Clinical Trials /

MEK and MET Inhibition in Colorectal Cancer

NCT02510001

Description:

This trial is designed to try two new cancer drugs together for the first time. The investigators think that they might be effective in some types of bowel cancer. The first part of the trial will see what doses of the two drugs can safely be given together. Once the investigators have identified a suitable dose combination they will look at how effective treatment is in bowel cancers where either the RAS gene is mutated, or MET is over-active. In the trial the investigators will look at samples of blood, skin and tumour to check the drugs are working in the way expected. The trial will take place in three sites in the UK and 5 sites in Europe. The trial is funded as part of the European commission's FP7 program.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

MErCuRIC1: MEK and <span class="go-doc-concept go-doc-biomarker">MET</span> Inhibition in <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span>

Title

  • Brief Title: MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer
  • Official Title: A Phase 1 Study of MEK 1/2 Inhibitor PD-0325901 With cMET Inhibitor PF-03241066 in RASMT and RASWT (With Aberrant c-MET) Colorectal Cancer Patients
  • Clinical Trial IDs

    NCT ID: NCT02510001

    ORG ID: OCTO-049

    Trial Conditions

    Solid Tumour

    Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    Crizotinib PF-02341066 Dose Escalation Phase 1., Dose Escalation Phase 2., Dose Escalation Phase 3., Diose Escalation Phase 4., Dose Escalation Phase 5., Dose Escalation Phase 6., Dose ExpansionPhase
    PD-0325901 Dose Escalation Phase 1., Dose Escalation Phase 2., Dose Escalation Phase 3., Diose Escalation Phase 4., Dose Escalation Phase 5., Dose Escalation Phase 6., Dose ExpansionPhase

    Trial Purpose

    This trial is designed to try two new cancer drugs together for the first time. The
    investigators think that they might be effective in some types of bowel cancer. The first
    part of the trial will see what doses of the two drugs can safely be given together. Once
    the investigators have identified a suitable dose combination they will look at how
    effective treatment is in bowel cancers where either the RAS gene is mutated, or MET is
    over-active. In the trial the investigators will look at samples of blood, skin and tumour
    to check the drugs are working in the way expected. The trial will take place in three sites
    in the UK and 5 sites in Europe. The trial is funded as part of the European commission's
    FP7 program.

    Detailed Description

    This is a two stage study. Firstly a dose escalation step is used to define the best dose
    for the drug combination, using the rolling 6 design where up to 6 patients are recruited at
    each dose level, and increasing the dose of one or other agent according to the side effects
    of treatment.

    Second the combination is observed in 24 patients with bowel cancer for its efficacy and
    tolerability. patients who give consent will have their archival tumour samples tested for
    RAS and c-MET status.

    Potential participants will, after giving consent, undergo screening tests to ensure that it
    is safe for them to take part. these involve a detailed medical history, physical exam,
    blood tests, ophthalmology exam, ECG and ultrasound and skin biopsies. The size and extent
    of tumours is also assessed by CT and/or MRI scan.

    Assuming that these test results are satisfactory, patients start on PD-0325901 first for
    one week. On Day -7 a physical exam, ECG and blood test is performed, with a repeat blood
    test on Day -6. End of first week PD samples of blood are taken to observe the level of
    PD-0325901. Day 1 PF-02341066 is introduced after further clinical safety assessments. There
    are further blood samples taken over 24 hours to measure levels of PD-0325901 and
    PF-02341066 on days 21 and 28 of the first cycle.

    Patients have weekly visits when side effects are reviewed and a physical examination is
    performed. On Day 15 a second skin biopsy is taken along with blood tests to assess liver
    and renal function. At the end of the first 4 weeks cycle an ophthalmology exam is compared
    with the baseline assessment.

    for subsequent cycles, visits remain weekly and include safety assessments as per Day 1.
    Blood levels of PD-0325901 and PF-02341066 are measured on day 21 of even numbered cycles.
    In addition the tumour size is checked every second cycle, and the study treatment stopped
    if the tumour continues to grow.

    When patients stop taking the study treatment they will be reviewed after 4 weeks for any
    side effects and have a physical examination and other safety tests performed.

