RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097
and capecitabine administered in patients with advanced solid tumors. (Part 1)

- To describe the dose-limiting toxicities of this regimen in these patients. (Part 1)

- To determine the safety of this regimen in these patients. (Part 1)

- To determine the safety of this regimen in patients with metastatic colorectal cancer
(CRC). (Part 2a)

- To evaluate the safety of this regimen in patients with HER2/neu-negative metastatic
breast cancer (MBC). (Part 2b)

Secondary

- To determine the clinical activity of this regimen in patients with advanced solid
tumors.

- To evaluate the changes in the expression of Notch1 signaling pathway members and
downstream targets of Notch by PCR (including HEs1, 3, and 5 and Hey 1 and 2) after
treatment.

- To determine the pharmacokinetic and pharmacogenomic profiles of this regimen.

- To determine the progression-free survival of patients with metastatic CRC with a
history of 1 or 2 prior therapies treated with this regimen at the MTD level. (Part 2a)

- To determine the response and overall survival (OS) of patients with metastatic CRC
treated with this regimen at the MTD level. (Part 2a)

- To determine the overall response rate of patients with HER2/neu-negative MBC treated
with this regimen as first- or second-line therapy. (Part 2b)

- To determine the progression-free and OS rates in patients with HER2/neu-negative MBC
treated with this regimen at the MTD level. (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).

PROJECTED ACCRUAL: A total of 30 patients will be accrued for part 1 and 10 patients will be
accrued for part 2 of this study.

DISEASE CHARACTERISTICS:

- Meets 1 of the following criteria:

- Histologically or cytologically confirmed advanced or metastatic solid tumor
(Part 1)

- Patients with lymphoma are eligible

- Histologically or cytologically confirmed advanced or metastatic colorectal
cancer (Part 2a)

- Have received 1-2 prior chemotherapy regimen(s)

- Histologically or cytologically confirmed advanced or metastatic breast cancer
(Part 2b)

- HER2/neu-negative disease, defined as HER2 neither over-expressed nor
amplified

- HER2 will be considered NOT over-expressed if the tumor stains as 0 or
1+ for HER2 by IHC

- If the IHC for HER2 is 2+, FISH ratio must be < 2 to be considered NOT
amplified

- Any tumor for which only FISH was performed must have a ratio of < 2
to be considered NOT amplified

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques
or as ≥ 10 mm with spiral CT scan

- History of treated brain metastases allowed provided the following criteria are met:

- At least 4 weeks since radiotherapy for brain metastases

- Stable brain imaging

- No concurrent medications used to treat brain metastases (except for
anti-epileptics not metabolized by cytochrome P450)

PATIENT CHARACTERISTICS:

- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Life expectancy > 3 months

- Leukocytes ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST/ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia, defined as < lower limit of normal despite adequate electrolyte
supplementation

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of contraception (i.e., barrier contraception and
one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months
after completion of study treatment

- Willing and able to undergo tumor biopsy for correlative studies (Parts 2a and 2b)

- A biopsy is not required if, in the opinion of the treating physician, a biopsy
would pose undue harm to the patient

- Able to swallow tablets

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption

- Baseline QTcF ≤ 450 msec (for male patients) or ≤ 470 msec (for female patients)

- No uncontrolled concurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia other than chronic, stable atrial fibrillation

- Psychiatric illness or social situations that would limit compliance with study
requirements

- No known dihydropyrimidine dehydrogenase (DPD)-deficiency enzyme

- HIV-positive patients are eligible provided they meet the following criteria:

- On highly-active antiretroviral therapy that are not CYP3A4 substrates,
inducers, and/or inhibitors

- No HIV-positive patients who are not on antiretroviral therapy but have CD4
cells < 200/mm³

- No serologic positivity for hepatitis A, B, or C or history of liver disease or other
forms of hepatitis or cirrhosis

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 or capecitabine

- Female patients may not donate ova during or after study treatment

- Male patients may not donate sperm during and for ≥ 12 months after completion of
study treatment

- Patients may not donate blood during and for ≥ 12 months after completion of study
treatment

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from the toxicities related to prior therapy to < CTCAE grade 2

- No more than 1 prior regimen of cytotoxic chemotherapy for metastatic disease (Part
2b)

- Prior endocrine or immunotherapy regimens for metastatic disease will not be
counted as cytotoxic

- At least 4 weeks since prior chemotherapy (6 weeks if the last regimen included
carmustine or mitomycin C)

- At least 4 weeks since prior radiotherapy and ≤ 35% of marrow irradiated

- No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450, including warfarin sodium (Coumadin®)

- No concurrent medications or food that may interfere with the metabolism of
gamma-secretase inhibitor RO4929097, including ketoconazole and fresh-squeezed
grapefruit juice

- No other concurrent investigational agents

- No other concurrent investigational or commercial agents or therapies administered
with the intent to treat the patient's malignancy