Clinical Trials /

Selumetinib and Cyclosporine in Treating Patients With Advanced Solid Tumors or Advanced or Metastatic Colorectal Cancer

NCT02188264

Description:

This phase I/Ib trial studies the side effects and best dose of selumetinib when given together with cyclosporine in treating patients with solid tumors or colorectal cancer that have spread to other places in the body and cannot be cured or controlled with treatment. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as cyclosporine, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Giving selumetinib and cyclosporine may be a better treatment for solid tumors or colorectal cancer.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Selumetinib</span> and <span class="go-doc-concept go-doc-intervention">Cyclosporine</span> in Treating Patients With Advanced Solid Tumors or Advanced or Metastatic <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span>

Title

  • Brief Title: Selumetinib and Cyclosporine in Treating Patients With Advanced Solid Tumors or Advanced or Metastatic Colorectal Cancer
  • Official Title: A Phase IB Study of the Combination of AZD6244 Hydrogen Sulfate (Selumetinib) and Cyclosporin A (CsA) in Patients With Advanced Solid Tumors With an Expansion Cohort in Metastatic Colorectal Cancer
  • Clinical Trial IDs

    NCT ID: NCT02188264

    ORG ID: NCI-2014-01484

    NCI ID: NCI-2014-01484

    Trial Conditions

    Recurrent Colorectal Carcinoma

    Solid Neoplasm

    Stage IIIA Colorectal Cancer

    Stage IIIB Colorectal Cancer

    Stage IIIC Colorectal Cancer

    Stage IVA Colorectal Cancer

    Stage IVB Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    Cyclosporine 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, CYCLOSPORINE, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya Treatment (selumetinib and cyclosporine)
    Selumetinib ARRY-142886, AZD6244, MEK Inhibitor AZD6244, SELUMETINIB Treatment (selumetinib and cyclosporine)

    Trial Purpose

    This phase I/Ib trial studies the side effects and best dose of selumetinib when given
    together with cyclosporine in treating patients with solid tumors or colorectal cancer that
    have spread to other places in the body and cannot be cured or controlled with treatment.
    Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for
    cell growth. Biological therapies, such as cyclosporine, use substances made from living
    organisms that may stimulate or suppress the immune system in different ways and stop tumor
    cells from growing. Giving selumetinib and cyclosporine may be a better treatment for solid
    tumors or colorectal cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the
    combination of AZD6244 (selumetinib) and cyclosporin A (cyclosporine) in adult patients with
    advanced solid tumors.

    SECONDARY OBJECTIVES:

    I. To determine the safety profile and tolerability of this regimen in this patient
    population.

    II. To determine the pharmacokinetics of the combination. III. To evaluate the selected
    biomarkers of drug effect in patients with advanced solid tumors or refractory metastatic
    colorectal cancer (CRC).

    IV. Evaluate the activity of the combination in terms of objective response rate (per
    Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), progression-free survival (PFS).

    OUTLINE: This is a phase I, dose-escalation study of selumetinib followed by a phase Ib
    study.

    Patients receive selumetinib orally (PO) twice daily (BID) on day -7 of course 1 and then on
    days 1-28. Patients also receive cyclosporine PO BID on day -3 of course 1 and then on days
    1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
    toxicity.

    After completion of study treatment, patients are followed up for 30 days.

    Trial Arms

    Name Type Description Interventions
    Treatment (selumetinib and cyclosporine) Experimental Patients receive selumetinib PO BID on day -7 of course 1 and then on days 1-28. Patients also receive cyclosporine PO BID on day -3 of course 1 and then on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cyclosporine, Selumetinib

    Eligibility Criteria

    Inclusion Criteria:

    - Before any study procedures are performed, subjects will have the details of the
    study described to them, and they will be given a written informed consent document
    to read; then, if subjects consent to participate in the study, they will indicate
    that consent by signing and dating the informed consent document in the presence of
    study personnel

    - DOSE ESCALATION PHASE: Histological or cytopathological diagnosis of an advanced
    cancer that is refractory to standard therapy or for which no standard therapy exists

    - COHORT EXPANSION PHASE: Histological or cytopathological diagnosis of
    advanced/metastatic unresectable colorectal cancer with known rat sarcoma viral
    oncogene homolog (RAS) mutational status; patients with known B-Raf proto-oncogene,
    serine/threonine kinase (BRAF) mutations will not be eligible for the expansion
    cohort; all patients must have received and progressed or be intolerant of an
    oxaliplatin-containing regimen and an irinotecan-containing regimen

    - COHORT EXPANSION PHASE: At least one tumor lesion amenable to core needle biopsy
    without unacceptable risk of a major procedural complication (one pretreatment and at
    least one on-treatment biopsy will be performed)

    - COHORT EXPANSION PHASE: Patient must have measurable lesions as defined by RECIST
    version 1.1 criteria

