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 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 1165402013-003596-35CTMT212X2101
• Study Type: interventional
• Target: 139
• Locations: 5 countries
• Sites: 16

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.

Conditions

Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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 (24)

• 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.

Study Arms (13)

Part A - TMT 0.0125 mg/kg/day

EXPERIMENTAL

Participants treated with trametinib 0.0125 mg/kg/day

Drug: Trametinib

Part A - TMT 0.025 mg/kg/day

EXPERIMENTAL

Participants treated with trametinib 0.025 mg/kg/day

Drug: Trametinib

Part A - TMT 0.032 mg/kg/day

EXPERIMENTAL

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Drug: Trametinib

Part A - TMT 0.04 mg/kg/day

EXPERIMENTAL

Participants treated with trametinib 0.04 mg/kg/day

Drug: Trametinib

Part B - Neuroblastoma

EXPERIMENTAL

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Drug: Trametinib

Part B - LGG fusion

EXPERIMENTAL

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Drug: Trametinib

Part B - NF-1 with PN

EXPERIMENTAL

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Drug: Trametinib

Part B - BRAF V600 mutant solid tumor

EXPERIMENTAL

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Drug: Trametinib

Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D

EXPERIMENTAL

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)

Drug: Trametinib; Drug: Dabrafenib

Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D

EXPERIMENTAL

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)

Drug: Trametinib; Drug: Dabrafenib

Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D

EXPERIMENTAL

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)

Drug: Trametinib; Drug: Dabrafenib

Part D - LGG

EXPERIMENTAL

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)

Drug: Trametinib; Drug: Dabrafenib

Part D - LCH

EXPERIMENTAL

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)

Drug: Trametinib; Drug: Dabrafenib

Interventions

Trametinib DRUG

Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Part A - TMT 0.0125 mg/kg/day; Part A - TMT 0.025 mg/kg/day; Part A - TMT 0.032 mg/kg/day; Part A - TMT 0.04 mg/kg/day; Part B - BRAF V600 mutant solid tumor; Part B - LGG fusion; Part B - NF-1 with PN; Part B - Neuroblastoma; Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D; Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D; Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D; Part D - LCH; Part D - LGG

Dabrafenib DRUG

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D; Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D; Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D; Part D - LCH; Part D - LGG

Eligibility Criteria

• Age: 1 Month - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (16)

Novartis Investigative Site

Phoenix, Arizona, 85016-7710, United States

Location

Novartis Investigative Site

San Francisco, California, United States

Location

Novartis Investigative Site

Washington D.C., District of Columbia, 20010, United States

Location

Novartis Investigative Site

Baltimore, Maryland, 21287, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02115, United States

Location

Novartis Investigative Site

Minneapolis, Minnesota, 55455, United States

Location

Novartis Investigative Site

New York, New York, 10065, United States

Location

Novartis Investigative Site

Cincinnati, Ohio, 45229, United States

Location

Novartis Investigative Site

Philadelphia, Pennsylvania, 19104, United States

Location

Novartis Investigative Site

Memphis, Tennessee, 38105-3678, United States

Location

Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

Location

Novartis Investigative Site

Paris, 75248, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

London, WC1N 3JH, United Kingdom

Location

Related Publications (3)

• Whitlock JA, Geoerger B, Dunkel IJ, Roughton M, Choi J, Osterloh L, Russo M, Hargrave D. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.

  PMID: 36884302 DERIVED

• Bouffet E, Geoerger B, Moertel C, Whitlock JA, Aerts I, Hargrave D, Osterloh L, Tan E, Choi J, Russo M, Fox E. Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. J Clin Oncol. 2023 Jan 20;41(3):664-674. doi: 10.1200/JCO.22.01000. Epub 2022 Nov 14.

  PMID: 36375115 DERIVED

• Shahid S, Kushner BH, Modak S, Basu EM, Rubin EM, Gundem G, Papaemmanuil E, Roberts SS. Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma. Pediatr Blood Cancer. 2021 Oct;68(10):e29265. doi: 10.1002/pbc.29265. Epub 2021 Jul 31.

  PMID: 34331515 DERIVED

MeSH Terms

Conditions

Neoplasms; Neuroblastoma; Histiocytosis, Langerhans-Cell; Neurofibroma, Plexiform

Interventions

trametinib; dabrafenib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Neurofibroma; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2014
• First Posted: April 28, 2014
• Study Start: January 15, 2015
• Primary Completion: December 29, 2020
• Study Completion: December 29, 2020
• Last Updated: July 14, 2021
• Results First Posted: July 14, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share

Locations

FR (2); GB (2); US (10); CA (1); AU (1)