    For patients entering the expansion phase of the trial the procedures are similar, except
    that there is a pre-screening stage where tumour biopsies are required. Patients will have a
    sample of their tumour assessed, following consent, to determine their RAS and cMET status.
    This may involve a fresh biopsy. If suitable, the patient will be entered into the screening
    for the dose expansion phase and a fresh tumour biopsy may be taken if not already done so.
    The study schedule is the same as for the escalation phase. At the end of treatment a
    further tumour biopsy is taken.

    After trial participation patients will be offered further care with the trial team or their
    referring oncology team as appropriate.

    Trial Arms

    Name Type Description Interventions
    Dose Escalation Phase 1. Experimental Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Dose Escalation Phase 2. Experimental Crizotinib 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Dose Escalation Phase 3. Experimental Crizotinib 250mg OD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Diose Escalation Phase 4. Experimental Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Dose Escalation Phase 5. Experimental Crizotinib 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Dose Escalation Phase 6. Experimental Crizotinib 200mg OD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle Crizotinib, PD-0325901
    Dose ExpansionPhase Experimental Crizotinib 200mg OD/200mg BD Days 1-28 continuously PD-0325901 2/4/8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle. Dosage to be determined once the recommended Phase II dose has been identified in the dose escalation phase. Crizotinib, PD-0325901

    Eligibility Criteria

    Inclusion Criteria:

    A patient will be eligible for inclusion in this study if all of the following criteria
    apply.

    All patients:

    - Age 16 years

    - ECOG performance status 0-1

    - Adequate respiratory and cardiac function (left ventricular function WNL on
    echocardiography)

    - Able to give informed consent and be capable of co-operating with the protocol

    - Haematological and biochemical indices within the ranges shown below:

    - Haemoglobin (Hb) 9g/dl (transfusion to achieve this allowed),

    - Neutrophils 1,500/l,

    - Platelet count 100,000/l,

    - AST or ALT 3 x ULN, alkaline phosphatase 2 x ULN,

    - Serum Bilirubin 1.5 x ULN,

    - Creatinine Clearance 30ml/min (Calculated by Cockcroft Gault equation, or by
    EDTA)

    - Able to swallow oral medication

    - Only well-controlled CNS metastatic disease ie stable for at least 12 weeks after
    therapy (surgery, radiotherapy) for brain metastases.

    - Life expectancy of at least 3 months.

    Dose escalation phase

    - Patients with any advanced solid tumours

    - Patients for whom the combination of PF-02341066 with PD0325901 is a reasonable
    option.

    Dose expansion phase

    Patients will be eligible for pre-screening for MErCuRIC provided that:

    - They have given informed consent to screening.

    - They are willing to undergo a biopsy for assessment of tumour RAS mutation status and
    c-MET assessment.

    - The Investigator anticipates that they are likely to satisfy the eligibility criteria
    for the trial. Formal screening should not be performed until the tumour
    pre-screening result is known.

    Eligibility for the trial, in patients passing pre-screening, requires:

    - Histologically confirmed colon adenocarcinoma RASMT (codon 12, 13, 61 mutations) or
    RASWT/c-MET+, with progressive disease on or within 6 months of completion of
    adjuvant therapy or after chemotherapy/targeted therapies for metastatic disease.

    - Metastases accessible for biopsy

    - At least one other measurable lesion (according to RECIST v1.1).

    - Unsuitable for potential curative resection.

    Exclusion Criteria:

    All patients

    - Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery
    bypass graft or cerebrovascular accident within 6 months prior to starting treatment.

    - Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade 2 or
    uncontrolled atrial fibrillation.

    - History of extensive disseminated/bilateral or known presence of Grade 3 or 4
    interstitial fibrosis or interstitial lung disease, including a history of
    pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung
    disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior
    radiation pneumonitis is allowed.

    - Spinal cord compression unless treated with the patient attaining good pain control
    and stable or recovered neurologic function.

    - Carcinomatous meningitis or leptomeningeal disease.

    - History of hypoalbuminaemia, with peritoneael disease or pleural disease, where
    patient has requirement for ascites or pleural taps.

