Clinical Trials /

Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations

NCT02124772

Description:

This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors. Part A is a repeat dose, dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on the continuous dosing schedule using a 3 + 3 dose- escalation procedure. Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical assessment of progression of disease). Part C is will be a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part C will enroll up to 24 subjects. Part D will evaluate the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects diagnosed with LGG and LCH. LGG cohort will enroll approximately 20 response-evaluable subjects and the LCH cohort will enroll approximately 10 response-evaluable subjects. The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Related Conditions:
  • Glioma
  • Neurofibroma
  • Solid Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations
  • Official Title: An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations

Clinical Trial IDs

  • ORG STUDY ID: 116540
  • NCT ID: NCT02124772

Conditions

  • Cancer

Interventions

DrugSynonymsArms
TrametinibPart B
DabrafenibPart C

Purpose

This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors. Part A is a repeat dose, dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on the continuous dosing schedule using a 3 + 3 dose- escalation procedure. Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical assessment of progression of disease). Part C is will be a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part C will enroll up to 24 subjects. Part D will evaluate the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects diagnosed with LGG and LCH. LGG cohort will enroll approximately 20 response-evaluable subjects and the LCH cohort will enroll approximately 10 response-evaluable subjects. The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Trial Arms

NameTypeDescriptionInterventions
Part AExperimentalTrametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).
  • Trametinib
Part BExperimentalTumor-Specific Expansion: Trametinib is administered orally once daily under fasting conditions in 4 disease-specific cohorts of subjects Trametinib will be continued until disease progression.
  • Trametinib
Part CExperimentalThe trametinib dose administered in Part C will be the trametinib monotherapy RP2D from Part A. The monotherapy RP2D of dabrafenib in children will be established on a separate trial (BRF116013). The specifics for Part C will be determined following completion of enrollment into Part A.
  • Trametinib
  • Dabrafenib
Part DExperimentalThe trametinib and dabrafenib doses administered in Part D will be the combination trametinib and dabrafenib RP2D from Part C.
  • Trametinib
  • Dabrafenib

Eligibility Criteria

        Inclusion Criteria:

          -  General Eligibility Criteria (All Parts)

          -  Written informed consent - a signed informed consent and/or assent (as age
             appropriate) for study participation including PK sampling will be obtained according
             to institutional guidelines.

          -  Male or female between one month and <18 years of age (inclusive) at the time of
             signing the informed consent form (Part C and Part D between 12 months and <18 years
             of age, inclusive).

          -  Must have a disease that is relapsed/refractory to all potentially curative standard
             treatment regimens or must have a current disease for which there is no known curative
             therapy, or therapy proven to prolong survival with an acceptable quality of life.

          -  Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1]
             with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have
             relapsed after or failed to respond to frontline curative therapy or there must not be
             other potentially curative treatment options available. Curative therapy may include
             surgery, radiation therapy, chemotherapy, or any combination of these modalities. All
             subjects must have recovered to grade <=1 from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy
             includes; myelosuppressive chemotherapy, differentiating agents/ biologic response
             modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent),
             non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem
             cell transplantation or infusion, number of prior treatment regimens, colony
             stimulating factors, corticosteroids.

          -  Performance score of >=50% according to the Karnofsky/Lansky performance status scale.

          -  Females of child-bearing potential must be willing to practice acceptable methods of
             birth control. Additionally, females of childbearing potential must have a negative
             serum pregnancy test within 7 days prior to start of study drugs, throughout treatment
             period and for 4 months after last dose of study drugs.

          -  Must have adequate organ function as defined by the following values: renal function -
             24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular
             filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square
             (mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and
             gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN
             for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment
             and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac
             function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular
             ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.

          -  Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube)
             administered medication and does not have any clinically significant gastrointestinal
             abnormalities that may alter absorption such as malabsorption syndrome or major
             resection of the stomach or bowels.

          -  Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for
             age, height, and gender.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

          -  Specific Eligibility Criteria, Part A

          -  Subjects must meet general eligibility criteria.

          -  For the initial dose escalation to identify the maximum tolerable or PK target dose,
             age between 2 years and <18 years (inclusive) at the time of signing the informed
             consent form. Children < 2 years of age will be enrolled once the age specific
             expansion cohorts are open.

