Everolimus in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Previous Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Study of Single Agent RAD001 in Patients With Colon Cancer and Activating Mutations in the PI3KCA Gene

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: everolimus
* Procedure: antiangiogenesis therapy
* Procedure: biopsy
* Procedure: diagnostic procedure
* Procedure: gene expression analysis
* Procedure: immunohistochemistry staining method
* Procedure: laboratory biomarker analysis
* Procedure: mutation analysis
* Procedure: protein tyrosine kinase inhibitor therapy
* Procedure: reverse transcriptase-polymerase chain reaction


Participation Criteria
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Eligibility Criteria
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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

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

| Intervention/Treatment |
| --- |
|Drug: everolimus|nan|
|Procedure: antiangiogenesis therapy|nan|
|Procedure: biopsy|nan|
|Procedure: diagnostic procedure|nan|
|Procedure: gene expression analysis|nan|
|Procedure: immunohistochemistry staining method|nan|
|Procedure: laboratory biomarker analysis|nan|
|Procedure: mutation analysis|nan|
|Procedure: protein tyrosine kinase inhibitor therapy|nan|
|Procedure: reverse transcriptase-polymerase chain reaction|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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