A Neoadjuvant Pharmacodynamic Study Of RO4929097 (RO) in Pancreas Cancer
A Neoadjuvant Pharmacodynamic Study Of RO4929097 (RO) in Pancreas Cancer
This phase I trial is studying the side effects of RO4929097 before surgery in treating patients with pancreatic cancer. RO4929097 may stop the growth of tumor cells by blocking some enzymes needed for cell growth. Giving RO4929097 before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
PRIMARY OBJECTIVES:
I. To evaluate the effects of neoadjuvant gamma-secretase inhibitor RO4929097 on Notch inhibition via interrogation of Hes-1 expression in patients with pancreatic cancer.
SECONDARY OBJECTIVES:
I. To evaluate the effects of this regimen on pancreatic cancer stem cell self-renewal and tumorigenesis as compared to pancreatic stem cells from controls (patients who do not receive treatment).
II. To evaluate the safety of this regimen in these patients.
OUTLINE: This is a multicenter study.
Patients receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10 in the absence of disease progression or unacceptable toxicity. Beginning 7 days after completion of gamma-secretase inhibitor RO4929097, patients undergo complete resection comprising pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy based on the anatomic location of the cancer. Tumor tissue from biopsy and surgery and blood samples are collected periodically for pharmacodynamic studies.
After completion of study therapy, patients are followed up every 6 months for 1 year.
Inclusion Criteria:
Histologically or cytologically confirmed pancreatic adenocarcinoma
Surgically resectable disease confirmed by a surgeon experienced in pancreatic surgery
No borderline resectable disease defined as any of the following:
No metastatic disease
ECOG performance status 0-1
Life expectancy > 6 months
WBC ≥ 3,000/mm³
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9 g/dL
Total bilirubin ≤ 2 mg/dL
AST and ALT ≤ 2.5 times upper limit of normal
Creatinine ≤ 2 mg/dL
Calcium, magnesium, phosphorous, and potassium normal
Negative pregnancy test
Not pregnant or nursing
Fertile patients must use effective barrier-method contraception 4 weeks before, during, and for ≥ 12 months after completion of treatment
Able to swallow tablets
No malabsorption syndrome or other condition that would interfere with intestinal absorption
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in the study
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
No uncontrolled intercurrent illness including, but not limited to, any of the following:
No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
Patients with a prior cancer with evidence of active cancer are excluded from this study
No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia
No symptomatic congestive heart failure, unstable angina pectoris, and a history of torsades de pointes or other significant cardiac arrhythmias
No requirement for antiarrhythmics or other medications known to prolong QTc
No other concurrent anticancer agents or therapies
Recovered to < grade 2 toxicity related to prior therapy
No prior chemotherapy or radiotherapy for pancreatic cancer
No other concurrent investigational agents
No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®), ketoconazole, or grapefruit juice
No concurrent strong inducers or inhibitors of CYP3A4
No concurrent combination antiretroviral therapy for HIV-positive patients