          -  Histologically confirmed solid tumors, which may include but are not limited to
             rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors,
             osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary
             brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the
             requirement for histological confirmation can be waived if a biopsy was not performed.
             For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the
             presence of consistent clinical and radiological findings, but should be considered if
             malignant degeneration of a PN is clinically suspected.

          -  Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by
             Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is
             only detected by bone marrow aspirate/biopsy or elevated homovanillic acid /
             vanillylmandelic acid (HVA/VMA) are not eligible.

          -  Adequate bone marrow function defined as absolute neutrophil count (ANC)
             >=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood
             cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined
             as not receiving platelet transfusions within a 7 day period prior to enrollment).

          -  Specific Eligibility Criteria, Part B

          -  Subjects must meet general eligibility criteria. The specific eligibility criteria
             listed here will apply to subjects enrolling to different cohorts of Part B.

          -  Tumor tissue (archived or fresh) is required and must be available to be shipped to
             GSK or site specific laboratory.

          -  Solid tumor cohort (B1) specific criteria

          -  B1: Refractory or relapsed neuroblastoma

          -  B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with
             fusion

          -  B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that
             are unresectable and medically significant.

          -  B4: BRAF V600 mutant tumors.

          -  Specific Eligibility Criteria, Part C - Subjects must meet general eligibility
             criteria.

          -  Tumors that have been documented by CLIA or equivalent certified laboratory test to
             harbor BRAF V600 mutation at diagnosis or relapse

          -  Measurable or evaluable disease

          -  Adequate bone marrow function

          -  Specific Eligibility Criteria, Part D - Subjects must meet general eligibility
             criteria

          -  Measurable or evaluable disease

          -  Recurrent or refractory BRAFV600 mutant LGG or LCH tumors

          -  Adequate bone marrow function

        Exclusion Criteria:

          -  Lactating or pregnant female.

          -  History of another malignancy including resected non-melanomatous skin cancer.

          -  Subjects with NF-1 associated optic pathway tumors are excluded if they are actively
             receiving therapy for the optic pathway tumor or do not meet criteria for PN or
             malignant solid tumor.

          -  Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).

          -  Subjects with NF-1 actively receiving therapy for the optic pathway tumor.

          -  Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis
             (only applicable to Part B).

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder or other
             conditions that could interfere with subject's safety, obtaining informed consent or
             compliance to the study procedures.

          -  Any prohibited medication(s), currently used or expected to be required.

          -  Any medications for treatment of left ventricular systolic dysfunction.

          -  Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF
             inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated
             kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients
             who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4.
             Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C
             or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy,
             as determined by the investigator.

          -  Administration of an investigational study treatment within 30 days preceding the
             first dose of study treatment(s) in this study.

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to study treatment or excipients that contraindicate their
             participation.

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones, or liver metastases).

          -  History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the
             prior 3 months.

          -  History of heparin-induced thrombocytopenia.

          -  History of interstitial lung disease or pneumonitis.

          -  History of or current evidence of retinal vein occlusion (RVO).

          -  For subjects with solid tumors that are not primary central nervous system (CNS)
             tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or
             untreated leptomeningeal or brain metastases or spinal cord compression are excluded.
             NOTE: Subjects previously treated for these conditions that have had stable CNS
             disease (verified with consecutive imaging studies) for >3 months, are asymptomatic
             and are not currently taking corticosteroids, or are on stable dose or decreasing of
             corticosteroids for at least 7 days prior to enrolment are permitted.

          -  A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
             Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.

          -  Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
             Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous
             anti-cancer therapy, except alopecia.

          -  Presence of active gastrointestinal (GI) disease or other condition that will
             interfere significantly with the absorption of drugs.

