Clinical Trials /

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

NCT01912625

Description:

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 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, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells. Giving trametinib, combination chemotherapy, and radiation therapy may be a better treatment for non-small cell lung cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trametinib, Combination Chemotherapy, and Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
  • Official Title: A Phase 1 Study of Trametinib in Combination With Chemoradiation for KRAS Mutant Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-01357
  • SECONDARY ID: NCI-2013-01357
  • SECONDARY ID: 763093
  • SECONDARY ID: 2012-1053
  • SECONDARY ID: 9448
  • SECONDARY ID: 9448
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: P50CA070907
  • SECONDARY ID: U01CA062461
  • SECONDARY ID: UM1CA186688
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT01912625

Conditions

  • KRAS Activating Mutation
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage III Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (trametinib, chemotherapy, radiation therapy)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (trametinib, chemotherapy, radiation therapy)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib, chemotherapy, radiation therapy)

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 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, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells. Giving trametinib, combination chemotherapy, and radiation therapy may be a better treatment for non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum-tolerated dose (MTD) of GSK1120212 (trametinib) combined with
      standard chemoradiation in unresectable 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 and 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 without disease progression after
      completion of chemoradiation 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 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib, chemotherapy, radiation therapy)ExperimentalCONCURRENT CHEMOTHERAPY: Patients undergo IMRT or 3D-CRT QD 5 days a week for 6 weeks. Patients receive trametinib PO QD and 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 without disease progression after completion of chemoradiation 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.
  • Carboplatin
  • Paclitaxel
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed, newly diagnosed or recurrent from a
             previously treated early stage lung cancers that are locally confined, non-small cell
             lung cancers that are considered unresectable and for which chemoradiation will be
             considered definitive therapy; patients with recurrent cancer that is amendable for
             chemoradiation can be eligible only if patients with prior lobectomy for stage I
             cancer had not had adjuvant chemotherapy, and more than 8 weeks have elapsed from
             surgery to allow for wound healing; patients who recur from prior X-ray therapy (XRT)
             or stereotactic body radiation therapy (SBRT) will not be eligible

          -  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) >= 1.5 x 10^9/L

          -  Hemoglobin >= 9 g/dL

          -  Platelets >= 100 x 10^9/L

          -  Albumin >= 2.5 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
             institutional ULN

          -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-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, during
             the study participation, and for four months after the last dose of the drug; women of
             child-bearing potential must have a negative serum pregnancy test within 14 days prior
             to registration and agree to use effective contraception throughout the treatment
             period and for 4 months after the last dose of study treatment; 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

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (any G12, G13,
             Q61) confirmed by Clinical Laboratory Improvement Act (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 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

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or to
             either carboplatin or paclitaxel

          -  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)

          -  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
                  registration are eligible)

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to registration

               -  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 hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with
             chronic or cleared HBV and HCV infection are eligible); patients with human
             immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

          -  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; women of childbearing potential should be advised
             to avoid pregnancy and use effective methods of contraception; men with a female
             partner of childbearing potential must have either had a prior vasectomy or agree to
             use effective contraception; if a female patient or a female partner of a patient
             becomes pregnant while the patient receives trametinib, the potential hazard to the
             fetus should be explained to the patient and partner (as applicable)

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity defined as any grade 3 or 4 non-hematologic toxicities according to Common Terminology Criteria for Adverse Events version 4.0 grading
Time Frame:Within 70 days from the start of radiation therapy
Safety Issue:
Description: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

Measure:Response rate based on CT or FDG-PET/CT imaging response assessment after completion of chemoradiation
Time Frame:Up to 4 years
Safety Issue:
Description:Response rate will be estimated and 95% confidence interval will be provided.
Measure:Overall survival (OS)
Time Frame:Up to 4 years
Safety Issue:
Description:Unadjusted OS will be estimated by the Kaplan and Meier method.
Measure:Patterns of recurrence
Time Frame:Up to 4 years
Safety Issue:
Description:Relapse-free survival will be estimated by the Kaplan and Meier method.
Measure:KRAS mutation status
Time Frame:Baseline
Safety Issue:
Description:KRAS and other biomarkers will be compared between pre-treatment tumors and recurrent tumors.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

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