Pazopanib Hydrochloride and Everolimus in Treating Patients with Advanced Solid Tumors or Previously Treated Advanced Urothelial Cancer

Inclusion Criteria

• Phase I: Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective (or who are intolerant of such therapy)
• Life expectancy of greater than 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Leukocytes >= 3,000/mm^3
• Absolute neutrophil count >= 1,500/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin >= 9 g/dL; subjects may not have had a red blood cell (RBC) transfusion within 7 days of screening assessment
• Total bilirubin =< 1.5 X normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min for subjects with creatinine levels about institutional normal
• Prothrombin time (PT) or international normalized ratio (INR) =< 1.5 X institutional upper limit of normal (ULN) unless patients are on therapeutic anticoagulation with warfarin
• Partial thromboplastin time (PTT) =< 1.5 X institutional ULN unless patients are on therapeutic anticoagulation with warfarin
• Urine protein to urine creatinine ratio (UPC) < 1.0; if UPC >= 1 then a 24 hour urine protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to be eligible
• Total cholesterol =< 300 mg/dL AND fasting triglycerides =< 2.5 x institutional ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• Able to swallow oral medications
• Resolution of any pre-existing toxicity from prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 =< grade 1 except neuropathy (=< grade 2) and tinnitus (=< grade 2), and hearing loss (=< grade 4)
• A female is eligible to enter and participate in this study if she is of: * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: ** A hysterectomy ** A bilateral oophorectomy (ovariectomy) ** A bilateral tubal ligation, or ** 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 > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L) * Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins; 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 postmenopausal, they must use adequate contraception as defined immediately below during the trial and for 8 weeks after the last dose * 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; acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: 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, 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 * Female subjects who are lactating should not be in the trial * 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
• 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 part of the subject’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol
• EXPANSION COHORT ONLY: Metastatic or locally advanced unresectable urothelial carcinoma with histologic or cytologic confirmation at Dana-Farber Cancer Institute (DFCI) or Memorial Sloan-Kettering Cancer Center (MSKCC)
• EXPANSION COHORT ONLY: Participants must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• EXPANSION COHORT ONLY: Previously treated with at least one and not more than 3 lines of systemic chemotherapy including at least one of the following: a platinum agent, a taxane, or gemcitabine
• EXPANSION COHORT ONLY: Patients must have pre-treatment archival tumor tissue; one paraffin block, frozen curls, or at least 10 freshly-prepared unstained slides from the most representative single paraffin-embedded tumor tissue block should be submitted; slides from the primary tumor are preferred; if both the primary and metastatic tumor blocks are available, at least 10 slides from each of the sites should be submitted, if possible; if tissue from the primary tumor is not available, a paraffin block or unstained slides from a metastatic site are acceptable; fine needle aspirates (FNAs) have insufficient tumor tissue and are not permitted
• EXPANSION COHORT ONLY: Life expectancy of greater than 3 months
• EXPANSION COHORT ONLY: Karnofsky >= 70% or ECOG =< 1
• EXPANSION COHORT ONLY: White blood cell (WBC) >= 3,00/mm^3
• EXPANSION COHORT ONLY: Absolute neutrophil count >= 1,500/mm^3
• EXPANSION COHORT ONLY: Platelets >= 100,000/mm^3
• EXPANSION COHORT ONLY: Hemoglobin >= 9 g/dL; subjects may not have had an RBC transfusion within 7 days of screening assessment
• EXPANSION COHORT ONLY: Total bilirubin =< 1.5 X normal institutional limits
• EXPANSION COHORT ONLY: AST (SGOT)/ALT (SGPT) =< 2.5 X institutional upper limit of normal
• EXPANSION COHORT ONLY: Creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min for subjects with creatinine levels about institutional normal
• EXPANSION COHORT ONLY: Prothrombin time (PT) or international normalized ratio (INR) =< 2 X institutional upper limit of normal (ULN) unless patients are on therapeutic anticoagulation with warfarin
• EXPANSION COHORT ONLY: Partial thromboplastin time (PTT) =< 1.5 X institutional ULN unless patients are on therapeutic anticoagulation with warfarin
• EXPANSION COHORT ONLY: Urine protein to urine creatinine ratio (UPC) < 1.0; if UPC >= 1 then a 24 hour urine protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to be eligible
• EXPANSION COHORT ONLY: Total cholesterol =< 300 mg/dL AND fasting triglycerides =< 2.5 x institutional ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• EXPANSION COHORT ONLY: Able to swallow oral medications
• EXPANSION COHORT ONLY: Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE version 4.0 =< grade 1 except neuropathy (=< grade 2) and tinnitus (=< grade 2), and hearing loss (=< grade 4)
• EXPANSION COHORT ONLY: A female is eligible to enter and participate in this study if she is of: * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: ** A hysterectomy ** A bilateral oophorectomy (ovariectomy) ** A bilateral tubal ligation, or ** 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 > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L) * Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins; 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 postmenopausal, they must use adequate contraception as defined immediately below during the trial and for 8 weeks after the last dose * 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; acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: 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, 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 * Female subjects who are lactating not be included in the trial * 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
