Everolimus in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Previous Therapy
Primary Purpose
Colorectal Cancer
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
everolimus
antiangiogenesis therapy
biopsy
diagnostic procedure
gene expression analysis
immunohistochemistry staining method
laboratory biomarker analysis
mutation analysis
protein tyrosine kinase inhibitor therapy
reverse transcriptase-polymerase chain reaction
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer focused on measuring adenocarcinoma of the colon, adenocarcinoma of the rectum, recurrent colon cancer, stage III colon cancer, stage IV colon cancer, recurrent rectal cancer, stage III rectal cancer, stage IV rectal cancer
Eligibility Criteria
DISEASE CHARACTERISTICS:
Cytologically or pathologically confirmed colorectal adenocarcinoma
- Advanced or metastatic disease
Refractory to ≥ 1 line of prior therapy
- Not amenable to potentially curative surgical resection
- Mutations in the PI3K gene in tumor tissue
Tumor tissue available for genetic testing OR willing to undergo baseline tumor biopsy
- Tumor amenable to sequential biopsies
- Willing to undergo 2 sequential tumor biopsies, and 2 sequential skin biopsies
- Measurable lesion with ≥ 1 diameter ≥ 2 cm by conventional CT scan (1 cm by spiral CT scan) in a nonirradiated area
- No known brain metastases
PATIENT CHARACTERISTICS:
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Life expectancy > 12 weeks
- WBC ≥ 3,000/mm³
- Absolute neutrophil count ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Bilirubin normal
- AST and ALT ≤ 2.5 times upper limit of normal (ULN)
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- Cholesterol and triglycerides ≤ 2.5 times ULN
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus
No uncontrolled intercurrent illness, including, but not limited to, any of the following:
- Hypertension
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situation that would preclude study compliance
- No evidence of bleeding diathesis
- Able to swallow tablets
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
- No prior targeted therapy against mTOR
- No other concurrent investigational agents
No concurrent therapeutic anticoagulation
- Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial access devices allowed provided the requirements for PT, INR or PTT are met.
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent anticancer therapy, including chemotherapy, hormonal therapy, immunotherapy, alternative therapy, or radiotherapy
- No concurrent live vaccination
Sites / Locations
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Outcomes
Primary Outcome Measures
Response Rate: The Total Number of Participants With Progression of Disease
To determine response rate and time to tumor progression of patients with colorectal cancer and mutations in the PI3KCA gene who are treated with RAD001. Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by CT (or MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesion. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesion.
The outcome measure will be the total number of subjects who show progression of disease.
Secondary Outcome Measures
Full Information
NCT ID
NCT00390364
First Posted
October 18, 2006
Last Updated
October 7, 2014
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00390364
Brief Title
Everolimus in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Previous Therapy
Official Title
Phase II Study of Single Agent RAD001 in Patients With Colon Cancer and Activating Mutations in the PI3KCA Gene
Study Type
Interventional
2. Study Status
Record Verification Date
October 2014
Overall Recruitment Status
Terminated
Why Stopped
Withdrawn due to low accrual
Study Start Date
October 2006 (undefined)
Primary Completion Date
October 2007 (Actual)
Study Completion Date
October 2007 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
4. Oversight
5. Study Description
Brief Summary
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
PURPOSE: This phase II trial is studying how well everolimus works in treating patients with advanced or metastatic colorectal cancer that did not respond to previous therapy.
Detailed Description
OBJECTIVES:
Determine response rate, time to tumor progression, and survival of patients with advanced or metastatic refractory colorectal cancer and mutations in the PI3K gene treated with everolimus.
Determine the toxicity profile of this drug in these patients.
Measure the signaling pathways activated in these patients.
Determine the pharmacodynamic effects of this drug in these patients.
OUTLINE: This is an open-label study.
Patients receive oral everolimus once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Patients undergo tumor biopsies and normal skin biopsies at baseline and after the first course of study treatment. Tumor tissue is examined for biological markers (e.g., epidermal growth factor receptor, ERK, Akt, p70s6k, p27, and Rb protein) by immunohistochemistry; apoptosis quantification by TUNEL assay; Ki-67 quantification and Ki-index; gene expression; and c-fos and p27 expression by reverse-transcriptase polymerase chain reaction.
PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
adenocarcinoma of the colon, adenocarcinoma of the rectum, recurrent colon cancer, stage III colon cancer, stage IV colon cancer, recurrent rectal cancer, stage III rectal cancer, stage IV rectal cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
everolimus
Intervention Type
Procedure
Intervention Name(s)
antiangiogenesis therapy
Intervention Type
Procedure
Intervention Name(s)
biopsy
Intervention Type
Procedure
Intervention Name(s)
diagnostic procedure
Intervention Type
Procedure
Intervention Name(s)
gene expression analysis
Intervention Type
Procedure
Intervention Name(s)
immunohistochemistry staining method
Intervention Type
Procedure
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Procedure
Intervention Name(s)
mutation analysis
Intervention Type
Procedure
Intervention Name(s)
protein tyrosine kinase inhibitor therapy
Intervention Type
Procedure
Intervention Name(s)
reverse transcriptase-polymerase chain reaction
Primary Outcome Measure Information:
Title
Response Rate: The Total Number of Participants With Progression of Disease
Description
To determine response rate and time to tumor progression of patients with colorectal cancer and mutations in the PI3KCA gene who are treated with RAD001. Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by CT (or MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesion. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesion.
The outcome measure will be the total number of subjects who show progression of disease.
Time Frame
1 month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS:
Cytologically or pathologically confirmed colorectal adenocarcinoma
Advanced or metastatic disease
Refractory to ≥ 1 line of prior therapy
Not amenable to potentially curative surgical resection
Mutations in the PI3K gene in tumor tissue
Tumor tissue available for genetic testing OR willing to undergo baseline tumor biopsy
Tumor amenable to sequential biopsies
Willing to undergo 2 sequential tumor biopsies, and 2 sequential skin biopsies
Measurable lesion with ≥ 1 diameter ≥ 2 cm by conventional CT scan (1 cm by spiral CT scan) in a nonirradiated area
No known brain metastases
PATIENT CHARACTERISTICS:
ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
Life expectancy > 12 weeks
WBC ≥ 3,000/mm³
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Bilirubin normal
AST and ALT ≤ 2.5 times upper limit of normal (ULN)
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Cholesterol and triglycerides ≤ 2.5 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus
No uncontrolled intercurrent illness, including, but not limited to, any of the following:
Hypertension
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Psychiatric illness or social situation that would preclude study compliance
No evidence of bleeding diathesis
Able to swallow tablets
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
No prior targeted therapy against mTOR
No other concurrent investigational agents
No concurrent therapeutic anticoagulation
Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial access devices allowed provided the requirements for PT, INR or PTT are met.
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent anticancer therapy, including chemotherapy, hormonal therapy, immunotherapy, alternative therapy, or radiotherapy
No concurrent live vaccination
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Manuel Hidalgo, MD, PhD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231-2410
Country
United States
12. IPD Sharing Statement
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Everolimus in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Previous Therapy
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