    - Eastern Cooperative Oncology Group (ECOG) performance status 0-1

    - Estimated life expectancy > 3 months

    - Absolute neutrophil count (ANC) >= 1,500/mcl

    - Platelets >= 100,000/mcl

    - Hemoglobin >= 9 g/dl

    - Estimated glomerular filtration rate (eGFR) greater than or equal to 60 ml/min/1.73
    m^2

    - Serum total bilirubin < 1.5 x upper limit or normal (ULN)

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]),
    alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
    x ULN; if liver involvement, AST, ALT =< 5.0 x ULN

    - Alkaline phosphatase =< 2.5 x ULN; if liver involvement, alkaline phosphatase =< 5.0
    x ULN

    - Serum albumin >= 2.5 g/dl

    - International normalized ratio (INR) =< 1.5 x ULN or prothrombin time (PT) =< 1.5 x
    ULN seconds above control unless patient is currently receiving warfarin therapy for
    the treatment or prevention of venous thrombosis

    - A male subject of fathering potential must use an adequate method of contraception to
    avoid conception throughout the study (and for up to 12 weeks after the last dose of
    study drug) to minimize the risk of pregnancy; if the partner is pregnant or
    breastfeeding, the subject must use a condom

    - Women of childbearing potential (WOCBP) must be using an adequate method of
    contraception to avoid pregnancy throughout the study and for up to 12 weeks after
    the last dose of study drug to minimize the risk of pregnancy; WOCBP must have a
    negative serum or urine pregnancy test within 72 hours before the start of the
    investigational product

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

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
    nitrosoureas or mitomycin C) prior to entering the study or those who have not
    recovered from adverse events due to agents administered more than 4 weeks earlier

    - Patients who are receiving any other investigational agents

    - Prior full field radiotherapy < 4 weeks or limited field radiotherapy < 2 weeks prior
    to first study drug administration

    - Patients with brain metastases may participate in this trial provided they are
    clinically stable; patients who are < 1 month from definitive therapy, receiving
    steroid therapy or taper, or anti-convulsant medications (started for brain
    metastases) must not be included

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to AZD6244 or cyclosporine A or their excipients

    - Patients with a history of thrombotic or embolic events within the last six months
    such as a cerebrovascular accident (including transient ischemic attacks), pulmonary
    embolism

    - Cardiac conditions as follows:

    - Active coronary artery disease, unstable or newly diagnosed angina or myocardial
    infarction less than 12 months prior to first study drug administration

    - Class II-IV New York Heart Association (NYHA) congestive heart failure

    - Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg and diastolic
    BP > 90 mmHg for 24 hours) despite optimal medical management; blood pressure
    must be below 140/90 mmHg at screening; subjects with a history of hypertension
    who are receiving treatment with calcium channel blockers that are cytochrome
    P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates should be changed
    to an alternative antihypertensive medication prior to first study drug
    administration

    - Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
    or digoxin

    - Corrected QT interval (QTc) (Frederica) prolongation > 480 msec

    - Subjects with valvular heart disease Common Terminology Criteria for Adverse
    Events (CTCAE) (version 4.0) grade 2

    - Known left ventricular ejection fraction (LVEF) < 50%

    - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris (Canadian
    Cardiovascular Society grade II-IV despite medical therapy), cardiac arrhythmia,
    active bleeding diatheses, or psychiatric illness/social situations that would limit
    compliance with study requirements

    - Known ophthalmological conditions as follows: intra-ocular pressure > 21 mmHg, or
    uncontrolled glaucoma (irrespective of intra-ocular pressure); current or past
    history of central serous retinopathy or retinal vein occlusion

    - Major surgical procedure, open biopsy, or significant traumatic injury less than 3
    weeks or those who receive minor surgical procedures (eg core biopsy or fine needle
    aspiration) within 1 week from first dose of first study drug administration

    - Known inability to swallow capsules

    - Known history of human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C
    (no additional laboratory tests for HIV, hepatitis [Hep] B, or Hep C are required for
    screening)

    - Inability to comply with study and/or follow-up procedures

    - Pregnant women are excluded from this study; breastfeeding should be discontinued if
    the mother is treated with AZD6244

    - Patients with hyponatremia (sodium < 130 mmol/L)

    - Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
    restore the serum potassium above this level prior to study entry)

    - Baseline serum calcium < 8.4 mg/dL (calcium supplementation may be given to restore
    the serum calcium above this level prior to study entry)

    - Prisoners or subjects who are involuntarily incarcerated

    - Patients who are compulsorily detained for treatment of either a psychiatric or
    physical (eg, infectious disease) illness

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of DLT defined as any grade 3 non-hematological toxicity or grade 4 hematological toxicity attributed to selumetinib or cyclosporine graded per National Cancer Institute (NCI) CTCAE version 4.0

    Secondary Outcome Measures

    Incidence of adverse events that occur after course 1, day 1 assessed using NCI CTCAE version 4.0

    Objective tumor response based on computed tomography scans (or magnetic resonance imaging if patients are allergic to iodinated contrast) per RECIST 1.1 criteria

    Pharmacokinetic (PK) parameters, including the distribution of area under the curve and maximum concentration

    Progression-free survival (PFS)

    Trial Keywords