• EXPANSION COHORT ONLY: 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 part of the subject’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol

Exclusion Criteria

• Participants 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; current treatment with leuprolide or other gonadotropin-releasing hormone (GnRH) agonists is permitted on the Phase I portion of the study
• Participants may not be receiving any other study agents during the study or within 4 weeks of the start of the trial
• Prior everolimus or pazopanib therapy; other mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are allowed
• 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 6 weeks prior to the first dose of study drug; screening with CNS imaging studies (CT or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period; anticonvulsants will not be allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or everolimus (such as sirolimus or temsirolimus)
• Patients who have any severe and/or uncontrolled medical conditions such as: * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease * Symptomatic congestive heart failure of New York Heart Association class III or IV * Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-DNA and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) * Known severely impaired lung function (e.g. spirometry and diffusing capacity of the lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air) * Active, bleeding diathesis
• Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >= 140 mmHg or diastolic blood pressure [DBP] of >= 90mmHg); 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 < 140/90 mmHg in order for a subject to be eligible for the study
• History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months; subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
• Prior major surgery (defined as requiring general anesthesia) or trauma within 28 days prior to first dose of study drug, and/or not recovered from effects of that surgery, and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major), or patients that may require surgery during the course of the study
• Evidence of active bleeding or bleeding diathesis
• Known endobronchial lesions or involvement of large pulmonary vessels by tumor
• Hemoptysis within 6 weeks of first dose of study drug
• 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
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal (GI) bleeding including, but not limited to: * Active peptic ulcer disease; * Known intraluminal metastatic lesion/s with suspected bleeding; * 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
• “Currently active” second malignancy other than non-melanoma skin cancers; patients are not considered to have a “currently active” malignancy if they have completed therapy more than 3 years ago and are considered to have a less than 30% risk of relapse based on the enrolling investigator’s assessment and documented in the medical record; a history of prostate cancer that was identified incidentally following cystoprostatectomy or cystectomy for bladder cancer is acceptable, provided that the following criteria are met: * Stage T2N0M0 or lower * Gleason score =< 7, negative margins at surgery, and prostate specific antigen (PSA) undetectable after surgery
• Presence of uncontrolled infection
• Liver disease such as chronic cirrhosis, active hepatitis or chronic persistent hepatitis
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• Current treatment on another clinical trial
• Pregnant or breastfeeding
• Chronic treatment with systemic corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
• Patient is unable or unwilling to discontinue predefined prohibited medications listed in the protocol for 4 weeks of a drug (whichever is longer) prior to Visit 1 and for the duration of the study
• Treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors: * Cardiovascular: verapamil and diltiazem; * Antibiotics: clarithromycin, telithromycin, troleandomycin, erythromycin; * Human Immunodeficiency Virus (HIV): protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir); * Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole; * Antidepressants: nefazodone
• Other prohibited medications: * Oral hypoglycemics: tolbutamide, chlorpropamide; * Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine; * Neuroleptics: pimozide; * Antiarrhythmics: amiodarone, bepridil, flecainide, lidocaine, mexiletine, quinidine, propafenone; * Immune modulators: cyclosporine, tacrolimus, sirolimus; * Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine
• Treatment with strong CYP3A4 inducers: * Anticonvulsants: phenytoin, carbamazepine, Phenobarbital, oxcarbazepine; * Human immunodeficiency virus (HIV) antiretrovirals: efavirenz, nevirapine; * Antibiotics: rifampin (rifampicin), rifabutin, rifapentine; * Miscellaneous: St. John's Wort, modafinil, pioglitazone, troglitazone
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period; patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacille Calmette-Guerin (BCG), yellow fever, varicella, and TY21a typhoid vaccines
• Prolongation of corrected QT interval (QTc) > 480 msecs
• History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of stomach or small bowel that could interfere with absorption, distribution, metabolism, or excretion of study drugs
• Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity; hypothyroidism treated with medication is not excluded if thyroid-stimulating hormone (TSH) is within normal limits
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject safety, obtaining informed consent or compliance to study procedures; examples of such include uncontrolled diabetes, nonhealing wound, severe or uncontrolled infection, severe malnutrition, severely impaired lung function as defined as spirometry and diffusion capacity of carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (02) saturation that is 88% or less at rest on room air, ventricular arrhythmias, active ischemic heart disease, chronic liver or renal disease, or active upper GI tract ulceration
• HIV-positive individuals on combination antiretroviral therapy are ineligible
• Patients unwilling or unable to comply with protocol therapy, tests, and visits, or with a history of noncompliance with medical regimens
• EXPANSION COHORT ONLY: Participants 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
