Clinical trial NCT02188264 (phase 1, status: active, not recruiting)
Conditions: recurrent colorectal carcinoma, solid neoplasm, stage iiia colorectal cancer ajcc v7, stage iiib colorectal cancer ajcc v7, stage iiic colorectal cancer ajcc v7, stage iva colorectal cancer ajcc v7, stage ivb colorectal cancer ajcc v7
ICD codes: C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2, C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2
Drugs: cyclosporine, selumetinib
SMILES: CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O)C(C)C, CN1C=NC2=C1C=C(C(O)=NOCCO)C(NC1=C(Cl)C=C(Br)C=C1)=C2F
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 (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