A Phase I Study Of Pazopanib With Either Erlotinib Or Pemetrexed In Patients With Advanced Solid Tumors

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.