Pertuzumab and Cetuximab in Treating Patients With Previously Treated Locally Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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Monoclonal antibodies, such as pertuzumab and cetuximab, 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. Giving pertuzumab together with cetuximab may kill more tumor cells. This phase I/II trial is studying the side effects and best dose of pertuzumab when given together with cetuximab and to see how well they work in treating patients with previously treated locally advanced or metastatic colorectal cancer

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety, tolerability, and recommended phase II dose of pertuzumab when administered in combination with cetuximab in patients with cetuximab-refractory locally advanced or metastatic colorectal cancer. II. To evaluate the objective tumor response rate (RR) in patients treated with this regimen. SECONDARY OBJECTIVES: I. To evaluate the median progression-free survival (PFS) of patients treated with this regimen. II. To evaluate the median overall survival (OS) of patients treated with this regimen. III. To evaluate the RR, PFS, and OS in a subgroup of patients who are EGFR-positive by immunohistochemistry. IV. To explore the relationship between skin rash and the efficacy outcomes of RR, PFS, and OS in these patients. V. To explore the relationship between objective tumor response on positron emission tomography (PET) scan after course two and the efficacy outcomes of RR, PFS, and OS in these patients. VI. To explore the relationship between a variety of laboratory correlates and the efficacy outcomes of RR, PFS, and OS in these patients. OUTLINE: This is a multicenter, phase I dose-escalation study of pertuzumab followed by a phase II study. PHASE I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I). Previously collected tumor tissue samples are analyzed for correlative studies. Samples are analyzed for KRAS mutations via polymerase chain reaction and pyrosequencing; EGFR expression via immunohistochemistry and fluorescent in situ hybridization (FISH); HER receptor and ligand gene expression; and circulating tumor cells. Additional blood samples are collected periodically to isolate circulating tumor cells and are analyzed via FISH analysis. After completion of study treatment, patients are followed at 30 days and then periodically thereafter.

Official Title
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A Phase I/II Trial of Pertuzumab in Combination With Cetuximab and Irinotecan in Previously Treated Metastatic Colorectal Cancer

