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

Johns Hopkins Medicine

Status and phase

Terminated

Phase 2

Conditions

Colorectal Cancer

Treatments

Procedure: diagnostic procedure

Procedure: mutation analysis

Procedure: antiangiogenesis therapy

Procedure: protein tyrosine kinase inhibitor therapy

Drug: everolimus

Procedure: reverse transcriptase-polymerase chain reaction

Procedure: laboratory biomarker analysis

Procedure: gene expression analysis

Procedure: immunohistochemistry staining method

Procedure: biopsy

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00390364

J05107 CDR0000508071

JHOC-J05107

NOVARTIS-JHOC-J05107

Details and patient eligibility

About

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.

Full 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.

Enrollment

1 patient

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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