Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Previously Treated Metastatic Pancreatic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01232829
First received: October 30, 2010
Last updated: March 19, 2014
Last verified: March 2014
  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
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. If patients are lost to follow-up prior to the time required for the applicable primary endpoint, the final point estimate of the primary endpoint will be reported via the method of Kaplan and Meier (1958) which accounts for the censoring of such data at the date of last contact (last known alive). Otherwise, ninety percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner (Duffy and Santer, 1987).


Secondary Outcome Measures:
  • Survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ] [ Designated as safety issue: No ]
    Will be estimated using the method of Kaplan-Meier (1958). Special attention will be paid to any registered patient who dies early (i.e., within 60 days) of initiating their treatment. Circumstances surrounding such early deaths will be classified as being either due to malignant disease, toxicity, other causes, or of unknown reasons.

  • Tumor response (complete or partial response) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Time to disease progression [ Time Frame: From registration to documentation of disease progression, assessed up to 2 years ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: From the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented, assessed up to 2 years ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: From the date of registration to the date at which the patient is removed from treatment due to progression, toxicity, or refusal, assessed up to 2 years ] [ Designated as safety issue: No ]
  • Adverse events [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. The descriptions and grading scales found in the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting.


Enrollment: 21
Study Start Date: October 2010
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
Other: diagnostic laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
  • ECOG performance status (PS) 0-1 (Karnofsky 70-100%)
  • WBC ≥ 3,000/mm³
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin normal
  • AST and 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 < 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

    • INR must be monitored as clinically indicated
  • No other concurrent investigational agents
  • No concurrent strong 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
Investigators
Principal Investigator: Wells Messersmith University of Colorado Cancer Center - Anschutz Cancer Pavilion
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01232829     History of Changes
Other Study ID Numbers: NCI-2011-02537, NCI-2011-02537, CDR0000687335, UCHSC-10-0273, 10-0273, 8490, U01CA070095, P30CA046934
Study First Received: October 30, 2010
Last Updated: March 19, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on July 22, 2014