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

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

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.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Procedure: biopsy; Drug: everolimus; Procedure: antiangiogenesis therapy; Procedure: gene expression analysis; Procedure: laboratory biomarker analysis; Procedure: protein tyrosine kinase inhibitor therapy; Procedure: diagnostic procedure; Procedure: immunohistochemistry staining method; Procedure: mutation analysis; Procedure: reverse transcriptase-polymerase chain reaction

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (ACTUAL): October 1, 2007
• Study Completion (ACTUAL): October 1, 2007

Study Registration Dates

• First Submitted: October 18, 2006
• First Submitted That Met QC Criteria: October 18, 2006
• First Posted (ESTIMATE): October 19, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): October 8, 2014
• Last Update Submitted That Met QC Criteria: October 7, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: J05107 CDR0000508071; JHOC-J05107; NOVARTIS-JHOC-J05107