Trametinib, Combination Chemotherapy, and Radiation Therapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot be Removed by Surgery

This study is currently recruiting participants.
Verified February 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01912625
First received: July 29, 2013
Last updated: April 7, 2014
Last verified: February 2014
  Purpose

This phase I trial studies the side effects and the best dose of trametinib when given together with combination chemotherapy and radiation therapy in treating patients with stage II-III non-small cell lung cancer that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. Giving trametinib, combination chemotherapy, and radiation therapy may be an effective treatment for non-small cell lung cancer.


Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IIB Non-small Cell Lung Cancer
Stage IIIA Non-small Cell Lung Cancer
Stage IIIB Non-small Cell Lung Cancer
Drug: trametinib
Drug: carboplatin
Drug: paclitaxel
Radiation: intensity-modulated radiation therapy
Radiation: 3-dimensional conformal radiation therapy
Radiation: image-guided radiation therapy
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Trametinib in Combination With Chemoradiation for KRAS Mutant Non-Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • DLT defined as any grade 3 or 4 non-hematologic toxicities according to CTCAE v. 4.0 grading occurring at any time within 70 days from the start of radiation therapy [ Time Frame: Within 70 days ] [ Designated as safety issue: Yes ]
    Toxicity will be tabulated by dose, type, and grade. The probability of toxicity over 70 days as a function of dose will be estimated by fitting a Bayesian binary outcome regression model.


Secondary Outcome Measures:
  • Response rate based on CT or FDG-PET/CT imaging response assessment after completion of chemoradiation [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rate will be estimated and 95% confidence interval will be provided.

  • Overall survival (OS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Unadjusted OS will be estimated by the Kaplan and Meier method.

  • Patterns of recurrence [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Relapse-free survival (RFS) will be estimated by the Kaplan and Meier (1958) method.

  • KRAS mutation status [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    KRAS and other biomarkers will be compared between pre-treatment tumors and recurrent tumors.


Estimated Enrollment: 30
Study Start Date: October 2013
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (trametinib, chemotherapy, radiation therapy)

CONCURRENT CHEMOTHERAPY: Patients undergo IMRT or 3D-CRT QD 5 days a week for 6 weeks. Patients receive trametinib PO QD, carboplatin IV over 30 minutes, and paclitaxel IV over 1 hour once weekly. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients achieving response or stable disease proceed to consolidation chemotherapy.

CONSOLIDATION CHEMOTHERAPY: Beginning 3 weeks after completion of concurrent chemoradiation, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on days 1 and 22. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Drug: trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • Mekinist
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Radiation: intensity-modulated radiation therapy
Undergo IMRT
Other Name: IMRT
Radiation: 3-dimensional conformal radiation therapy
Undergo 3D-CRT
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: image-guided radiation therapy
Undergo IGRT
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum-tolerated dose (MTD) of GSK1120212 (trametinib) combined with standard chemoradiation in unresectable stage II-III non-small cell lung cancer (NSCLC) and safety as measured by the rate of grade 3 or worse non-hematological toxicities occurring prior to the beginning of consolidation therapy (including all toxicities attributed to chemoradiation occurring within 10 weeks of the start of radiation therapy).

II. Pharmacokinetic (PK) analysis of carboplatin, paclitaxel, and trametinib.

SECONDARY OBJECTIVES:

I. Response rate based on computed tomography (CT) or fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT imaging response assessment after completion of chemoradiation.

II. Biomarker correlate to response and resistance. III. Overall survival. IV. Patterns of recurrence. V. Determine dose delay and the percentage of dose delivered for each agent.

OUTLINE: This is a dose-escalation study of trametinib.

CONCURRENT CHEMOTHERAPY: Patients undergo intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) once daily (QD) 5 days a week for 6 weeks. Patients receive trametinib orally (PO) QD, carboplatin intravenously (IV) over 30 minutes, and paclitaxel IV over 1 hour once weekly. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients achieving response or stable disease proceed to consolidation chemotherapy.

CONSOLIDATION CHEMOTHERAPY: Beginning 3 weeks after completion of concurrent chemoradiation, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on days 1 and 22. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed non-small cell lung cancers that are considered unresectable and for which chemoradiation will be considered definitive therapy
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Prior thoracic radiation allowed only if there is minimal to no overlap with the treatment area estimated at the time of consultation, and there is no cumulative esophageal dose that exceeds more than 50% of the maximal acceptable dose tolerance
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Life expectancy of greater than 6 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
  • Absolute neutrophil count (ANC) >= 1.5x10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100 x 10^9/L
  • Albumin >= 2.5 g/dL
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x institutional ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN
  • Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x institutional ULN
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration
  • Ability to understand and the willingness to sign a written informed consent document
  • Activating v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (any G12, G13, Q61) confirmed by Clinical Laboratory Improvement Amendments (CLIA)-certified testing
  • The availability of formalin-fixed paraffin embedded archival tissue from core biopsy of tumors is recommended for exploratory analysis

Exclusion Criteria:

  • 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 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization
  • 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
  • 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
    • Concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
  • History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):

    • History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
    • Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure >21 mm Hg
  • History or evidence of cardiovascular risk including any of the following:

    • Left ventricular ejection fraction (LVEF) < LLN
    • A QT interval corrected for heart rate using the Bazett's formula corrected QT (QTcB) >= 480 msec
    • History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
    • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
    • History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
    • Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
    • Known cardiac metastases
  • Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women or nursing mothers
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Patients who do not consent for PK studies to be performed (alternatively: patients who initially consent to be on study but withdraws consent for PK study will be taken off study and replaced)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01912625

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Jamie E. Chaft    646-888-4545    chaftj@mskcc.org   
Principal Investigator: Jamie E. Chaft         
United States, Ohio
Case Comprehensive Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44106-5065
Contact: Afshin Dowlati    216-844-8797    axd44@case.edu   
Principal Investigator: Afshin Dowlati         
Ohio State University Medical Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Meng X. Welliver    614-293-0216    meng.welliver@osumc.edu   
Principal Investigator: Meng X. Welliver         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Steven H. Lin    713-563-8490    shlin@mdanderson.org   
Principal Investigator: Steven H. Lin         
Sponsors and Collaborators
Investigators
Principal Investigator: Steven Lin M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01912625     History of Changes
Other Study ID Numbers: NCI-2013-01357, NCI-2013-01357, 2012-1053, 9448, P30CA016672, U01CA062461
Study First Received: July 29, 2013
Last Updated: April 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carboplatin
Paclitaxel
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on April 17, 2014