Erlotinib, Modified FOLFOX6, and Bevacizumab as First-Line Therapy Metastatic Colorectal Cancer

Sponsor

Case Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00118261

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

5.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Erlotinib may help chemotherapy work better by making tumor cells more sensitive to the drugs. Giving erlotinib together with combination chemotherapy and bevacizumab may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of erlotinib when given together with combination chemotherapy and bevacizumab as first-line therapy in treating patients with metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: bevacizumab Drug: erlotinib hydrochloride Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin	Phase 1

Detailed Description

OBJECTIVES:

Determine the toxicity of erlotinib, mFOLFOX6, and bevacizumab in patients with metastatic colorectal cancer.
Determine the efficacy of this regimen in these patients.
Determine the feasibility of escalating the dose of erlotinib in order to maximize the likelihood of developing a grade 2 skin rash in select patients.

OUTLINE: This is a multicenter study.

Single-agent erlotinib: Patients receive oral erlotinib once daily on days 1-14 (course 1).
Erlotinib, modified FOLFOX6, and bevacizumab chemotherapy: Patients receive oral erlotinib* once daily on days 1-14, oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46 hours on days 1 and 2 in course 2. Beginning in course 3, patients also receive bevacizumab IV over 30 minutes. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

NOTE: Patients who do not develop grade 2 toxicity after the first 3 courses (6 weeks) will have their erlotinib dose escalated.

PROJECTED ACCRUAL: A total of 22 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

17 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase IB Study in Patients With Metastatic Colorectal Cancer to Evaluate Pharmacodynamic Effects of Erlotinib and Safety and Efficacy of Erlotinib in Combination With Modified FOLFOX6 (mFOLFOX6) and Bevacizumab

Study Start Date :

Mar 1, 2005

Actual Primary Completion Date :

Jan 1, 2011

Actual Study Completion Date :

Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Erlotinib, modified FOLFOX6, and bevacizumab	Biological: bevacizumab Beginning in course 3, patients also receive bevacizumab IV over 30 minutes. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Drug: erlotinib hydrochloride Courses 1-3: oral erlotinib once daily on days 1-14. Patients who do not develop grade 2 toxicity after the first 3 courses (6 weeks) will have their erlotinib dose escalated. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Drug: fluorouracil Starting with course 2: fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Drug: leucovorin calcium Starting with course 2: Leucovorin calcium IV over 2 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Drug: oxaliplatin Starting with course 2: oxaliplatin IV over 2 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Arm

Intervention/Treatment

Experimental: Erlotinib, modified FOLFOX6, and bevacizumab

Biological: bevacizumab

Beginning in course 3, patients also receive bevacizumab IV over 30 minutes. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: erlotinib hydrochloride

Courses 1-3: oral erlotinib once daily on days 1-14. Patients who do not develop grade 2 toxicity after the first 3 courses (6 weeks) will have their erlotinib dose escalated. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: fluorouracil

Starting with course 2: fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: leucovorin calcium

Starting with course 2: Leucovorin calcium IV over 2 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: oxaliplatin

Starting with course 2: oxaliplatin IV over 2 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Outcome Measures

Primary Outcome Measures

Number of patients that develop study drug related toxicity [3 courses (6 weeks)]
Dose-limiting toxicities will be tracked in the first three cycles. The occurrence of DLT in 2 of the first 6 patients, 3 of the first 9 patients, or 4 of the first 12 patients (whichever occurs soonest)will require that subsequent patients are enrolled to the study at 100 mg erlotinib daily.

Secondary Outcome Measures

Patient Response to Treatment Measured by RECIST Criteria [3 courses (6 weeks)]
The overall response is the number of participants who experience a confirmed complete (CR) or partial response (PR) of the total analysis population. Per the Response Evaluation Criteria In Solid Tumors (RECIST): CR = all detectable tumor has disappeared, PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum, Progressive disease (PD) = a >=20% increase in target lesions, Stable Disease = small changes that do not meet previously given criteria.
Number of patients that can increase the erlotinib dose to 200mg [14 days]
The number of patients requiring an increase in erlotinib dose to 200 mg will be reported as well as the toxicities observed at 200 mg daily erlotinib, the median onset to grade 2 or higher rash and diarrhea at 200 mg erlotinib, and the number of patients requiring a decrease in erlotinib from 200 mg.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed colorectal cancer
Biopsy-accessible metastatic disease
Measurable disease
No CNS metastases

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

ECOG 0-2

Life expectancy

At least 3 months

Hematopoietic

WBC ≥ 4,000/mm^3 OR
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10 g/dL
No bleeding disorder

Hepatic

Bilirubin ≤ 1.5 mg/dL
Albumin ≥ 2.5 g/dL

Renal

Creatinine ≤ 1.5 mg/dL
Urine protein:creatine ratio < 1.0

Cardiovascular

Blood pressure ≤ 150/100 mmHg
No arterial thrombotic event within the past 6 months
No New York Heart Association grade II-IV congestive heart failure

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 1 month after completion of study treatment
No other malignancy within the past 3 years except nonmelanoma skin cancer, carcinoma in situ of the cervix, or other malignancy with < 10% chance of relapse within 3 years
No uncontrolled infection
No severe uncontrolled illness that would preclude study participation
No peripheral neuropathy interfering with function
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No serious non-healing wound, ulcer, or bone fracture

PRIOR CONCURRENT THERAPY:

Biologic therapy

No concurrent immunotherapy
No concurrent sargramostim (GM-CSF)

Chemotherapy

No prior chemotherapy, including oxaliplatin, for metastatic disease
Prior adjuvant oxaliplatin allowed provided disease progressed > 12 months after completion of oxaliplatin
At least 3 weeks since prior cytotoxic chemotherapy (6 weeks for mitomycin or nitrosoureas)
No more than 2 courses of prior mitomycin
No concurrent chemotherapy

Endocrine therapy

No concurrent anticancer hormonal therapy

Radiotherapy

At least 2 weeks since prior radiotherapy
No prior radiotherapy to > 15% of bone marrow
No concurrent radiotherapy

Surgery

At least 4 weeks since prior major surgery
At least 1 week since prior minor surgery

Other

Recovered from prior therapy
No prior epidermal growth factor receptor inhibitor therapy
No other concurrent antineoplastic or antitumor therapy
No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
2	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio	United States	44109
3	UHHS Chagrin Highlands Medical Center	Cleveland	Ohio	United States	44122