RO4929097 Before Surgery in Treating Patients With Pancreatic Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Neoadjuvant Pharmacodynamic Study Of RO4929097 (RO) in Pancreas Cancer

Conditions
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Adenocarcinoma of the Pancreas, Stage IA Pancreatic Cancer, Stage IB Pancreatic Cancer, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer

Intervention / Treatment
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* Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: neoadjuvant therapy
* Procedure: therapeutic conventional surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed pancreatic adenocarcinoma T1-3, N0-1, and M0 disease Surgically resectable disease confirmed by a surgeon experienced in pancreatic surgery No borderline resectable disease defined as any of the following: Tumors with severe unilateral or bilateral SMV/portal involvement impingement Abutment (or) encasement of hepatic artery SMA or celiac encasement (or) presence of SMV occlusion by tumor 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 Grade 1 hyponatremia with sodium ≤ 131 mg/dL is permissible No uncontrolled intercurrent 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/social situations that would limit compliance with study requirements 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 Patients with a prior cancer are permitted to enter this study as long as there is no documented evidence of active malignancy 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097<br>* Given orally<br>* Other names: RO4929097;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Notch activity (expression of Hes-1) | Summarized as a binary endpoint for both the RO4929097 population and the stage-matched controls by the proportion and 95% exact binomial confidence interval. | Up to day 3 (of course 1) | 
| Frequency and severity of adverse events as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) | Toxicity will be determined with a 95% exact binomial confidence interval. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of cancer stem cells (CD44+, CD24+, ESA+ population of cells) self-renewal and tumorigenesis as measured by FACS |  | Up to day 3 (of course 1) |