Radiolabeled Monoclonal Antibody Therapy, Combination Chemotherapy, and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

Phase I Trial of Radioimmunotherapy (Y-90 M5A) in Combination With FOLFIRI and Bevacizumab Chemotherapy for Metastatic Colorectal Carcinoma

RATIONALE: Radiolabeled monoclonal antibodies can find tumor cells and either kill them or carry tumor-killing substances to them without harming normal cells. Giving radioactive substances together with antibodies may be effective treatment for some advanced cancers. Drugs used in chemotherapy, such as irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI), 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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving radiolabeled monoclonal antibodies together with combination chemotherapy and bevacizumab may be an effective treatment for colorectal cancer.

PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of yttrium Y 90 DOTA anti-CEA (Carcinoembryonic antigen) monoclonal antibody M5A when given together with combination chemotherapy and bevacizumab in treating patients with metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Stage IV Colon Cancer; Stage IV Rectal Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: bevacizumab; Drug: leucovorin calcium; Drug: fluorouracil; Drug: irinotecan hydrochloride; Radiation: yttrium Y 90 DOTA anti-CEA monoclonal antibody M5A

Detailed Description

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of a combination of FOLFIRI chemotherapy, and intravenous yttrium-90 (90Y) M5A anti-CEA antibody.

SECONDARY OBJECTIVES:I. To study the progression free survival and response rate of this combined treatment in patients with stage IV colorectal cancer.II. To evaluate the biodistribution, clearance and metabolism of 90Y and 111In (indium-111) M5A administered intravenously.

OUTLINE: This is a dose-escalation study of yttrium Y 90 DOTA anti-CEA monoclonal antibody M5A. Patients receive irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46-48 hours, and bevacizumab IV over 30-90 minutes once every 2 weeks. Patients also receive yttrium Y 90 DOTA anti-CEA monoclonal antibody M5A IV over 25 minutes once in weeks 3 and 9. Treatment continues in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

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

Inclusion Criteria:

• Patients must have a Karnofsky performance status of > 60%
• Patients must have histological confirmation of colorectal carcinoma with stage IV disease or with unresectable disease
• Patients must have colorectal tumors that produce CEA as documented by either immunohistochemistry or by an elevated serum CEA
• Prior radiotherapy, immunotherapy, or chemotherapy must have been completed no less than 28 days prior to patient entry on this study and patients must have recovered from all acute expected side effects of the prior therapy. For patients who have undergone port placement, study treatment initiation must be at least 7 days post port placement
• Adequate bone marrow function as evidenced by hemoglobin > 10 g/dL, WBC > 4000/ul, an absolute granulocyte count of > 1,500/mm^3, and platelets > 150,000/ul; patients may be transfused to reach a hemoglobin > 10 g/dL
• In the dose-escalation phase, patients may have had a history of a prior malignancy; for the dose-expansion cohort, patients may have history of prior malignancy for which they have been disease free for five years with the exception of basal or squamous cell skin cancers or carcinoma in situ of the cervix
• Patients must have a total bilirubin < 1.5 mg/dL and a serum creatinine of < 2.0 mg/dL
• If a patient has previously received antibody, then serum anti-antibody testing must be negative
• Serum HIV testing and hepatitis B surface antigen and C antibody testing must be negative
• Women of childbearing potential must have a negative serum pregnancy test prior to entry and while on study must be practicing an effective form of contraception
• Patients must have measurable disease as defined by the modified RECIST criteria

Exclusion Criteria:

• Patients who have received radiation therapy to greater than 50% of their bone marrow
• Patients with any nonmalignant intercurrent illness (example cardiovascular, pulmonary, or central nervous system disease) that is either poorly controlled with currently available treatment or that is of such severity that the investigators deem it unwise to enter the patient on protocol shall be ineligible
• Patients with > 2+ protein by dipstick should undergo a 24 hour urine collection; patients with > 1gram proteinuria/ 24 hours are not eligible
• Patients may have received neoadjuvant and/or adjuvant chemotherapy and/or radiotherapy and present to the study in relapse; otherwise, no prior therapy is allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm I; Patients receive irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46-48 hours, and bevacizumab IV over 30-90 minutes once every 2 weeks. Patients also receive yttrium Y 90 DOTA anti-CEA monoclonal antibody M5A IV over 25 minutes once in weeks 3 and 9.Treatment continues in the absence of disease progression or unacceptable toxicity.

Other: laboratory biomarker analysis; Correlative studies; Biological: bevacizumab; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF; anti-VEGF rhuMAb; Drug: leucovorin calcium; Given IV; Other Names: CF; CFR; LV; Wellcovorin; citrovorum factor; calcium folinate; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Adrucil; Efudex; FU; Drug: irinotecan hydrochloride; Given IV; Other Names: irinotecan; Campto; Camptosar; U-101440E; CPT-11; camptothecin-11; Radiation: yttrium Y 90 DOTA anti-CEA monoclonal antibody M5A; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of yttrium-90 (90Y) M5A anti-CEA antibody when given in combination with FOLFIRI chemotherapy and bevacizumab	1 year post treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	2 years post treatment
Overall survival	2 years post treatment
Response rates	2 years post treatment
Biodistribution, clearance, and metabolism of Y-90 and In-111-M5A	At baseline, 1 hour, and 4 hours post start of infusion and at scan times at 1 day, 2 days, 3-5 days, and 6-7 days post antibody infusion
Estimation of radiation doses to whole body, normal organs, and tumor through serial nuclear imaging	At 1-3 hours post start of antibody infusion, 1 day, 2 days, 3-5 days, and 6-7 days post antibody infusion

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jeffrey Wong, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: September 16, 2010
• First Submitted That Met QC Criteria: September 17, 2010
• First Posted (Estimate): September 20, 2010

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: June 3, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Antibodies; Fluorouracil; Immunoglobulins; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Calcium, Dietary; Camptothecin
• Other Study ID Numbers: 10038 (DAIDS ES); NCI-2010-01962