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

Novartis Pharmaceuticals139 enrolled

Overview

This was 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 was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy using a 3 + 3 dose- escalation procedure. The starting dose level of trametinib was 0.0125 mg/kg/day, the second dose level was 0.025 mg/kg/day and the third dose level was 0.040 mg/kg/day. Additionally, in Part A extension an intermediate trametinib dose level of 0.032 mg/kg/day was assessed in subjects under 6 years of age. In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject. Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects: B1: Refractory or relapsed neuroblastoma B2: Recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion (glioma fusion) B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant B4: BRAF V600 mutant tumors In Part B it was used the RP2D of trametinib (0.025 mg/kg/day) determined in Part A. Part C was 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. The trametinib dose administered in Part C was based on the trametinib monotherapy RP2D from Part A (0.025 mg/kg/day). For the evaluation of combination therapy in this study, the starting dose of dabrafenib was 50% of the monotherapy RP2D established in a separate study: 2.63 mg/kg/day (\<12 years old subjects) and 2.25 mg/kg/day (≥12 years old subjects). The second dose level of dabrafenib was 100% of the monotherapy RP2D: 5.25 mg/kg/day (\<12 years old subjects) and 4.5 mg/kg/day (≥12 years old subjects). Additionally, in Part C extension, the trametinib dose determined from Part A extension (0.032 mg/kg/day) with 100% pediatric RP2D of dabrafenib (5.25 mg/kg/day) was assessed in subjects under 6 years of age. In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject and the total daily dabrafenib dose was not to exceed the adult dose (300 mg) in any subject. Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in two disease-specific cohorts of subjects diagnosed with low grade glioma (LGG) and Langerhans cell histiocytosis (LCH). In Part D it was used the RP2D of the combination treatment determined in Part C (0.025 mg/kg/day trametinib and the 100% RP2D of dabrafenib) in subjects 6 years to \< 18 years of age. Additionally, once Part C extension had defined the trametinib RP2D for subjects under 6 years of age, this dose was used for the remaining subjects enrolled in Part D (0.032 mg/kg/day trametinib and the 100% RP2D of dabrafenib). The overall goal of this trial was 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.

Eligibility

Sex: ALLMin age: 1 MonthMax age: 17 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy

Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.

Time frame: From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months

Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.

Time frame: pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Secondary Outcomes

Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.

Time frame: pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

Time frame: pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Trametinib When Administered Alone and in Combination With Dabrafenib

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.

Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Trametinib When Administered Alone and in Combination With Dabrafenib

Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.

Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib

Time frame: pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib

Time frame: From the day of the first dose of the combination up to 30 days after the last dose, up to maximum duration of 53 months

Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment

Response evaluations were assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for subjects with solid tumors except neuroblastomas, primary central nervous system tumors (gliomas) or plexiform neurofibromas (PNs). Response evaluations for subjects with neuroblastomas could have included: measureable disease (by CT/MRI alone) assessed according to RECIST v1.1, evaluable disease assessed for meta-iodobenzylguanidine (MIBG) response, and biochemical (urine HVA/VMA) with bone marrow involvement assessed by Hematoxylin and Eosin staining of bilateral bone marrow biopsies and aspirates. Response evaluations for glioma subjects was assessed using Response Assessment in Neuro Oncology (RANO) criteria with solid tumors through MRI scans. Response evaluations of PNs were assessed using volumetric determination and Dombi criteria through MRI scans. The number of participants in each response category is reported in the table.

Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment

Objective response rate (ORR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR) or partial response (PR) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment

Clinical Benefit Rate (CBR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR), partial response (PR) or stable disease (SD) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model

Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model

Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model

Significant Covariates Estimated With a PopPK Model

The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Sex and weight are significant covariates on apparent clearance (CL/F), and weight is also a significant covariate on apparent intercompartmental clearance (Q/F). Use of dabrafenib, yes or no, is a covariate on the relative bioavailability of trametinib, reflecting the effect of dabrafenib on the PK of trametinib. The estimates of these covariates (effect of weight on CL/F, effect of sex on CL/F, effect of weight on Q/F, effect of combination with dabrafenib on relative bioavailability F1) calculated with the PopPK model are summarized in this record.

Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.

Time frame: pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.