Conditions
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Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage III Colon Cancer, Stage III Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Biological: pertuzumab
* Biological: cetuximab
* Drug: irinotecan hydrochloride
* Other: immunohistochemistry staining method
* Other: fluorescence in situ hybridization
* Other: gene expression analysis
* Other: mutation analysis
* Other: polymerase chain reaction
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a history of colorectal cancer (CRC) treated by surgical resection and who develop radiological or clinical evidence of metastatic disease do not require separate histological or cytological confirmation of metastatic disease unless 1 of the following criteria are met: More than 5 years has elapsed between the primary surgery and the development of metastatic disease The primary cancer was stage I Patients must have representative tumor specimens in paraffin blocks or at least 15 unstained slides with an associated pathology report obtained at any time prior to study entry: Cytology specimens are not acceptable replacements Patients must have their tumor tissue screened for KRAS mutation status, and be found to have a KRAS wild-type tumor: No KRAS-mutated tumor Locally advanced or metastatic disease Not curable by surgery or amenable to radiotherapy with curative intent Must have received an cetuximab-containing regimen for at least 6 weeks for treatment of metastatic disease Documented progression of disease or intolerable toxicity during or within 3 months of receiving this regimen Patients who have received an cetuximab-containing regimen as adjuvant therapy for resected stage II or III CRC are eligible provided recurrent disease is documented < 6 months after completion of adjuvant treatment Must have received >= 1 prior chemotherapeutic regimen for treatment of metastatic disease with any of the following: Cetuximab Must have resolution of any skin rash related to prior treatment with cetuximab No prior cetuximab which required a dose reduction for toxicity 5-fluorouracil or capecitabine Irinotecan hydrochloride or oxaliplatin Measurable disease by CT scan or physical exam ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%) Life expectancy > 12 weeks Absolute neutrophil count >= 1,500/mcL Platelet count >= 100,000/mcL Leukocytes >= 3,000/mcL Hemoglobin >= 9 g/dL (transfusion, erythropoietin, or other approved hematopoietic growth factors allowed) Total bilirubin =< 1.5 times upper limit of normal (ULN) AST and ALT =< 5 times ULN Creatinine normal OR Creatinine clearance >= 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to and during study therapy Cardiac left ventricular ejection fraction >= 50% OR >= lower limit of normal No evidence of left ventricular wall motion abnormalities as measured by ECHO or MUGA scan None of the following cardiac conditions: Uncontrolled high blood pressure Unstable angina Symptomatic congestive heart failure Congestive heart failure, cardiac dysfunction, or cardiomyopathy requiring medication treatment Myocardial infarction within the past 6 months Serious uncontrolled cardiac arrhythmia New York Heart Association class III or IV heart disease No active or uncontrolled infection No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of > 3 loose stools/day (in patients without a colostomy or ileostomy) Patients with a colostomy or ileostomy may be eligible at investigator discretion No psychiatric illness/social situation that would limit compliance with study requirements No other prior or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ carcinoma of the cervix, lobular carcinoma in situ in one breast, or other cancer from which the patient has been disease-free for at least 5 years No other medical or psychiatric disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or render the patient at high risk for treatment complications No history of allergic reactions, hypersensitivity, or intolerance to cetuximab, and/or compounds of similar chemical or biologic composition to pertuzumab or cetuximab (i.e., other monoclonal antibodies such as bevacizumab) that led to discontinuation of the drug Patients able to tolerate subsequent infusions after a reaction are eligible At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered (Insertion of a vascular access device is not considered major or minor surgery) At least 2 weeks since prior minor surgery and recovered (Insertion of a vascular access device is not considered major or minor surgery) At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy) At least 4 weeks since prior bevacizumab More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered No prior agents directed against EGFR and/or HER2 No more than one prior treatment regimen for metastatic disease; Prior chemotherapy in the adjuvant setting following resection of stage II or III disease allowed provided the regimen did not contain irinotecan hydrochloride and/or an agent directed against EGFR and/or HER2 No prior doxorubicin or liposomal doxorubicin at doses > 360 mg/m^2; epirubicin at doses > 720 mg/m^2; mitoxantrone at doses > 120 mg/m^2; or idarubicin at doses > 90 mg/m^2 No prior radiotherapy to > 15% of the bone marrow No prior standard adjuvant chemoradiotherapy for rectal cancer No phenytoin, phenobarbital, carbamazepine, or any other enzyme-inducing anti-convulsant drugs (EIACDs) for at least 7 days before, during, and for 7 days after the final dose of irinotecan hydrochloride Concurrent gabapentin or other non-EIACDs are allowed No St. John's wort for at least 14 days before, during, and for 7 days after the final dose of irinotecan hydrochloride No concurrent corticosteroids, except for stable doses of prednisone (< 20 mg/day or equivalent), topical or inhaled corticosteroids, or corticosteroids for reasons unrelated to treatment of colorectal cancer No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) for any of the following reasons: To avoid dose reductions or delays Prophylactic treatment Treatment of febrile neutropenia No other concurrent HER family-targeted therapy No concurrent rifampin No concurrent herbal remedies unless initiated prior to study entry No other concurrent investigational agents No other concurrent anticancer therapy, including cytotoxic chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or biological anticancer therapy Histologically or cytologically confirmed adenocarcinoma of the colon or rectum Site of the primary lesion must be or have been confirmed endoscopically, radiologically, or surgically to be or have been in the large bowel No known brain metastases No concurrent fluconazole

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I). | Biological: pertuzumab<br>* Given IV<br>* Other names: rhuMAb-2C4;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: immunohistochemistry staining method<br>* Correlative study<br>* Other names: immunohistochemistry;Other: fluorescence in situ hybridization<br>* Correlative study<br>* Other names: fluorescence in situ hybridization (FISH);Other: gene expression analysis<br>* Correlative study<br>Other: mutation analysis<br>* Correlative study<br>Other: polymerase chain reaction<br>* Correlative study<br>* Other names: PCR;Other: laboratory biomarker analysis<br>* Correlative study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose of Pertuzumab When Administered in Combination With Cetuximab (Phase I) | The regimen was deemed intolerable so there was no recommended phase II dose. | 28 days | 
| Objective Tumor Response Rate Defined as the Proportion of Patients With a Best Overall Response of CR or PR, Per RECIST Criteria (Phase II) | Objective tumor response rate defined as the proportion of patients with a best overall response of CR or PR, per RECIST criteria (Phase II). | Best tumor response from time period of start of study treatment to study discontinuation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | The duration of time from start of study treatment to time of objective disease progression or death. | The duration of time from start of study treatment to time of objective disease progression or death. | 
| Overall Survival | The duration of time from start of study treatment to death from any cause. | The duration of time from start of study treatment to death from any cause. |