Clinical Trials /

BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)

NCT01750918

Description:

This is an open-label, four-part Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR therapy. Part 1 of the study will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. Part 2 of the study will consist of expansion cohorts to investigate safety and clinical activity of dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab. Part 3 of the study will be a randomized Phase II study comparing dosing with dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab as compared to the chemotherapy comparator (a regimen of leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX), leucovorin calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) or irinotecan with or without panitumumab or bevacizumab). Subjects will be assigned to treatment groups in a randomized fashion to compare safety and clinical activity. Part 4 of the study will investigate the trametinib/panitumumab combination, including dose escalation and subsequent cohort expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance to prior anti-EGFR therapy. The objective of Part 4 is to identify the recommended Phase 2 dose/regimen for trametinib dosed in combination with panitumumab in dose escalation and to identify an initial signal of clinical activity in expansion cohorts.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-biomarker">BRAF</span>/MEK/<span class="go-doc-concept go-doc-intervention">EGFR Inhibitor</span> Combination Study in <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span> (CRC)

Title

  • Brief Title: BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)
  • Official Title: An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy
  • Clinical Trial IDs

    NCT ID: NCT01750918

    ORG ID: 116833

    Trial Conditions

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib Part 2: Dabrafenib, Trametinib and Panitumumab, Part 1: Dabrafenib and Panitumumab, Part 2: Dabrafenib and panitumumab, Part 3a: Dabrafenib and Panitumumab, Part 3b: Dabrafenib, Trametinib and Panitumumab, Part 1: Dabrafenib, Trametinib and Panitumumab
    Trametinib Part 2: Dabrafenib, Trametinib and Panitumumab, Part 4b: Trametinib and Panitumumab, Part 3b: Dabrafenib, Trametinib and Panitumumab, Part 4a: Trametinib and Panitumumab, Part 1: Dabrafenib, Trametinib and Panitumumab
    Panitumumab Part 2: Dabrafenib, Trametinib and Panitumumab, Part 1: Dabrafenib and Panitumumab, Part 2: Dabrafenib and panitumumab, Part 3a: Dabrafenib and Panitumumab, Part 4b: Trametinib and Panitumumab, Part 3b: Dabrafenib, Trametinib and Panitumumab, Part 4a: Trametinib and Panitumumab, Part 1: Dabrafenib, Trametinib and Panitumumab
    5-fluorouracil Part 3c: Chemotherapy comparator

    Trial Purpose

    This is an open-label, four-part Phase I/II study to investigate the safety,
    pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and
    dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody
    panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in
    subjects with CRC with secondary resistance to prior anti-EGFR therapy. Part 1 of the study
    will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. Part 2 of the
    study will consist of expansion cohorts to investigate safety and clinical activity of
    dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination
    with panitumumab. Part 3 of the study will be a randomized Phase II study comparing dosing
    with dabrafenib in combination with panitumumab and trametinib plus dabrafenib in
    combination with panitumumab as compared to the chemotherapy comparator (a regimen of
    leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX), leucovorin calcium, fluorouracil,
    irinotecan hydrochloride (FOLFIRI) or irinotecan with or without panitumumab or
    bevacizumab). Subjects will be assigned to treatment groups in a randomized fashion to
    compare safety and clinical activity. Part 4 of the study will investigate the
    trametinib/panitumumab combination, including dose escalation and subsequent cohort
    expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects
    with CRC who developed secondary resistance to prior anti-EGFR therapy. The objective of
    Part 4 is to identify the recommended Phase 2 dose/regimen for trametinib dosed in
    combination with panitumumab in dose escalation and to identify an initial signal of
    clinical activity in expansion cohorts.

    Detailed Description

    This is an open-label, four-part Phase I/II study to investigate the safety,
    pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and
    dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody
    panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in
    subjects with CRC with secondary resistance to prior anti-EGFR therapy. Part 1 of the study
    will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. Part 2 of the
    study will consist of expansion cohorts to investigate safety and clinical activity of
    dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination
    with panitumumab. Part 3 of the study will be a randomized Phase II study comparing dosing
    with dabrafenib in combination with panitumumab and trametinib plus dabrafenib in
    combination with panitumumab as compared to the chemotherapy comparator (a regimen of
    FOLFOX, FOLFIRI or irinotecan with or without panitumumab or bevacizumab). Subjects will be
    assigned to treatment groups in a randomized fashion to compare safety and clinical
    activity. Part 4 of the study will investigate the trametinib/panitumumab combination,
    including dose escalation and subsequent cohort expansion in two patient populations: 1)
    BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance
    to prior anti-EGFR therapy. The objective of Part 4 is to identify the recommended Phase 2
    dose/regimen for trametinib dosed in combination with panitumumab in dose escalation and to
    identify an initial signal of clinical activity in expansion cohorts.

