RO4929097 Before Surgery in Treating Patients With Pancreatic Cancer

Adenocarcinoma of the Pancreas Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01192763
• Other study ID #: NCI-2011-02523
• Secondary ID: NCI-2011-02523CD
• Status: Terminated
• Phase: Phase 1
• First received: August 31, 2010
• Last updated: September 27, 2013
• Start date: August 2010

Study information

• Verified date: September 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 30
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma of the Pancreas
• Pancreatic Neoplasms
• Stage IA Pancreatic Cancer
• Stage IB Pancreatic Cancer
• Stage IIA Pancreatic Cancer
• Stage IIB Pancreatic Cancer

Intervention

Drug:
• gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally

Other:
• laboratory biomarker analysis
Correlative studies
• pharmacological study
Correlative studies

Procedure:
• neoadjuvant therapy

• therapeutic conventional surgery

Locations

Country	Name	City	State
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	City of Hope Medical Center	Duarte	California
United States	Fort Wayne Medical Oncology and Hematology Inc - State Boulevard	Fort Wayne	Indiana
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Central Illinois Hematology Oncology Center	Springfield	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Primary	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	Yes
Secondary	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)	No