          -  A history or evidence of cardiovascular risk including: a QT interval corrected for
             heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of
             current clinically significant uncontrolled arrhythmias (clarification: Subjects with
             atrial fibrillation controlled for >30 days prior to dosing are eligible); a history
             of acute coronary syndromes (including myocardial infarction or unstable angina),
             coronary angioplasty, or stenting within 6 months prior to randomization; a history or
             evidence of current >=Class II congestive heart failure as defined by the New York
             Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators;
             abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects
             with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
             study). Subjects with moderate valvular thickening should not be entered on study.
             Subjects with prosthetic valves can be considered eligible provided they meet the
             criteria as stated above; Treatment refractory hypertension defined as a blood
             pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or
             above 95th age-specific percentile listed in protocol), which cannot be controlled by
             anti-hypertensive therapy.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety Assessment of trametinib as assessed by Adverse Events (AEs)
Time Frame:From screening up to 63 months
Safety Issue:
Description:Single 12-lead ECGs will be obtained to assess safety

Secondary Outcome Measures

Measure:PK Assessment of trametinib
Time Frame:Day 15 and Day 22
Safety Issue:
Description:PK parameters including Ctau (trough concentration), area under the concentration-time curve over a period of time (AUC [0-t]), area under the concentration-time curve over the dosing interval (AUC [0-tau]), apparent clearance following oral dosing (CL/F), maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax) (tmax) and half-life (t1/2) of trametinib will be assessed
Measure:Safety and tolerability assessments for trametinib for AEs
Time Frame:From screening up to 63 months
Safety Issue:
Description:
Measure:Safety and tolerability assessments for trametinib for ECG
Time Frame:From screening up to 63 months
Safety Issue:
Description:12-lead ECGs will be performed to assess safety and tolerability
Measure:Safety and tolerability assessments for trametinib for changes in laboratory values
Time Frame:From screening up to 63 months
Safety Issue:
Description:Laboratory parameter including chemistry and hematology
Measure:Safety and tolerability assessments for trametinib for vital signs
Time Frame:From screening up to 63 months
Safety Issue:
Description:Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Measure:Tumor response for trametinib
Time Frame:From screening up to 63 months
Safety Issue:
Description:Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
Measure:Effect of age and weight on the PK of trametinib
Time Frame:Day 15 and Day 22
Safety Issue:
Description:PK parameter will include CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates
Measure:PK assessment of trametinib and dabrafenib when administered in combination
Time Frame:Day 1, Day 15 and Day 22 of Part C and Part D
Safety Issue:
Description:PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F, Cmax, tmax, and Cavg
Measure:Palatability of trametinib and/or dabrafenib in pediatric subjects assessed by palatability questionnaire
Time Frame:Day 8
Safety Issue:
Description:To be completed after the first dose of study drug and no later than Day 8 (+/-3 days). Subjects will complete a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste).
Measure:Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Adverse Events (AEs)
Time Frame:From screening up to 63 months
Safety Issue:
Description:
Measure:Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by ECGs.
Time Frame:From screening up to 63 months
Safety Issue:
Description:12-lead ECGs will be performed to assess safety and tolerability
Measure:Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Echo.
Time Frame:From screening up to 63 months
Safety Issue:
Description:
Measure:Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in laboratory values
Time Frame:From screening up to 63 months
Safety Issue:
Description:Laboratory parameter including chemistry, hematology and urinalysis.
Measure:Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in vital sign values
Time Frame:From screening up to 63 months
Safety Issue:
Description:Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by AEs
Time Frame:From screening up to 63 months
Safety Issue:
Description:
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by ECGs
Time Frame:From screening up to 63 months
Safety Issue:
Description:12-lead ECGs will be performed to assess safety and tolerability
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by Echo
Time Frame:From screening up to 63 months
Safety Issue:
Description:
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in lab values
Time Frame:From screening up to 63 months
Safety Issue:
Description:Laboratory parameter including chemistry, hematology and urinalysis.
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in vital sings
Time Frame:From screening up to 63 months
Safety Issue:
Description:Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate.
Measure:Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by steady state Ctau of trametinib and by steady state AUC (0-12) of dabrafenib
Time Frame:Day 15 and Day 22 of Part C and Part D
Safety Issue:
Description:
Measure:Tumor response for trametinib in combination with dabrafenib
Time Frame:From screening up to 63 months
Safety Issue:
Description:Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • v600-mutation
  • neuroblastoma
  • Trametinib
  • pediatrics
  • Langerhans Cell Histiocytosis
  • low grade glioma plexiform neurofibromas

Last Updated