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Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01232829
First Posted: November 2, 2010
Last Update Posted: November 26, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This phase II trial is studying how well RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) works in treating patients with previously treated metastatic pancreatic cancer. RO4929097 may stop the growth of tumor cells by blocking some enzymes needed for cell growth.

Condition Intervention Phase
Adenocarcinoma of the Pancreas Recurrent Pancreatic Cancer Stage IV Pancreatic Cancer Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of the Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Survival Rate [ Time Frame: 6 months ]
    The primary endpoint of the study was 6-month survival. The proportion of successes was estimated by the number of successes divided by the total number of evaluable patients.


Secondary Outcome Measures:
  • Survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
    Survival was estimated using the Kaplan-Meier (1958) method.

  • Time to Disease Progression [ Time Frame: From registration to documentation of disease progression, assessed up to 2 years ]
    Eighteen patients were evaluable for the time to disease progression endpoint.


Enrollment: 18
Study Start Date: October 2010
Study Completion Date: May 2014
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (RO4929097)

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Patients may undergo tumor biopsy at baseline and on days 16 or 17 of course one for biomarker and other correlative studies. Blood samples may also collected at baseline and periodically during study for pharmacokinetic and angiogenesis marker studies.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given PO
Other Names:
  • R4733
  • RO4929097

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the 6-month survival of patients with previously treated metastatic pancreas cancer treated with gamma secretase RO4929097.

II. To determine the adverse events of RO4929097 in this patient population. III. To correlate changes in tumor markers with RO4929097 exposure.

SECONDARY OBJECTIVES:

I. To evaluate the response rate and overall survival of this population treated with RO4929097.

II. To correlate clinical outcome with tumor markers (including stem cell markers) obtained from pre- and post- treatment biopsies. (exploratory) III. To assess variants in genes involved in RO4929097 disposition and their relation to RO4929097 exposure.

OUTLINE: This is a multicenter study.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Patients may undergo tumor biopsy at baseline and on days 16 or 17 of course one for biomarker and other correlative studies. Blood samples may also collected at baseline and periodically during study for pharmacokinetic and angiogenesis marker studies.

After completion of study therapy, patients are followed up periodically for 2 years.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma

    • Not amenable to potentially curative surgical resection
  • At least 1 prior regimen of chemotherapy, preferably gemcitabine-based, for metastatic disease

    • Evidence of disease progression
  • Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan
  • Available archived tumor tissue (baseline core biopsies or surgical tumor blocks)

    • No diagnosis by fine-needle aspiration only
  • No known brain metastases
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (Karnofsky 70-100%)
  • White blood cell count (WBC) ≥ 3,000/mm³
  • Absolute neutrophil count (ANC) ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin normal
  • Aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases present)
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Willingness to undergo 2 tumor biopsies, if required
  • Fertile patients must use 2 forms of contraception (i.e., barrier contraception and one other method of contraception) ≥ 4 weeks prior to, during, and for ≥ 12 months after completion of therapy
  • Negative pregnancy test
  • Not pregnant or nursing
  • Able to swallow pills
  • No patients with 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
  • Not serologically positive for hepatitis A, B, or C
  • No history of liver disease, other forms of hepatitis, or cirrhosis
  • 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:

    • 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)
  • No other malignancy within the past 5 years except curatively treated basal cell carcinoma of the skin or carcinoma in-situ of the uterine cervix
  • No combination antiretroviral therapy for HIV-positive patients
  • Recovered to < Common Toxicity Criteria for Adverse Effects (NCI CTCAE) grade 2 toxicities from prior therapy
  • More than 3 weeks since prior chemotherapy for metastatic disease (6 weeks for carmustine or mitomycin C)
  • At least 4 weeks since prior radiotherapy
  • Concurrent low-molecular weight heparin (LMWH) or full-dose coumadin allowed

    • International normalized ratio (INR) must be monitored as clinically indicated
  • No other concurrent investigational agents
  • No concurrent strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers, including the following:

    • Strong inhibitors: Amiodarone, erythromycin, clarithromycin, grapefruit juice, isoniazid, ketoconazole, itraconazole, or nefazodone

      • Patients taken off strong inhibitors allowed provided they have ≥ 1-week washout period
    • Strong inducers: Carbamazepine, pentobarbital, phenobarbital, phenytoin, Rifabutin, Rifampin, or St. John wort

      • Patients taken off strong inducers allowed provided they have ≥ 2-week washout period
  • No concurrent antiarrhythmics or other medications known to prolong QTc
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01232829


Locations
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion
Aurora, Colorado, United States, 80045
University of Colorado
Denver, Colorado, United States, 80217-3364
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Wells Messersmith University of Colorado Cancer Center - Anschutz Cancer Pavilion
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01232829     History of Changes
Other Study ID Numbers: NCI-2011-02537
NCI-2011-02537 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000687335
10-0273 ( Other Identifier: Colorado Multiple Institutional Review Board )
8490 ( Other Identifier: CTEP )
U01CA070095 ( U.S. NIH Grant/Contract )
P30CA046934 ( U.S. NIH Grant/Contract )
First Submitted: October 30, 2010
First Posted: November 2, 2010
Results First Submitted: November 19, 2014
Results First Posted: November 26, 2014
Last Update Posted: November 26, 2014
Last Verified: June 2014

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Pancrelipase
Gastrointestinal Agents