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.

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.

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