S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification
Overview
- Phase
- Phase 2
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Colon Adenocarcinoma
- Sponsor
- SWOG Cancer Research Network
- Enrollment
- 240
- Locations
- 798
- Primary Endpoint
- Progression-free Survival(PFS)
- Status
- Completed
- Last Updated
- 2 months ago
Overview
Brief Summary
This randomized 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 and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and 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.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm (Arm 2) 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 treatment Arms 1 and 2. II. To evaluate the overall survival (OS) in treatment Arms 1 and 2. III. To evaluate the safety and toxicity of TP compared to CETIRI. TERTIARY OBJECTIVES: I. To estimate the rates of PFS, OS, and ORR in patients who crossover to TP (Arm 3) after disease progression on CETIRI. II. To bank images for future retrospective analysis. III. To evaluate if HER-2/centromeric probe (CEP17) signal ratio and HER-2 gene copy number (GCN) are predictive of clinical efficacy for patients receiving TP versus CETIRI. IV. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study. OUTLINE: Patients with HER2 gene amplification 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. Courses 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. Courses 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 for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •STEP 1 INITIAL REGISTRATION: HER2 TESTING
- •Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable
- •Mutation results:
- •All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 \[codons 12 and 13\], exon 3 \[codons 59 and 61\] and exon 4 \[codons 117 and 146\]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible
- •Patients must not have been treated with any of the following prior to step 1 initial registration:
- •Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR
- •HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible
- •Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab
- •Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization
- •Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I (pertuzumab, trastuzumab)
Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm I (pertuzumab, trastuzumab)
Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pertuzumab
Arm I (pertuzumab, trastuzumab)
Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Trastuzumab
Arm I (pertuzumab, trastuzumab)
Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: HER-2 testing
Arm II (cetuximab, irinotecan hydrochloride)
Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.
Intervention: Cetuximab
Arm II (cetuximab, irinotecan hydrochloride)
Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.
Intervention: Irinotecan Hydrochloride
Arm II (cetuximab, irinotecan hydrochloride)
Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.
Intervention: Laboratory Biomarker Analysis
Arm II (cetuximab, irinotecan hydrochloride)
Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.
Intervention: HER-2 testing
Outcomes
Primary Outcomes
Progression-free Survival(PFS)
Time Frame: Up to 3 years post randomization
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 (CETIRI). Progression-free survival is defined as the time from date of randomization to date of first documentation of progression. Using RECIST 1.1, progression is defined as a 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed and an absolute increase of at least 0.5 cm, unequivocal progression of non-measurable disease in the opinion of the treating physician, appearance of any new lesion/site, death due to disease without prior documentation of progression and without symptomatic deterioration (defined as, global deterioration of health status requiring discontinuation of treatment without objective evidence of progression), or death due to any cause.
Secondary Outcomes
- Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs.(Duration of treatment and follow-up until death or 3 years post Step 2 Randomization.)
- 2 Year Overall Survival (OS) for TP and CETIRI Treatment Arms(from the date of the last accrual to registration step 2 to date of death due to any cause, up to 2 years)
- Overall Response Rate (ORR) for TP and CETIRI Treatment Arms(From baseline, through duration of treatment (once per cycle while on treatment), and every 8 weeks after treatment until progression, up to 3 years after the last accrual to registration step 2)