Expanded Phase I Pazopanib and Everolimus in Advanced Solid Tumors and Previously Treated Advanced Urothelial Cancer
Condition: Solid Tumor; Kidney Cancer
MeSH terms: Kidney Neoplasms
Intervention: pazopanib; everolimus
Intervention MeSH terms: Everolimus
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: This is a Phase I study with multiple arms related to planned dose escalation.
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: RAD001; pazopanib; everolimus; advanced cancer

Summary:

      This research study is evaluating the combination of pazopanib and everolimus in patients
      that have a malignancy that is metastatic or unresectable and for which standard curative or
      palliative measures do not exist or are no longer effective, or metastatic or locally
      advanced unresectable kidney cancer. In this research study the investigators are testing the
      safety of the combination of pazopanib and everolimus and finding the appropriate doses to
      use for further studies.
    

Eligibility criteria:

        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 effected.

          -  Expansion Cohort Only: Participants must have histologically or cytologically
             confirmed metastatic or locally advanced unresectable kidney cancer.

          -  Expansion Cohort Only: Participants must have measurable disease, defined as at least
             one lesion that can be accurately measured in at least one dimension at 20mm or
             greater with conventional techniques or as 10mm or greater with spiral CT.

          -  Expansion Cohort Only: Previously treated with at least one anti-angiogenic agent,
             including but not limited to bevacizumab, sunitinib, or sorafenib. No more than 4
             lines of prior systemic therapy for kidney cancer, mTOR pathway inhibitors other than
             RAD001 are allowed.

          -  18 years of age or older

          -  Life expectancy of greater than 3 months

          -  ECOG performance status of 0 or 1

          -  Normal organ and marrow function as outlined in the protocol

          -  Able to swallow oral medications

          -  Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE v4.0 grade 1
             or less

          -  Women are eligible to participate if she is of non-child bearing potential or agrees
             to use adequate contraception

          -  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 must use a barrier method of
             contraception or abstinence during the study

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 4 weeks prior to
             entering the study or thos who have not recovered from adverse events due to agents
             administered more than 4 weeks earlier. Current treatment with leuprolide or other
             GnRH agonists is permitted on the Phase 1 portion of the study.

          -  Participants may not be receiving any other study agents.

          -  Prior RAD001 or pazopanib therapy

          -  History of 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.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib or everolimus

          -  History of any of the following cardiovascular conditions within the past 6 months:
             Cardiac angioplasty or stenting; myocardial infarction; unstable angina; coronary
             artery by-pass graft surgery; symptomatic peripheral vascular disease; Class III or IV
             congestive heart failure

          -  Poorly controlled hypertension

          -  History of cerebrovascular accident, pulmonary embolism, or untreated deep venous
             thrombosis within the past 6 months

          -  Prior major surgery or trauma within 28 days prior to first dose of study drug, and/or
             not recovered from effects of that surgery, and/or presences of an non-healing wound,
             fracture or ulcer, or patients that may require surgery during the course of treatment

          -  Evidence of active bleeding or bleeding diathesis

          -  Known endobronchial lesions or involvement of large pulmonary vessels by tumor

          -  Hemoptysis within 6 weeks of the first dose of study drug

          -  Clinically significant gastrointestinal abnormalities that may increase the risk of GI
             bleeding

          -  Expansion Cohort Only: Currently active second malignancy other than non-melanoma skin
             cancers

          -  Presence of uncontrolled infection

          -  Liver disease such as chronic cirrhosis, active hepatitis or chronic persistent
             hepatitis

          -  Uncontrolled diabetes

          -  Pregnant or breastfeeding

          -  Chronic treatment with systemic corticosteroids or other immunosuppressive agent

          -  Treatment with strong CYP3A4 inhibitors

          -  Treatment with strong CYP3A4 inducers

          -  Patients should not receive immunization with attenuated live vaccines within one week
             of study entry or during study period

          -  Prolongation of corrected QT interval > 480msecs

          -  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 greater than grade 1
             and/or that is progressing in severity.

          -  Any serious and/or pre-existing medical, psychiatric, or other condition that could
             interfere with subject safety, obtaining informed consent or compliance with study
             procedures

          -  HIV-positive individuals on combination antiretroviral therapy