Clinical Trials /

Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer

NCT01740648

Description:

This phase I trial studies the side effects and best dose of trametinib when given together with fluorouracil and radiation therapy before surgery in treating patients with stage II-III rectal cancer. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, 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 together with fluorouracil and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed

Related Conditions:
  • Rectal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Trametinib</span>, <span class="go-doc-concept go-doc-intervention">Fluorouracil</span>, and <span class="go-doc-concept go-doc-intervention">Radiation</span> Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer

Title

  • Brief Title: Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer
  • Official Title: A Phase I Trial of MEK Inhibitor Trametinib in Combination With Neoadjuvant 5-Fluorouracil Chemoradiation in the Treatment of KRAS, BRAF, and NRAS-MUTANT Rectal Cancers
  • Clinical Trial IDs

    NCT ID: NCT01740648

    ORG ID: OSU-12054

    NCI ID: NCI-2012-02158

    Trial Conditions

    Recurrent Rectal Cancer

    Stage IIA Rectal Cancer

    Stage IIB Rectal Cancer

    Stage IIC Rectal Cancer

    Stage IIIA Rectal Cancer

    Stage IIIB Rectal Cancer

    Stage IIIC Rectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    trametinib GSK1120212 Treatment (trametinib, fluorouracil, radiation, surgery)
    fluorouracil 5-fluorouracil, 5-Fluracil, 5-FU Treatment (trametinib, fluorouracil, radiation, surgery)

    Trial Purpose

    This phase I trial studies the side effects and best dose of trametinib when given together
    with fluorouracil and radiation therapy before surgery in treating patients with stage
    II-III rectal cancer. Trametinib may stop the growth of tumor cells by blocking some of the
    enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, 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 together with fluorouracil and radiation therapy before surgery may make the
    tumor smaller and reduce the amount of normal tissue that needs to be removed

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To identify the maximally tolerated dose and recommended phase II dose of trametinib to
    be used in combination with 5FU (fluorouracil) and radiation in patients with rectal
    cancers.

    II. To determine a recommended phase II dose of trametinib to be used with 5FU
    chemoradiation in patients with locally advanced rectal cancer.

    SECONDARY OBJECTIVES:

    I. Evaluation of the tolerability and safety of the combination of trametinib and 5-FU
    chemoradiation in locally advanced rectal cancer.

    II. Evaluation of post-therapy pathologic response.

    III. Evaluation of the rate of local control, disease-free survival and overall survival.

    IV. Analysis of biomarkers - total mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene
    homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1(BRAF), and neuroblastoma RAS
    viral (v-ras) oncogene homolog (NRAS), as well as RAS/mitogen-activated protein kinase
    (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/v-akt murine thymoma viral
    oncogene homolog 1 (AKT) pathway signaling pathways to potentially correlate with clinical
    benefit.

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

    Patients receive trametinib orally (PO) once daily (QD) on days -14 to -10 and 1-38 and
    fluorouracil intravenously (IV) continuously 5 days a week from days 1-38. Patients also
    undergo radiation therapy 5 days a week on days 1-33. Patients then undergo surgery 6-10
    weeks later.

    Patients achieving negative surgical margins after complete resection of tumor receive
    postoperative chemotherapy comprising leucovorin calcium IV over 2 hours and fluorouracil IV
    continuously over 46 hours on days 1 and 15 OR oxaliplatin IV over 2 hours, leucovorin
    calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15.
    Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or
    unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 months for 2 years,
    and then annually for 3 years.

    Trial Arms

    Name Type Description Interventions
    Treatment (trametinib, fluorouracil, radiation, surgery) Experimental Patients receive trametinib PO (by mouth) QD (daily) on days -14 through -10 and 1-38 and fluorouracil IV continuously 5 days a week from days 1-38. Patients also undergo radiation therapy 5 days a week on days 1-33. Patients then undergo surgery 6-10 weeks later. Patients achieving negative surgical margins after complete resection of tumor receive postoperative chemotherapy comprising leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15 OR oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. trametinib, fluorouracil

    Eligibility Criteria

    Inclusion Criteria:

    - 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 >= 1.5 x 10^9/L

    - Hemoglobin >= 9 g/dL

    - Platelets >= 100 x 10^9/L

    - Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x upper limit of
    normal (ULN)

    - Partial thromboplastin time (PTT) =< 1.5 x ULN

    - Albumin >= 2.5 g/dL

    - Total bilirubin =< 1.5 x ULN

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

    - Creatinine =< 1.5 ULN or calculated creatinine clearance >= 50 mL/min or 24-hour
    urine creatinine clearance >= 50 mL/min

    - Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by
    echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

    - Life expectancy of at least 3 months in the opinion of investigator

    - 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

    - Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    - Ability to provide written informed consent obtained prior to participation in the
    study and any related procedures being performed

    - Women of child-bearing potential (WOCBP) must have a negative pregnancy test within
    14 days of the first administration of study treatment, and counseled on
    contraception/abstinence while receiving the study treatment; urine human chorionic
    gonadotropin (HCG) is an acceptable pregnancy assessment

    - A histologically confirmed rectal cancer with measurable or evaluable disease on
    imaging or endoscopy

    - Stage II or III disease by the American Joint Committee on Cancer (AJCC) 7th edition

    - Specific tumor genetic eligibility criteria include:

    - Presence of KRAS gene mutation (at codon 12, 13, or 61) for patients on
    expansion cohort.

    - Presence of V600E BRAF gene mutation, or

    - Presence of an NRAS mutation at codon 12, 13, or 61

    Exclusion Criteria:

    - History of another malignancy; exception: subjects who have been disease-free for 5
    years, or subjects with a history of completely resected non-melanoma skin cancer or
    successfully treated in situ carcinoma are eligible

    - Any serious and/or unstable pre-existing medical disorder (aside from malignancy
    exception above), psychiatric disorder, or other conditions that could interfere with
    subject's safety, obtaining informed consent or compliance to the study procedures,
    in the opinion of the Investigator

    - Prior chemotherapy treatment unless > 5 years ago

    - Prior treatment with a selective inhibitor of v-raf-1 murine leukemia viral oncogene
    homolog 1 (RAF) or mitogen-activated protein kinase kinase 1 (MEK)

    - Prior radiation therapy to the abdomen or pelvis

    - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
    chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)

    - Current use of a prohibited medication

    - 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 optic disc cupping

    - Evidence of visual field defects

    - Intraocular pressure > 21 mm Hg

    - 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)

    - History or evidence of cardiovascular risk including any of the following:

    - Bazett correction QT (QTcB) >= 480 msec

    - History or evidence of current clinically significant uncontrolled arrhythmias;
    exception: subjects with controlled atrial fibrillation for >30 days prior to
    enrollment are eligible

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

    - History or evidence of current >= class II congestive heart failure as defined
    by New York Heart Association (NYHA)

    - Treatment refractory hypertension defined as a blood pressure of systolic > 140
    mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
    therapy

    - Patients with intra-cardiac defibrillators or permanent pacemakers

    - Cardiac metastases

    - Pregnancy or breastfeeding: 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; should a woman
    become pregnant or suspect she is pregnant while participating in this study, she
    should inform her treating physician immediately; no breastfeeding while patient is
    on study

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Identify the maximally tolerated dose of Trametinib to be used in combination with 5FU and radiation in patients with rectal cancers.

    Secondary Outcome Measures

    Frequency of dose-limiting toxicities, assessed according to the NCI CTCAE version 4

    Local failure rate

    Progression free survival

    Overall survival

    Pathological response rate, defined as extent of tumor in the resected specimen that is classified by tumor, lymph node, metastasis (TNM) staging of the AJCC/International Union Against Cancer (UICC)

    Frequency of patients undergoing sphincter preserving surgery

    Trial Keywords

    MEK Inhibitor

    Trametinib

    Rectal Cancers

    KRAS

    BRAF

    NRAS Mutant

    Fluorouracil