Phase II Study of Irinotecan and Panitumumab

Study Overview
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Brief Summary
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This study proposes a single-arm, phase II study of irinotecan with panitumumab as second-line therapy for patients with advanced esophageal adenocarcinoma. Efficacy will be assessed by response rate, with an exploratory outcome endpoint of time to progression (as panitumumab may result in prolonged stable disease). In addition to the usual safety assessments, molecular correlates will be carried out in order to search for pharmacodynamic and pharmacogenomic features that may correlate with response. Measures of host/patient immune function will be assessed by evaluating the relationship between Fc receptor polymorphisms and response in patients treated with panitumumab. Measures of EGFR protein and phosphoprotein expression by immunohistochemical- (IHC-) staining, K-ras mutation status1 and reverse-phase protein arrays (RPPA) and EGFR gene amplification by fluorescence in situ hybridization (FISH) will be assessed as exploratory correlates.

Detailed Description
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Esophageal cancer is a highly lethal malignancy that is increasing in incidence, especially the histologic subtype of adenocarcinoma. Fully 50% of patients present with advanced, incurable disease. Of the remainder who are diagnosed at curable stages, at most 30% are long-term survivors. Advances in therapy for both local and advanced disease have been stagnant in the past few decades. As such, there is an urgent need for advances in therapy. The development of modern cytotoxic chemotherapy and in particular, biologically targeted agents, provides hope for improving the outcome in these patients. The semi-synthetic derivative of camptothecin, irinotecan, is active in esophageal adenocarcinoma, both alone and in combination with cisplatin. Use as front-line therapy in both multi-modality regimens and combination chemotherapy is common. More recently, the elucidation of the role of the epidermal growth factor receptor (EGFR) pathway in esophageal cancer has resulted in the pre-clinical and clinical study of the activity of EGFR directed agents for treatment of esophageal cancer. The anti-EGFR antibodies, panitumumab and cetuximab, are active as both single agents and in combination with cytotoxic chemotherapy in patients with colorectal adenocarcinoma. In particular, the combination of irinotecan and cetuximab is active for irinotecan refractory colorectal cancer, while panitumumab is active compared with best supportive care. In our clinic, we have empiric evidence for the unexpectedly significant activity of the combination of cetuximab and irinotecan as third-line treatment for advanced esophageal adenocarcinoma. Panitumumab has the clinical advantages, compared with cetuximab, of being fully human,, thus resulting in a lower frequency of infusion reactions. This recent experience with these targeted agents in solid tumors, while still promising, has yielded relatively modest results.7-11 Notably, however, retrospective analyses of clinical trials are consistently revealing that differences in treatment effect between subgroups of patients can be associated with specific molecular profiles.12-18 These findings suggest the potential for a more rational approach to trial design that would use patient and tumor characteristics to select patients for therapy, thus enriching the population of responders.

Official Title
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Phase II Study of Irinotecan and Panitumumab as Second-Line Therapy for Patients With Advanced Esophageal Adenocarcinoma

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: Panitumumab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed diagnosis of locally recurrent or metastatic adenocarcinoma of the esophagus which is incurable with standard therapy. Patients must have measurable disease outside a previous radiation port, or which has developed in the port since the conclusion of radiation and is biopsy-proven to be recurrent cancer. One prior chemotherapy regimen for metastatic disease, with the exception of prior irinotecan or panitumumab. Prior radiation therapy to no more than 20% of the bone marrow is allowed. No treatment with wide field radiation within 4 weeks of entry onto this study. Full recovery from the effects of any prior surgery. Man or woman >18 years of age. ECOG performance status <2 (Karnofsky >60%) Life expectancy of >3 months Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin ≥ 9.0 g/dL Creatinine < or = to 1.5 mg/dL Creatinine clearance > or = to 50 mL/min calculated by the Cockcroft-Gault method as follows: Male creatinine clearance = (140 - age) x (weight in Kg) / (serum Cr x 72) Female creatinine clearance = (140 - age) x (weight in Kg) x 0.85 / (serum Cr x 72) Aspartate aminotransferase (AST) < or = to 3 x ULN (if liver metastases less than or equal to 5 x ULN) Alanine aminotransferase (ALT) < or = to 3 x ULN (if liver metastases less than or equal to 5 x ULN) Total bilirubin < or = to 1.5 x ULN Magnesium ≥ lower limit of normal Potassium > or = to lower limit of normal Because the effects of irinotecan and panitumumab on the developing human fetus are unknown, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Exclusion Criteria: History or known presence of central nervous system (CNS) metastases unless CNS metastases have been irradiated and are stable. History of another primary cancer, except: Curatively treated in situ cervical cancer Curatively resected non-melanoma skin cancer Other primary solid tumor curatively treated with no known active disease present and no treatment administered for greater than or equal to 5 years prior to enrollment Pre-existing peripheral neuropathy > grade 1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to panitumumab or irinotecan. Patients receiving any medications or substances that are established or probable inhibitors or inducers of P450 3A4 are ineligible. Prior anti-EGFr antibody therapy (eg, cetuximab) or treatment with small molecule EGFr inhibitors (eg, gefitinib, erlotinib, lapatinib) Radiotherapy < or = to 14 days prior to enrollment. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (or small molecules for Phase I studies) (eg, bevacizumab)< or = to 30 days before enrollment Subjects requiring chronic use of immunosuppressive agents (eg, methotrexate, cyclosporine) Any investigational agent or therapy < or = to 30 days before enrollment Prior therapy with Irinotecan or panitumumab. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or any evidence of interstitial lung disease on baseline chest CT scan History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results. Women who test positive for serum or urine pregnancy test < 72 hours before randomization or is breast feeding Known positive test(s) for acute or chronic active hepatitis B infection Major surgery within 28 days or minor surgery within 14 days of study enrollment Men or women of child-bearing potential (women who are post-menopausal < 52 weeks, not surgically sterilized, or not abstinent) not consenting to use adequate contraception (per institutional standard of care) during treatment and for six months after the last investigational product(s) administration Any underlying condition which in the opinion of the principal investigator will interfere with safety or with compliance with the study.

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: Irinotecan plus panitumumab<br>Irinotecan 100 mg/m2 IV Day 1 and Day 8 + Panitumumab 9mg/kg IV Day 1 Cycle = 21 days | Drug: Panitumumab<br>* 9mg/kg IV Day 1 Cycle = 21 days<br>* Other names: ABX-EGF;Drug: Irinotecan<br>* 125mg/m2 IV Day 1 and Day 8<br>* Other names: CPT-11;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) | Response rate (RR) = the # participants with partial response (PR) + # participants with (CR) / # participants with (PR) + # participants with (CR ) + # participants with (SD) + # participants with (PD). This proportion was subsequently multiplied by 100. RECIST v1.0 criteria for Target Lesions was used: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | Up to 14 months | 
| Clinical Benefit Rate (CBR) | Using RECIST v1.0 criteria, clinical benefit rate (CBR) = # participants with (PR) + # participants with (CR) + # participants with (SD) / # participants with (PR) + # participants with (CR) + # participants with (SD) + # participants with (PD). This proportion was subsequently multiplied by 100. RECIST v1.0 criteria for Target Lesions is defined as: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Survival time the is free of disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Up to 45 months (cohort) | 
| Overall Survival (OS) |  | Up to 45 months (cohort) | 
| 1-year (Overall) Survival Rate |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Panitumumab, Irinotecan, Esophageal Adenocarcinoma, Phase II