Trametinib in Treating Patients With Advanced Cancer With or Without Hepatic Dysfunction

NCT02070549 | Completed Phase 1 DMC

• 16 other identifiers: NCI-2014-00416NCI 95919591/PJC-015PJC-0159591N01CM00100U01CA132123U01CA062487U01CA062490UM1CA186644UM1CA186689UM1CA186690UM1CA186704UM1CA186709UM1CA186712UM1CA186717
• Study Type: interventional
• Target: 46
• Locations: 2 countries
• Sites: 11

Brief Summary

This phase I trial studies the side effects and best dose of trametinib in treating patients with cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) with or without liver (hepatic) dysfunction. Trametinib may stop the growth of tumor cells by blocking proteins needed for cell growth. When these proteins are blocked, the growth of cancer cells may be stopped and the cancer cells will then die. Hepatic dysfunction is frequently found in patients with advanced cancer and usually prevents patients from receiving standard treatments or from participating in clinical trials. Patients may also need dose adjustments or absorb drugs differently. Trametinib may be a better treatment for patients with advanced cancers and hepatic dysfunction.

Conditions

Advanced Malignant Solid Neoplasm; Metastatic Malignant Neoplasm in the Liver; Metastatic Malignant Solid Neoplasm; Unresectable Solid Neoplasm

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose of trametinib

  Dose escalation and determination of the maximum tolerated dose will be carried out separately for each cohort or stratum. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

  28 days

• Dose-limiting toxicity

  Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018). Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

  28 days

• Pharmacokinetic profile of trametinib

  Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

  Baseline and 0.5, 1, 2, 3, 4, 6, 10, and 24 hours on days 15 and 16 of cycle 1

Secondary Outcomes (3)

• Non-dose-limiting toxicities associated with the administration of trametinib

  Up to 4 weeks post treatment

• Objective response to treatment

  Up to 4 weeks post treatment

• Predictive biomarkers for individual cancer patients

  Up to 4 weeks post treatment

Study Arms (1)

Treatment (trametinib)

EXPERIMENTAL

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Trametinib

Interventions

Trametinib DRUG

Given PO

Also known as: GSK 1120212, GSK 212, GSK-1120212, GSK-212, GSK1120212, GSK212, JTP 74057, JTP-74057, JTP74057, MEK Inhibitor GSK1120212

Treatment (trametinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective
• Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment
• Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts:
• Pancreatic cancer patients
• Colorectal cancer patients
• BRAF V600E melanoma patients who have failed BRAF inhibitors
• Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist
• All patients must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study principal investigator), surgery, anti-angiogenic therapy or interferon \>= 28 days before study entry
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Life expectancy of greater than 3 months
• Able to swallow and retain orally-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
• All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade =\< 1 (except alopecia) at the time of enrollment
• Absolute neutrophil count (ANC) \>= 1.2 x 10\^9/L
• Hemoglobin \>= 9 g/dL
• Platelets \>= 75 x 10\^9/L

You may not qualify if:

• History of another malignancy
• Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above
• History of interstitial lung disease or pneumonitis
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment
• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study; patients previously treated with v-raf murine sarcoma (RAF) and/or mitogen-activated protein kinase (MEK) inhibitors are excluded from the study; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO)
• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
• Other anti-cancer therapy while on study treatment; (Note: megestrol \[Megace\] if used as an appetite stimulant is allowed)
• Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
• Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra \[ma huang\], ginkgo biloba, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng)
• History or current evidence/risk of retinal vein occlusion (RVO)
• History or evidence of cardiovascular risk including any of the following:
• LVEF \< LLN
• A QT interval corrected for heart rate using the Bazett's formula QTcB \>= 480 msec

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (11)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

BCCA-Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, L8V 5C2, Canada

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• Voon PJ, Chen EX, Chen HX, Lockhart AC, Sahebjam S, Kelly K, Vaishampayan UN, Subbiah V, Razak AR, Renouf DJ, Hotte SJ, Singh A, Bedard PL, Hansen AR, Ivy SP, Wang L, Stayner LA, Siu LL, Spreafico A. Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction. J Exp Clin Cancer Res. 2022 Feb 7;41(1):51. doi: 10.1186/s13046-021-02236-7.

  PMID: 35130943 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

trametinib; omipalisib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Lillian L Siu

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2014
• First Posted: February 25, 2014
• Study Start: March 10, 2014
• Primary Completion: December 18, 2024
• Study Completion: December 18, 2024
• Last Updated: February 13, 2025

Record last verified: 2025-02

Locations

CA (3); US (8)