• EXPANSION COHORT ONLY: Participants may not be receiving any other study agents during the study or within 4 weeks of the start of the study
• EXPANSION COHORT ONLY: Prior mTOR pathway inhibitors or VEGF receptor inhibitor therapy
• EXPANSION COHORT ONLY: 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 6 weeks prior to the first dose of study drug; screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period; anticonvulsants will not be allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded
• EXPANSION COHORT ONLY: Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or everolimus (such as sirolimus or temsirolimus)
• EXPANSION COHORT ONLY: Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject safety, obtaining informed consent or compliance to study procedures * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, ventricular arrhythmias, active ischemic heart disease, or any other clinically significant cardiac disease * Symptomatic congestive heart failure of New York heart Association Class III or IV * Active (acute or chronic) or uncontrolled severe infection * Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) * Known severely impaired lung function (e.g. spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air)active, bleeding diathesis * Severe or uncontrolled infection, severe malnutrition * Chronic renal disease * Active upper GI tract ulceration
• EXPANSION COHORT ONLY: Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >= 140 mmHg or diastolic blood pressure [DBP] of >= 90mmHg); 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 < 140/90 mmHg in order for a subject to be eligible for the study
• EXPANSION COHORT ONLY: History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months; subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
• EXPANSION COHORT ONLY: Prior major surgery (defined as requiring general anesthesia) or trauma within 28 days prior to first dose of study drug, and/or not recovered from effects of that surgery, and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major), or patients that may require surgery during the course of the study
• EXPANSION COHORT ONLY: Evidence of active bleeding or bleeding diathesis
• EXPANSION COHORT ONLY: Known endobronchial lesions or involvement of large pulmonary vessels by tumor
• EXPANSION COHORT ONLY: Hemoptysis within 6 weeks of first dose of study drug
• EXPANSION COHORT ONLY: 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
• EXPANSION COHORT ONLY: Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding including, but not limited to: * Activepeptic ulcer disease * Known intraluminal metastatic lesion/s with suspected bleeding * Inflammatory bowel disease * Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
• EXPANSION COHORT ONLY: History of another malignancy within 3 years, except the following: cured basal/squamous cell carcinoma of the skin, excised carcinoma in situ of the cervix; a history of prostate cancer that was identified incidentally following cystoprostatectomy or cystectomy for bladder cancer is acceptable provided that that following criteria are met: * Stage T2N0M0 or lower * Gleason score =< 7 * Negative margins at surgery, and * PSA undetectable after surgery
• EXPANSION COHORT ONLY: Liver disease such as chronic cirrhosis, active hepatitis or chronic persistent hepatitis
• EXPANSION COHORT ONLY: Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• EXPANSION COHORT ONLY: Current treatment on another clinical trial
• EXPANSION COHORT ONLY: Pregnant or breastfeeding
• EXPANSION COHORT ONLY: Chronic treatment with systemic corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
• EXPANSION COHORT ONLY: Patient is unable or unwilling to discontinue predefined prohibited medications listed in the protocol for 4 weeks of a drug (whichever is longer) prior to visit 1 and for the duration of the study
• EXPANSION COHORT ONLY: Treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors: * Cardiovascular: verapamil and diltiazem; * Antibiotics: clarithromycin, telithromycin, troleandomycin, erythromycin; * Human Immunodeficiency Virus (HIV): protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir); * Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole; * Antidepressants: nefazodone
• EXPANSION COHORT ONLY: Other prohibited medications: * Oral hypoglycemics: tolbutamide, chlorpropamide; * Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine; * Neuroleptics: pimozide; * Antiarrhythmics: amiodarone, bepridil, flecainide, lidocaine, mexiletine, quinidine, propafenone; * Immune modulators: cyclosporine, tacrolimus, sirolimus; * Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine
• EXPANSION COHORT ONLY: Treatment with strong CYP3A4 inducers: * Anticonvulsants: phenytoin, carbamazepine, Phenobarbital, oxcarbazepine; * Human immunodeficiency virus (HIV) antiretrovirals: efavirenz, nevirapine; * Antibiotics: rifampin (rifampicin), rifabutin, rifapentine; * Miscellaneous: St. John's Wort, modafinil, pioglitazone, troglitazone
• EXPANSION COHORT ONLY: Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period; patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacille Calmette-Guerin (BCG), yellow fever, varicella, and TY21a typhoid vaccines
• EXPANSION COHORT ONLY: Prolongation of corrected QT interval (QTc) > 480 msecs
• EXPANSION COHORT ONLY: History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of stomach or small bowel that could interfere with absorption, distribution, metabolism, or excretion of study drugs
• EXPANSION COHORT ONLY: Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity; hypothyroidism treated with medication is not excluded if TSH is within normal limits
• EXPANSION COHORT ONLY: Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject safety, obtaining informed consent or compliance to study procedures
• EXPANSION COHORT ONLY: HIV-positive individuals on combination antiretroviral therapy are ineligible
• EXPANSION COHORT ONLY: Patients unwilling or unable to comply with protocol therapy, tests, and visits, or with a history of noncompliance with medical regimens
• EXPANSION COHORT ONLY: Female subjects who are pregnant or lactating are not eligible to participate in this study
• EXPANSION COHORT ONLY: Male patients whose sexual partner(s) are women of child-bearing potential (WOCBP) who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment