Clinical trial NCT00619424 (phase 1, status: completed)
Conditions: lung cancer, non-small cell
ICD codes: C78.00, C78.01, C78.02, D14.30, D14.31, D14.32, C34.2
Drugs: pazopanib, erlotinib, pemetrexed
SMILES: ClCCN(CCCl)P1(=O)NCCCO1, COCCOC1=CC2=C(C=C1OCCOC)C(NC1=CC(=CC=C1)C#C)=NC=N2, [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H]
Eligibility criteria:

        Inclusion Criteria:

        A subject will be considered eligible for inclusion in this study only if all of the
        following criteria are met:

          -  Subjects must provide written informed consent prior to performance of study specific
             procedures or assessments, and must be willing to comply with treatment and follow up.

             ·Procedures conducted as a part of routine clinical management of the subject (e.g.,
             blood count, imaging study) and obtained prior to signed informed consent may be
             utilized for Screening or Baseline purposes provided these tests are obtained as
             specified in the protocol.

          -  Histologically- or cytologically-confirmed diagnosis of advanced solid tumor that has
             failed standard therapy or for which there is no standard therapy. Subjects for whom
             erlotinib or pemetrexed are standard therapy may also be entered.

          -  Age ≥18 years.

          -  ECOG Performance status must be ≤1.

          -  Adequate organ system function as defined in Table 9. System (Laboratory Values)

        Hematologic:

        Absolute neutrophil count (ANC) ((≥1.5 X 10^9/L)) Hemoglobin (≥10 g/dL) Platelets (≥ 100 X
        10^9/L) Prothrombin time (PT) or international normalized ration (INR) (≤ 1.2 X upper limit
        of normal (ULN)) Activated partial thromboplastin time (APTT) (≤ 1.2 X ULN)

        Hepatic:

        Total bilirubin (≤1.5 X ULN) AST and ALT (≤ 2.5 X ULN)

        Renal:

        Serum creatinine (≤ 1.5 mg/dL) Or, if greater than 1.5 mg/dL Calculated creatinine
        clearance (≤ 50 mL/min) Urine Protein to Creatinine Ratio (UPC)2 < 1

          1. Subjects may not have had a transfusion within 7 days of screening assessment.

          2. If UPC ≥ 1, then a 24-hour urine protein must be assessed and 24-hour urine protein
             must be <1 g protein to be eligible.

               -  Measurable disease on CT scan.

               -  A female subject is eligible to enter and participate in the study if she is of:
                  • Non-childbearing potential (i.e., physiologically incapable of becoming
                  pregnant), including any woman who has had:• A hysterectomy

               -  A bilateral oophorectomy (ovariectomy)

               -  A bilateral tubal ligation

               -  Is post-menopausal:

               -  Subjects not using hormone replacement therapy (HRT) must have experienced total
                  cessation of menses for ≥1 year and be greater than 45 years in age, OR, in
                  questionable cases, have a follicle stimulating hormone (FSH) value >40mIU/mL and
                  an estradiol value <40pg/mL (<140pmol/L).

               -  Subjects must discontinue HRT prior to study enrollment due to the potential for
                  inhibition of CYP enzymes that metabolize estrogens and progestins (see Section
                  8). For most forms of HRT, at least 2 4 weeks must elapse between the cessation
                  of HRT and determination of menopausal status; length of this interval depends on
                  the type and dosage of HRT. If a female subject is determined not to be
                  post-menopausal, they must use adequate contraception, as defined immediately
                  below.

               -  OR of Childbearing potential, including any female who has had a negative serum
                  pregnancy test within 2 weeks prior to the first dose of study treatment,
                  preferably as close to the first dose as possible, and agrees to use adequate
                  contraception. GSK acceptable contraceptive methods, when used consistently and
                  in accordance with both the product label and the instructions of the physician,
                  are as follow:

               -  An intrauterine device with a documented failure rate of less than 1% per year.

               -  Vasectomized partner who is sterile prior to the female subject's entry and is
                  the sole sexual partner for that female.

               -  Complete abstinence from sexual intercourse for 14 days before exposure to
                  investigational product, through the dosing period, and for at least 21 days
                  after the last dose of investigational product.

               -  Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
                  film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

        Note: Oral contraceptives are not reliable due to potential drug-drug interactions.

