Clinical Trials /

TAK-580 In Gliomas and Other Tumors

NCT03429803

Description:

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)

Related Conditions:
  • Glioma
  • Malignant Solid Tumor
  • Neurofibromatosis Type 1
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TAK-580 In Gliomas and Other Tumors
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 17-589
  • SECONDARY ID: P50CA165962
  • NCT ID: NCT03429803

Conditions

  • Low-grade Glioma

Interventions

DrugSynonymsArms
TAK-580MLN2480TAK-580 (MLN2480)

Purpose

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)

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.
    

Trial Arms

NameTypeDescriptionInterventions
TAK-580 (MLN2480)ExperimentalPhase 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
  • TAK-580
TAK-580 (MLN2480) Stratum IExperimentalPhase 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
  • TAK-580
TAK-580 (MLN2480) Stratum IIExperimentalPhase 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
  • TAK-580

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 (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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT)
Time Frame:Greater and equal 28 days
Safety Issue:
Description: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)

Secondary Outcome Measures

Measure:• 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)
Safety Issue:
Description:measurement of phosphorylated ERK in peripheral blood mononuclear cells, will be performed on all patients in the phase I component of the trial
Measure:Tumor response
Time Frame:48 Weeks
Safety Issue:
Description: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.
Measure:Complete Response Rate (Stratum 1)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
Measure:Partial Response Rate (Stratum 1)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
Measure:Stable Disease Rate (Stratum 1)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
Measure:Progression Free Survival Rate (Stratum 1)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
Measure:Overall Survival Rate (Stratum 1)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients with radiographically recurrent or progressive LGG characterized by BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1)
Measure:Complete Response Rate (Stratum 2)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients (>1 year and <18 years of age) with Neurofibromatosis 1 (NF1) and radiographically recurrent or radiographically progressive LGG (Stratum 2)
Measure:Partial Response Rate (Stratum 2)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
Measure:Stable Disease Rate (Stratum 2)
Time Frame:48 Weeks
Safety Issue:
Description:pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
Measure:Progression Free Survival (Stratum 2)
Time Frame:48 Weeks
Safety Issue:
Description:in pediatric patients (>1 year and <18 years of age) with NF1 and radiographically recurrent or radiographically progressive LGG (Stratum 2)
Measure:Overall Survival Rate (Stratum 2)
Time Frame:48 Weeks
Safety Issue:
Description: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
Measure:Number of participants with adverse events (phase 1)
Time Frame:48 Weeks
Safety Issue:
Description:Frequency of adverse events (AEs) with once weekly administration of TAK-580
Measure:Number of participants with serious adverse events
Time Frame:48 weeks
Safety Issue:
Description:Frequency of serious adverse events (SAEs) with once weekly administration of TAK-580

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mark W. Kieran, MD, PhD

Trial Keywords

  • low-grade glioma

Last Updated

April 2, 2018