    Trial Arms

    Name Type Description Interventions
    Part 1: Dabrafenib and Panitumumab Experimental In Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams [mg] twice daily) and panitumumab (6 milligrams per kilogram [mg/kg] every-2-week [Q2W]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated. Dabrafenib, Panitumumab
    Part 1: Dabrafenib, Trametinib and Panitumumab Experimental In Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined. Dabrafenib, Trametinib, Panitumumab
    Part 2: Dabrafenib and panitumumab Experimental In Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab Dabrafenib, Panitumumab
    Part 2: Dabrafenib, Trametinib and Panitumumab Experimental In Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab. Dabrafenib, Trametinib, Panitumumab
    Part 3a: Dabrafenib and Panitumumab Experimental Subjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. Dabrafenib, Panitumumab
    Part 3b: Dabrafenib, Trametinib and Panitumumab Experimental Subjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. Dabrafenib, Trametinib, Panitumumab
    Part 3c: Chemotherapy comparator Experimental Subjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy 5-fluorouracil
    Part 4a: Trametinib and Panitumumab Experimental Subject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W Trametinib, Panitumumab
    Part 4b: Trametinib and Panitumumab Experimental In Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E). Trametinib, Panitumumab

    Eligibility Criteria

    Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the
    following criteria

    - Provided written informed consent,

    - Male or female >=18 years of age and able to swallow and retain orally administered
    study treatment and does not have any clinically significant gastrointestinal (GI)
    abnormalities that may alter absorption such as malabsorption syndrome or major
    resection of the stomach and/or bowels.

    - Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced
    or metastatic BRAF V600E mutation positive CRC

    - Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced
    or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by
    relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy,
    defined as patients that derived benefit (disease control based on investigator
    assessment for >6 months OR partial response [confirmed or unconfirmed] based on
    RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then
    subsequently progressed on therapy. The anti-EGFR therapy must have been the most
    recent therapy and the patient must have progressed based on investigator assessment
    within 3 months of screening. Acceptable prior anti-EGFR-containing therapies
    include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b.
    irinotecan/anti-EGFR combo after previously having disease progression (based on
    investigator assessment) on an irinotecan-containing regimen

    - Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation
    positive advanced or metastatic colorectal cancer (CRC who are eligible to receive
    fluoropyrimidine-containing chemotherapy regimen that have experienced documented
    radiographic progression on one prior line of fluoropyrimidine-containing
    chemotherapy (previous anti-EGFR therapy is excluded), Second-line for
    advanced/metastatic disease, having failed or been intolerant to at least one regimen
    of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in
    the advanced/metastatic setting. Enrollment in Part 3 may only occur following
    confirmation of KRAS wild-type cancer.

    - Archival tissue is required; if archival tissue is not available or found to not
    contain tumor tissue, a fresh biopsy is required.

    - Measurable disease per RECIST version 1.1.

    - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

    - Men with a female partner of childbearing potential must have either had a prior
    vasectomy or agree to use one of the contraception methods listed in protocol.

    - Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal
    females with a documented tubal ligation or hysterectomy; or post-menopausal female
    defined as 12 months of spontaneous amenorrhea to be verified with a
    follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter
    (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing
    potential and agrees to use one of the contraceptive methods listed in protocol.

    - Female subjects must agree to use contraception from 7 days prior to the first dose
    of study drug(s) until 6 months after the last dose of panitumumab, until 4 months
    after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib,
    whichever is longer. Additionally, women of childbearing potential must have had a
    negative serum pregnancy test within 7 days prior to the first dose of study drug(s).

    - Adequate organ system function as defined in absolute neutrophil count greater than
    or equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per
    deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or
    equal to 75 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and
    Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal
    (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN);
    albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total
    bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and
    Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than
    or equal to 1.5XULN or calculated creatinine clearance greater than or equal to
    50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN
    by echocardiography (ECHO) or multigated acquisition scan (MUGA).

    - Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible
    for inclusion in this study only if either affiliated to, or a beneficiary of, a
    social security category.

    Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in
    the study

    - History of prior malignancy, other than colorectal cancer.

    - 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.

    - Current active liver or biliary disease (with the exception of Gilbert's syndrome or
    asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
    per investigator's assessment).

    - History of sensitivity to heparin or heparin-induced thrombocytopenia.

    - Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or
    biologic therapy).

    - Prior exposure to a MEK inhibitor.

    - Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF
    inhibitor.

    - Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of
    KRAS-mutation based on previous KRAS-testing. Note: Propsective KRAS testing is not
    required. However, if the results of previous KRAS testing are known, they must be
    used in assessing eligibility. KRAS testing will be performed retrospectively for
    all patients.

    - Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody

    - Received an investigational or approved anti-cancer drug within 4 weeks, or within 5
    half-lives (whichever is shorter) of the first dose of study drug(s). At least 14
    days must have passed between the last dose of prior investigational agent and the
    first dose of study drug(s).

