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
Overview
- Phase
- Phase 1
- Intervention
- Trametinib
- Conditions
- Cancer
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 139
- Locations
- 1
- Primary Endpoint
- Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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. Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Part C was aimed to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects.
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.
Detailed Description
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.
Investigators
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.
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 B
Arms & Interventions
Part A - TMT 0.0125 mg/kg/day
Participants treated with trametinib 0.0125 mg/kg/day
Intervention: Trametinib
Part A - TMT 0.025 mg/kg/day
Participants treated with trametinib 0.025 mg/kg/day
Intervention: Trametinib
Part A - TMT 0.032 mg/kg/day
Participants under 6 years of age treated with trametinib 0.032 mg/kg/day
Intervention: Trametinib
Part A - TMT 0.04 mg/kg/day
Participants treated with trametinib 0.04 mg/kg/day
Intervention: Trametinib
Part B - Neuroblastoma
Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
Intervention: Trametinib
Part B - LGG fusion
Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
Intervention: Trametinib
Part B - NF-1 with PN
Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day
Intervention: Trametinib
Part B - BRAF V600 mutant solid tumor
Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day
Intervention: Trametinib
Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D
Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for \<12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects)
Intervention: Trametinib
Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D
Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for \<12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects)
Intervention: Dabrafenib
Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D
Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Trametinib
Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D
Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Dabrafenib
Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D
Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)
Intervention: Trametinib
Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D
Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)
Intervention: Dabrafenib
Part D - LGG
Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Trametinib
Part D - LGG
Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Dabrafenib
Part D - LCH
Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Trametinib
Part D - LCH
Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Intervention: Dabrafenib
Outcomes
Primary Outcomes
Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
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
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.
Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)
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.
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.
Secondary Outcomes
- Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib(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(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(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.)
- 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(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.)
- 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(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.)
- Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib(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.)
- Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib(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(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(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(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(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(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.)
- Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model(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.)
- Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model(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.)
- Significant Covariates Estimated With a PopPK Model(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.)
- Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib(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(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Dabrafenib When Administered in Combination With Trametinib(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Dabrafenib When Administered in Combination With Trametinib(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib(pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.)
- Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire(After the first dose of trametinib oral solution and no later than Day 8 (±3 days))
- Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire(After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days))