: 48 Weeks ]
   pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
6. Progression Free Survival Rate (Stratum 1) [ Time Frame: 48 Weeks ]
   pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
7. Overall Survival Rate (Stratum 1) [ Time Frame: 48 Weeks ]
   pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
8. Complete Response Rate (Stratum 2) [ Time Frame: 48 Weeks ]
   pediatric patients (>1 year and <18 years of age) with Neurofibromatosis 1 (NF1) and radiographically recurrent or radiographically progressive LGG (Stratum 2)
9. Partial Response Rate (Stratum 2) [ Time Frame: 48 Weeks ]
   pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
10. Stable Disease Rate (Stratum 2) [ Time Frame: 48 Weeks ]
    pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
11. Progression Free Survival (Stratum 2) [ Time Frame: 48 Weeks ]
    in pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
12. Overall Survival Rate (Stratum 2) [ Time Frame: 48 Weeks ]

    pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)

    pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)

    pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2

13. Number of participants with adverse events (phase 1) [ Time Frame: 48 Weeks ]
    Frequency of adverse events (AEs) with once weekly administration of TAK-580
14. Number of participants with serious adverse events [ Time Frame: 48 weeks ]
    Frequency of serious adverse events (SAEs) with once weekly administration of TAK-580

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 (Central Nervous System (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 Neurofibromatosis 1 (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., United States Protection and Investigations (USPI), Summary of Product Characteristics (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 central serous retinopathy (CSR), retinal vein occlusion (RVO), 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.

Contacts and Locations

Locations

United States, Massachusetts

Massacusetts General Hospital

Boston, Massachusetts, United States, 02114

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

Dana-Farber Cancer Institite

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Karen D. Wright MD

PALGA foundation

Millennium Pharmaceuticals, Inc.

National Cancer Institute (NCI)

Pacific Pediatric Neuro-Oncology Consortium

Team Jack Foundation

Investigators

• Principal Investigator: Karen D. Wright, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Karen D. Wright MD, Sponsor Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03429803
• Other Study ID Numbers: 17-589; P50CA165962 ( U.S. NIH Grant/Contract ); PNOC 014 ( Other Identifier: Pacific Pediatric Neuro-Oncology Consortium )
• First Posted: February 12, 2018
• Last Update Posted: September 11, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Karen D. Wright MD, Dana-Farber Cancer Institute:

low-grade glioma

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue