A Study of RO4929097 in Patients With Advanced Renal Cell Carcinoma That Have Failed Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptor (VEGFR) Therapy
Condition: Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Renal Cell Cancer
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Gamma-Secretase Inhibitor RO4929097; Laboratory Biomarker Analysis
Intervention description: Given PO; Correlative studies
Intervention MeSH terms: 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Gamma Secretase Inhibitors and Modulators
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the activity of RO4929097 in renal cell carcinoma
      patients that have failed therapy with VEGF/VEGFR directed agents.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed predominant clear cell,
             renal cell carcinoma, NOS, that is recurrent or metastatic

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as >=
             20 mm with conventional techniques or as >= 10 mm with spiral CT scan; scans must be
             completed within 4 weeks prior to starting study treatment

          -  Patients must have had one prior therapy for non-resectable renal cell carcinoma with
             a VEGF/VEGFR targeted therapy (e.g. sunitinib, sorafenib, other VEGFR tyrosine kinase
             inhibitor, or bevacizumab)

               -  Prior treatment with mTOR inhibitors (Everolimus, Temsirolimus, or rapamycin) for
                  non-resectable disease is permitted

               -  Prior immunotherapy is permitted

               -  Only one line of prior VEGF/VEGFR is permitted

          -  Life expectancy of greater than 3 months

          -  ECOG performance status =< 2 (Karnofsky >= 60%)

          -  Patients must have normal organ and marrow function as defined below (within 7days
             prior to starting study treatment):

          -  Hemoglobin >= 90 g/L

          -  Absolute granulocyte count >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin =< 1.25 x ULN

          -  AST (SGOT)/ALT (SGPT) =< 1.5 x institutional upper limit of normal (=< 5 x ULN for
             patients with liver metastases)

          -  Creatinine =< within institutional normal limits OR creatinine clearance >=
             mL/min/1.73 m^2 for patients with creatinine levels above institutional (using
             Cockcroft-Gault formula)

          -  Patients must have no serious medical conditions such as myocardial infarction within
             6 months prior to entry, congestive heart failure, unstable angina, active
             cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension,
             uncontrolled psychotic disorders, serious infections, active peptic ulcer disease,
             psychiatric illness, or any other medical conditions that might be aggravated by
             treatment or limit compliance

          -  Patients must have no active malignancy at any other site

          -  Patients must be able to take oral medication and have no evidence of bowel
             obstruction

          -  The effects of RO4929097 on the developing human fetus at the recommended therapeutic
             dose are unknown; for this reason and because Notch signal pathway inhibitors are
             known to be teratogenic, if women of childbearing potential do not abstain from sexual
             activity (documentation that they have been abstinent from sexual activity at least 4
             weeks prior to study entry) they must use two forms of contraception (i.e., barrier
             contraception and one other method of contraception) at least 4 weeks prior to study
             entry; women of childbearing potential be can either be abstinent or use two forms of
             contraception for the duration of study participation, and be either abstinent or use
             two forms of contraception for at least 12 months post-treatment; men must use condoms
             when sexually active with women for the duration of study participation and at least
             12 months post-treatment

               -  Should a woman become pregnant or suspect she is pregnant while she or her
                  partner are participating in this study and for 12 months after study
                  participation, the patient should inform the treating physician immediately

               -  Pregnancy Testing; women of childbearing potential are required to have a
                  negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within
                  10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or
                  urine); a pregnancy test (serum or urine) will be administered every 4 weeks if
                  their menstrual cycles are regular or every 2 weeks if their cycles are irregular
                  while on study within the 24-hour period prior to the administration of
                  RO4929097; a positive urine test must be confirmed by a serum pregnancy test;
                  prior to dispensing RO4929097, the investigator or clinical staff must confirm
                  and document the patient's use of two contraceptive methods or abstinence, dates
                  of negative pregnancy test, and confirm the patient's understanding of the
                  teratogenic potential of RO4929097

               -  Female patients of childbearing potential are defined as follows:

                    -  Patients with regular menses

                    -  Patients, after menarche with amenorrhea, irregular cycles, or using a
                       contraceptive method that precludes withdrawal bleeding

                    -  Women who have had tubal ligation

               -  Female patients may be considered to NOT be of childbearing potential for the
                  following reasons:

                    -  The patient has undergone total abdominal hysterectomy with bilateral
                       salpingo-oophorectomy or bilateral oophorectomy

                    -  The patient is medically confirmed to be menopausal (no menstrual period)
                       for 24 consecutive months

                    -  Pre-pubertal females; the parent or guardian of young female patients who
                       have not yet started menstruation should verify that menstruation has not
                       begun; if a young female patient reaches menarche during the study, then she
                       is to be considered as a woman of childbearing potential from that time
                       forward

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients must not have had major surgery, chemotherapy, or radiation therapy within 4
             weeks of starting the study treatment (6 weeks for nitrosoureas or mitomycin C); prior
             palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at
             least one measurable lesion that had not been irradiated; patients must have recovered
             from the toxic effects from any prior therapy to =< grade 1, except alopecia

          -  Patients may not be receiving any other investigational agents concurrently

          -  Patients with controlled brain metastases (no radiographic progression following
             radiation and/or surgical treatment and no neurological signs or symptoms) that are
             clinically and radiologically stable for at least 6 months will be allowed but must
             NOT be currently taking corticosteroids (e.g. dexamethasone) to control neurologic
             symptoms of brain metastases

               -  Patients with unstable or symptomatic brain metastases, spinal core compression,
                  or carcinomatosis meningitis, or evidence of brain or leptomeningeal disease on
                  screening CT or MRI scan are excluded

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to RO4929097 or other agents used in the study

          -  Patients taking medications with narrow therapeutic indices that are metabolized by
             cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

          -  Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of
             CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently
             with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are
             taking concurrent medications that are strong inducers/inhibitors or substrates of
             CYP3A4 should be switched to alternative medications to minimize any potential risk;
             if such patients cannot be switched to alternative medications, they will be
             ineligible to participate in this study

          -  Patients with malabsorption syndrome or other condition that would interfere with
             intestinal absorption; patients must be able to swallow tablets

          -  Patients who are serologically positive for Hepatitis A, B or C, or have a history of
             liver disease, other forms of hepatitis or cirrhosis are ineligible

          -  Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia,
             hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the
             institution, despite adequate electrolyte supplementation are excluded from this study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia other than chronic, stable atrial fibrillation, or psychiatric
             illness/social situations that would limit compliance with study requirements

          -  Pregnant women are excluded from this study because RO4929097 is a Notch
             pathway-inhibiting agent with the potential for teratogenic or abortifacient effects;
             because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with RO4929097, breastfeeding should be
             discontinued if the mother is treated with RO4929097; these potential risks may also
             apply to other agents used in this study

          -  Known HIV-positive patients on combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with RO4929097; in addition,
             these patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy; appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated

          -  Cardiovascular: baseline (within 7days prior to starting study treatment) QTc > 450
             msec (male) or QTc > 470 msec (female)

               -  History of risk factors for QT interval prolongation, including, but not limited
                  to family or personal history of long QT syndrome, recurrent syncope without
                  known etiology or sudden unexpected death

               -  History of Torsades de Pointes or other significant cardiac arrhythmias or the
                  need for concomitant meds with known potential to prolong QT interval or
                  antiarrhythmics