RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors
RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors
This phase I clinical trial is studying the side effects and best dose of RO4929097 when
 given together with capecitabine in treating patients with refractory solid tumors. RO4929097
 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
 Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either
 by killing the cells or by stopping them from dividing. Giving RO4929097 together with
 chemotherapy may kill more tumor cells.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) of RO4929097 and capecitabine administered
 in subjects with advanced solid tumors. (Part 1) II. To describe the dose-limiting toxicities
 (DLTs) of combined RO492097 and capecitabine. (Part 1) III. To determine the safety of
 RO4929097 and capecitabine administered in combination. (Part 1) IV. To determine the safety
 of RO4929097 and capecitabine in subjects with metastatic CRC. (Part 2a) V. To evaluate the
 safety of RO4929097 and capecitabine in combination for subjects with HER2/neu negative MBC.
 (Part 2b)

 SECONDARY OBJECTIVES:

 I. To determine the clinical activity of RO4929097 and capecitabine administered in
 combination to subjects with advanced solid tumors. (Parts 1, 2a, and 2b) II. To evaluate the
 changes in the expression of Notch1 signaling pathway members and downstream targets of Notch
 by PCR including HEs1, 3 and 5; Hey 1 and 2 after treatment with RO4929097 at the MTD
 expansion cohorts. (Parts 1, 2a, and 2b) III. To determine the pharmacokinetic and
 pharmacogenomic profiles of the combination of RO4929097 and capecitabine. (Parts 1, 2a, and
 2b) IV. To determine the progression-free survival (PFS) of RO4929097 and capecitabine when
 administered at the MTD level in patients with metastatic colorectal cancer (CRC) and a
 history of 1 or 2 prior therapies. (Part 2a) V. To determine the response and overall
 survival (OS) rates following RO4929097 and capecitabine administration at the MTD level in
 subjects with metastatic CRC. (Part 2a) VI. To determine the overall response rate (ORR) of
 RO4929097 and capecitabine when administered at the MTD level to subjects when administered
 first or second line for HER2/neu negative metastatic breast cancer (MBC). (Part 2b) V. To
 determine the progression-free and overall survival rates following RO4929097 and
 capecitabine administration at the MTD level in subjects with HER2/neu negative MBC. (Part
 2b)

 OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097.

 Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and
 15-17 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the
 absence of disease progression or unacceptable toxicity.

 Patients may undergo tumor biopsy before and after treatment for biomarker analysis and blood
 sample collection periodically for pharmacokinetic and pharmacogenomic studies.

 After completion of study treatment, patients are followed up for 30 days (Part 1) or every 3
 months (Parts 2a and 2b).
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed advanced or metastatic
 solid tumor; patients with lymphoma will be eligible

 -  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

 -  Patients must be at least 4 weeks since prior chemotherapy, 6 weeks if the last
 regimen included BCNU or mitomycin C; prior radiation is allowed as long as the
 radiation was completed 4 weeks prior to study treatment and no more than 35% of
 marrow irradiated

 -  Life expectancy of greater than 3 months

 -  ECOG performance status =< 2 (Karnofsky >= 60%)

 -  Hemoglobin >= 9 g/dL

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  Total bilirubin within normal institutional limits

 -  AST (SGOT)/ALT (SGPT) =< 2.5 X institutional upper limit of normal

 -  Creatinine within normal institutional limits OR creatinine clearance >= 60
 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal; a 24
 hour urine collection and creatinine clearance can be measured if indicated

 -  Treated, stable brain metastases are allowed; patients must be four weeks from
 radiation with stable brain imaging and off any medications used to treat brain
 metastases, excepting those anti-epileptics not metabolized by cytochrome P450

 -  Women of childbearing potential and men must use two forms of contraception (i.e.,
 barrier contraception and one other method of contraception) at least 4 weeks prior to
 study entry, for the duration of study participation, and for 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

 -  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 must confirm and
 document the patient's use of two contraceptive methods, 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 NOT to 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

 -  Patients must demonstrate an ability to understand and the willingness to sign a
 written informed consent document

 -  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

 -  PART 2A (MTD EXPANSION COLORECTAL CANCER):

 -  For this cohort patients must have histologically or cytologically documented advanced
 or metastatic colorectal cancer; patients must have had at least one prior
 chemotherapy regimen for their disease but no more than 2

 -  All 5 patients in this cohort must be willing and able to have tumor biopsies
 performed as part of the correlative studies associated with this trial

 -  PART 2B (MTD EXPANSION BREAST CANCER):

 -  For this cohort, patients must have histologically or cytologically documented
 advanced or metastatic breast cancer

 -  Patient must be HER2/neu negative; HER2 negative will be defined as HER2 neither
 over-expressed or amplified; HER2 will be considered NOT over-expressed if the tumor
 stains as 0 or 1+ for HER2 by immunohistochemistry (IHC); if the IHC for HER2 is 2+,
 fluorescence in-site hybridization (FISH) ratio must be less than 2 to be considered
 NOT amplified; any tumor for which only FISH was performed must have a ratio of less
 than 2 to be considered NOT amplified

 -  All 5 patients in this breast cancer cohort must be willing and able to have tumor
 biopsies performed as part of the correlative studies associated with this trial

 Exclusion Criteria:

 -  Patients may not be receiving any other investigational agents

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to RO4929097 or capecitabine

 -  Patients taking medications with narrow therapeutic indices that are metabolized by
 cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

 -  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; note: it is acceptable to use corrected calcium when interpreting calcium
 levels

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, and a
 history of torsades de pointes or other significant 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; breastfeeding should be discontinued

 -  HIV-positive patients, who are not on anti-retroviral therapy but have CD4 cells less
 than 200, should be excluded; HIV-positive patients are eligible if they are on HAART
 (highly active anti-retroviral therapy) which are not CYP3A4 substrates, inducers
 and/or inhibitors and meet all other criteria

 -  Cardiovascular: baseline QTcF > 450 msec

 -  Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency enzyme are
 excluded

 -  Patients who have not recovered to < CTCAE grade 2 toxicities related to prior therapy
 are not eligible to participate in this study

 -  A requirement for antiarrhythmics or other medications known to prolong QTc

 -  PART2B (MTD EXPANSION BREAST CANCER):

 -  Patients may not have had more than 1 prior cytotoxic chemotherapy for metastatic
 disease; prior endocrine or immunotherapy regimens for metastatic disease will not be
 counted as cytotoxic