    - History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient
    considered at risk of retinal vein thrombosis.

    - Active infections (including chronic hepatitis type B or C and HIV infection if
    status known), severe immunologic defect, compromised bone marrow function

    - Other severe acute or chronic medical (including severe gastro-intestinal disorders
    e.g. partial bowel obstruction, malabsorption, active inflammatory bowel disease) or
    psychiatric conditions or laboratory abnormalities that the investigator considers
    would make the patient a poor trial candidate, would impart excess risk associated
    with study participation or drug administration or could interfere with protocol
    compliance or the interpretation of trial results.

    - Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are
    CYP3A4 substrates with narrow therapeutic indices.

    - Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or
    chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C)
    and four weeks for investigational medicinal products before treatment. Patients with
    prostate cancer may continue to receive endocrine therapy to maintain castrate levels
    of androgens.

    - Resting ECG with QTc >480msec at 2 or more time points within a 24h period.

    - Requirement for medication known to prolong QT interval.

    - History of other malignancy less than 5 years before the diagnosis of current cancer,
    EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix
    treated surgically with curative intent, other malignant tumours that have been
    treated curatively and patient is deemed disease-free

    - Women with the ability to become pregnant (or already pregnant or lactating).
    However, those female patients who have a negative serum or urine pregnancy test
    before enrolment and agree to use two highly effective forms of contraception (oral,
    injected or implanted hormonal contraception and condom plus spermicide, have an
    intra-uterine device and condom plus spermicide, diaphragm with spermicidal gel and
    condom plus spermicide) for four weeks before entering the trial, during the trial
    and for six months afterwards are considered eligible.

    - Male patients with partners of child-bearing potential (unless they agree to take
    measures not to father children by using any two forms of highly effective
    contraception including: oral, injected or implanted hormonal contraception and
    condom plus spermicide, have an intra-uterine device and condom plus spermicide,
    during the trial and for six months afterwards). Men with pregnant or lactating
    partners should be advised to use barrier method contraception (condom plus
    spermicidal gel) during the trial and for six months afterwards to prevent exposure
    to the foetus or neonate.

    - Prior exposure to a HGF or cMET inhibitor and/or a MEK inhibitor.

    Minimum Eligible Age: 16 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximal tolerated dose (MTD) of PD-0325901 with PF-02341066

    Clinical response to PD-0325901combined with PF-02341066

    Radiological response to PD-0325901 with PF-02341066

    Secondary Outcome Measures

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to safety blood samples for haematology, biochemistry and coagulation data.

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ECOG data.

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to vital signs of temperature, blood pressure and heart rate data.

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ECG measurements.

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to weight measurements.

    Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ophthalmic measurements.

    Recommended phase II (RPII) dose and schedule guided by PK data.

    Recommended phase II (RPII) dose and schedule guided by PD data.

    Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic plasma oral clearance and t1/2 etc for PF-02341066 and PD0325901and its metabolite.

    Pharmacodynamic (PD) biomarkers of PD-0325901 and PF-02341066 in paired skin biopsies, tumour biopsies (where possible), in serum and PBMCs.

    Tumour assessment using CT scan and modified RECIST version 1.1 and progression free and overall survival.

    Carinoembryonic antigen blood level assessments.

    Tumour assessment using CT scan and modified RECIST version 1.1, and progression free and overall survival.

    Carcinoembryonic antigen blood level assessment.

    Adverse events according to NCI CTCAE v4.03 across all treatment cycles.

    Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and PD0325901and its metabolite.

    Pharmacokinetic oral clearance and plasma t1/2 for PF-02341066 and PD0325901and its metabolite.

    Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD0325901 in paired skin biopsies.

    Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD0325901 in paired tumour biopsies (where possible).

    Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD0325901 in paired tumour biopsies (where possible).

    Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD0325901 in plasma blood samples.

    Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD0325901 in plasma PBMC blood samples.

    Trial Keywords

    RASMT CRC

    RASWT/c-MET CRC

    Dose Escalation

    histologically or cytologically confirmed

    Dose Expansion