        Female subjects who are lactating should discontinue nursing prior to the first dose of
        study drug and should refrain from nursing throughout the treatment period and for 14 days
        following the last dose of study drug.

        A male with a female partner of childbearing potential is eligible to enter and participate
        in the study if he uses a barrier method of contraception or abstinence during the study.

          -  For Arm B (pemetrexed plus pazopanib) subjects:

          -  Must be able to permanently discontinue aspirin dose of ≥1.3 g/day for ≥10 days before
             through ≥10 days after pemetrexed disodium treatment. All subjects should be able to
             interrupt intake of NSAIDs with longer half lives (e.g., nabumetone, piroxicam,
             oxaprozin) for at least 5 days before, the day of, and 2 days following pemetrexed
             disodium administration.

          -  With mild to moderate renal insufficiency (CrCl from 50-79mL/min) should avoid taking
             NSAIDs with short elimination half lives (e.g., fenoprofen, indomethacin, ketoprofen,
             tolmetin, meclofenamate) for a period of 2 days before, the day of, and 2 days
             following administration of pemetrexed disodium.

        Exclusion Criteria:

          -  Prior use of pazopanib, erlotinib (for subjects in Arm A), or pemetrexed (for subjects
             in Arm B).

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
             metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
             medication for one week prior to date of first dose of study drug. Screening with CNS
             imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is
             required for all subjects.

          -  Clinically significant gastrointestinal abnormalities which might interfere with oral
             dosing, including but not limited to:

          -  Malabsorption syndrome

          -  Major resection of the stomach or small bowel that could affect the absorption of
             study drug

          -  Active peptic ulcer disease

          -  Inflammatory bowel disease

          -  Ulcerative colitis, or other gastrointestinal conditions with increased risk of
             perforation

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 28 days prior to beginning study treatment.

          -  Presence of uncontrolled infection

          -  Prolongation of corrected QT interval (QTc) > 480 msecs.

          -  History of any one of more of the following cardiovascular conditions within the past
             6 months:

          -  Cardiac angioplasty or stenting

          -  Myocardial infarction

          -  Unstable angina

          -  Symptomatic peripheral vascular disease

          -  Class III or IV congestive heart failure as defined by the New York Heart Association
             (NYHA)

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140mmHg
             or diastolic blood pressure (DBP) of ≥ 90mmHg]. Note: Initiation or adjustment of
             antihypertensive medication(s) is permitted prior to study entry. Blood pressure must
             be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean
             SBP / DBP values from each blood pressure assessment must be < 140/90mmHg in order for
             a subject to be eligible for the study.

          -  History of cerebrovascular accident (CVA), pulmonary embolism or insufficiently
             treated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with
             recent DVT who have been treated with therapeutic anti coagulant agents (excluding
             therapeutic warfarin) for at least 6 weeks are eligible. As noted in Section 8.2, use
             of therapeutic levels of warfarin must have ended more than 14 days prior to first
             dose of study drug.

          -  Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
             presence of any non-healing wound, fracture, or ulcer.

          -  Evidence of active bleeding or bleeding diathesis.

          -  Hemoptysis within 6 weeks prior to first dose of study drug.

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with subject's safety, provision of informed consent, or compliance to
             study procedures.

          -  Is unable or unwilling to discontinue prohibited medications, as listed in Section
             8.2, for 14 days or five half-lives (whichever is longer) of a drug prior to the first
             dose of study drug and for the duration of the study.

          -  Use of an investigational agent, including an investigational anti-cancer agent,
             within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study
             drug.

          -  Prior use of an investigational or licensed tyrosine kinase inhibitor that targets
             VEGF receptors. Note: Prior use of bevacizumab is allowed.

          -  Is now undergoing and/or has undergone in the 28 days immediately prior to first dose
             of study drug, any cancer therapy (surgery, tumor embolization, chemotherapy,
             radiation therapy, immunotherapy, biological therapy, or hormonal therapy). Note: For
             prior bevacizumab therapy, at least 40 days should have elapsed between last dose of
             bevacizumab and first dose of study drug.

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 (with the
             exception of Grade 2 alopecia) and/or that is progressing in severity.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib, erlotinib, or pemetrexed.