Summary

This phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body (advanced/metastatic) and cannot be removed by surgery. Trastuzumab is a form of “targeted therapy” because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body’s immune system. Immunotherapy with monoclonal antibodies, such as pertuzumab and cetuximab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm of cetuximab and irinotecan hydrochloride (irinotecan) (CETIRI).

SECONDARY OBJECTIVES:
I. To evaluate the overall response rate (ORR), including confirmed complete and partial response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in the TP and CETIRI treatment arms.
II. To evaluate the overall survival (OS) in the TP and CETIRI treatment arms.
III. To evaluate the safety and toxicity of TP compared to CETIRI.

ADDITIONAL OBJECTIVES:
I. To estimate the rates of PFS, OS, and ORR in patients who crossover to TP after disease progression on CETIRI.
II. To bank images for future retrospective analysis.

TRANSLATIONAL OBJECTIVES:
I. To evaluate if the following are prognostic of clinical efficacy (PFS and ORR) in patients receiving TP or CETIRI:
Ia. HER-2/CEP17 signal ratio.
Ib. HER-2 gene copy number (GCN).
II. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.

After completion of study treatment, patients are followed up every 8 weeks until disease progression, then every 6 months for 3 years.