GSK-MEK116540: 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

Why are we doing this research?

PURPOSE:

This is a 3-part (Part A, Part B, Part C), 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). The specifics around the Part C will be determined after completion of enrollment into Part A. The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or unresectable childhood tumors.
 

DETAILED DESCRIPTION:

PRIMARY OUTCOME MEASURES:

·         Safety Assessment of trametinib as assessed by Adverse Events (AEs) [ Time Frame: From screening up to 24 months ] [ Designated as safety issue: No ]

·         Safety Assessment of trametinib as assessed by electrocardiogram (ECG) [ Time Frame: From screening up to 24 months ] [ Designated as safety issue: No ]

o    Single 12-lead ECGs will be obtained to assess safety

·         Safety Assessment of trametinib as assessed by echocardiogram (ECHO) [ Time Frame: From screening up to 24 months ] [ Designated as safety issue: No ]

o    ECHOs will be performed to assess cardiac ejection fraction and cardiac valve morphology

·         Safety Assessment of trametinib as assessed by changes in laboratory values [ Time Frame: From screening up to 24 months ] [ Designated as safety issue: No ]

o    Laboratory assessments will include Hematology, Clinical Chemistry, Routine Urinalysis and Other screening tests

·         Safety Assessment of trametinib assessed by changes in vital signs [ Time Frame: From screening up to 24 months ] [ Designated as safety issue: No ]

o    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate

·         To determine the dose of trametinib that achieves similar exposures (Ctau) to the recommended adult dose [ Time Frame: Days 15 and 22 ] [ Designated as safety issue: No ]

o    Steady state Ctau of trametinib

Study Type: Interventional

Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 1 month to 17 Years

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 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 drug.
  • 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 - to be determined after completion of enrollment into Part A

 

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.
  • 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 and Part C only: Previous treatment with dabrafenib (cohort B4), trametinib or another MEK inhibitor (exception: prior treatment with sorafenib is permitted).
  • 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 Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
  • 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. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GlaxoSmithKline (GSK) medical monitor for guidance to enroll the subject.
  • 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.

Ages

  • From 0 to 17 years old

Conditions

  • Brain Spinal Neurofibromatosis Plexiform Neurofibroma
  • Sarcoma Ewing Relapse
  • Sarcoma Osteosarcoma Relapse
  • Sarcoma Rhabdomyosarcoma Relapse
  • Neuroblastoma Relapse - Refractory
  • Liver Relapse - Refractory
  • Kidney Relapse - Refractory
  • Solid Tumor Retinoblastoma Relapse - Refractory
  • Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Solid Tumor Melanoma Relapse - Refractory
  • Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Solid Tumors - All Other
  • Solid Tumor Neurofibromatosis Plexiform Neurofibroma

Contact

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati OH 45229-3039

Phone: 513-636-2799

cancer@cchmc.org