    - Part 3: Received more than one prior anti-cancer therapy in the metastatic setting,
    exclusive of previous adjuvant regimens. Previous investigational anti-cancer
    therapy in the metastatic setting is prohibited.

    - Current use of a prohibited medication or requirement to dose with any of these
    medications during treatment with study drug(s).

    - Known Hepatitis B, or Hepatitis C infection.

    - Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first
    dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose
    of study drug(s).

    - Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of
    study drug(s). Chemotherapy regimens given continuously or on a weekly basis with
    limited potential for delayed toxicity within 2 weeks prior to first dose of study
    drug(s).

    - Unresolved toxicity greater than National Cancer Institute Common Terminology
    Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer
    therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory
    values that are allowed per inclusion criteria.

    - History of retinal vein occlusion (RVO).

    - Presence of active gastrointestinal disease or other condition that will interfere
    significantly with the absorption, distribution, metabolism or excretion of drugs.
    Previous colectomy is acceptable.

    - Subjects with brain metastases are excluded, unless: All known lesions must be
    previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s),
    if present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days
    prior to first dose of study drug(s). This must be documented with two consecutive
    MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement
    for >=30 days prior to first dose of study drug(s), and No enzyme-inducing
    anticonvulsants for >=14 days prior to first dose of study drug(s). In addition, for
    subjects that had brain metastases but currently have no evidence of disease (NED),
    NED for >=12 weeks is required and must be confirmed by two consecutive MRI or CT
    scans (using contrast) separated by >=6 weeks, prior to randomization. Enrollment of
    a subject with brain metastases who meet the above criteria requires approval of a
    GlaxoSmithKline (GSK) Medical Monitor.

    - Psychological, familial, sociological or geographical conditions that do not permit
    compliance with the protocol.

    - 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
    milliseconds (msec);.History or evidence of current clinically significant
    uncontrolled arrhythmias. Exception: Subjects 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 New York Heart Association (NYHA).
    Treatment refractory hypertension defined as a blood pressure of systolic> 140
    millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled
    by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent
    pacemakers; Known cardiac metastases

    - Unstable pulmonary embolism, deep vein thrombosis, or other significant
    arterial/venous thromboembolic event <=30 days before randomization. If on
    anticoagulation, subject must be on stable therapeutic dose prior to randomization.

    - Subjects with a history of pneumonitis or interstitial lung disease (ILD).

    - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
    chemically related to the study drug(s) or their excipients.

    - Pregnant or lactating female.

    - Unwillingness or inability to follow the procedures outlined in the protocol.

    - Uncontrolled diabetes or other medical condition that may interfere with assessment
    of toxicity.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Part 1, Part 2, Part 4A and Part 4B: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations

    Part 2 and Part 4B: Response rate (Complete Response [CR] + Partial Response [PR]) in subjects in the dosing groups

    Part 3: Progression -free survival (PFS)

    Secondary Outcome Measures

    Part 1: Plasma pharmacokinetics (PK) profile of dabrafenib, trametinib and panitumumab in combination dosing

    Part 1: Response rate (CR +PR) of dabrafenib dosed orally in combination with panitumumab

    Part 1 and Part 2: Progression free survival of subjects treated with dabrafenib dosed orally in combination with panitumumab

    Part 1 and Part 2: Duration of response of dabrafenib dosed orally in combination with panitumumab

    Part 1: Response rate (CR +PR) of trametinib dosed orally in combination with dabrafenib and panitumumab

    Part 1 and Part 2: Progression free survival subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab

    Part 1 and Part 2: Duration of response of trametinib dosed orally in combination with dabrafenib and panitumumab

    Part 1, Part 2, Part 4A and Part 4B: Change in levels of proteins/ Ribonucleic acid (RNA) in pre- and post-dose tumor tissue

    Part 2: Plasma pharmacokinetics profile of of dabrafenib and trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)

    Part 2: Overall survival (OS) of subjects treated with dabrafenib dosed orally in combination with panitumumab

    Part 2: OS of subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab

    Part 3: Response rate (CR +PR) of dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

    Part 3: Duration of response to dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

    Part 3: OS of subjects treated with dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

    Part 3: To evaluate and compare the PFS of the trametinib/dabrafenib/panitumumab combination as compared to the dabrafenib/panitumumab combination

    Part 3: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations

    Part 4A: Plasma pharmacokinetics profile of trametinib and panitumumab after combination therapy

    Part 4A: Response rate (CR +PR) of panitumumab/trametinib combination therapy in patient populations

    Part 4A and Part 4B: Progression free survival of panitumumab/trametinib combination therapy in patient populations

    Part 4A and Part 4B: Duration of response of panitumumab/trametinib combination therapy in patient populations

    Part 4B Plasma pharmacokinetics profile of trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)

    Part 4B Overall survival of response with trametinib dosed in combination with panitumumab

    Trial Keywords

    anti-EGFR antibody

    BRAF inhibitor

    MEK inhibitor

    colorectal cancer