Early-Line Anti-EGFR Therapy to Facilitate Retreatment for Select Patients With mCRC

Study Overview
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Brief Summary
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The study will use previously established doses of panitumumab or cetuximab in the metastatic setting for the treatment of unresectable colorectal cancer (CRC). It is designed to investigate an alternative treatment strategy to maximize the benefit to inhibition of epidermal growth factor receptor (EGFR) for a highly selected patient population. It will enroll 110 participants with left-sided, unresectable metastatic CRC. Participants will be on study up to 5 years.

Official Title
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Phase II Trial of Early-Line Anti-EGFR Therapy to Facilitate Retreatment for Select Patients With Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Panitumumab
* Drug: Cetuximab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information As determined by the enrolling physician or protocol designee, ability of the participant to understand and comply with study procedures for the entire length of the study Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 Have a diagnosis of histologically confirmed metastatic colorectal cancer with primary tumor located beyond the splenic flexure. Histologic confirmation of a colorectal primary tumor is acceptable if accompanied by radiographic evidence of metastatic disease. For Cohort A: Participants must enroll for study treatment in the first or second-line metastatic setting. Participants may receive 1 month of standard chemotherapy in the metastatic setting and still be eligible to initiate protocol therapy in the first-line setting. Adjuvant or neoadjuvant therapy does not count as a line of therapy even if given in the setting of metastatic disease (oligometastatic), unless disease recurrence was noted within 6 months of completing the last dose of the adjuvant of neoadjuvant therapy. For Cohort B: Participants must have had at least stable disease (per treatment physician) on a prior EGFR inhibitor containing regimen and it must be at least 4 months since the prior anti-EGFR inhibitor treatment was completed. Participants previously enrolled in Cohort A can later enroll in Cohort B should the eligibility criteria be met. Evaluable disease according to RECIST v1.1. Participants do not have to have measureable disease. Participants with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. Demonstrate adequate organ function; all screening labs to be obtained within 7 days prior to registration. Note minimum platelet requirement differs between Cohort A and B. Absolute Neutrophil Count (ANC) ≥ 1,000 / mcL Platelets ≥ 50,000 / mcL (Cohort A); ≥ 75,000 mcL (Cohort B receiving irinotecan and EGFRi); ≥ 50,000 / mcL (Cohort B receiving only EGFRi) Serum creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 2.0 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 2.0 X institutional ULN Bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for subjects with bilirubin levels >1.5 x ULN Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 5 × ULN Albumin ≥ 2.5 mg/dL Females of childbearing potential must have a negative serum pregnancy test within 7 days of registration and not be breastfeeding. Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Tumor must be mismatch repair (MMR) proficient as determined by microsatellite instability or immunohistochemistry for MMR proteins Microsatellite instability (MSI) testing must be MSI-stable or MSI-low. Or IHC for MMR proteins must demonstrate intact MMR proteins. Standard tumor molecular profiling with no pathologic variants in KRAS or NRAS or BRAF V600 mutations (Cohort A); Tumor molecular profiling from prior to anti-EGFR therapy with no pathologic variants in KRAS or NRAS or BRAF V600 mutations. If additional molecular profiling is completed (tissue or blood based testing) after receiving cetuximab or panitumumab treatment and variants in KRAS or NRAS are found, those patients will be considered eligible for this study. Patients with BRAF V600 mutations are not eligible. (Cohort B) Participants must not have known additional malignancy that is requiring systemic treatment. Participants taking hormonal treatments for breast or prostate cancer are still eligible. No major surgery within prior 2 weeks of treatment initiation. No history of allergic reactions attributed to compounds of similar chemical or biologic composition to panitumumab or cetuximab, including known severe hypersensitivity reactions to monoclonal antibodies. Participants must have no metastatic cancer lesions greater than 3.5cm in diameter. Any number of metastatic lesions will be allowed.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is an open label phase 2 clinical trial with 2 independent study arms conducted through the University of Wisconsin Carbone Cancer Center
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: No Previous EGFR<br>Participant who have not be previously exposed to anti-EGFR therapies and are in the first or second-line metastatic treatment setting. Panitumumab (6mg/kg) or Cetuximab 500mg (per treating physician) on day 1 and 15 of a 28-day cycle | Drug: Panitumumab<br>* Epidermal growth factor receptor inhibitor, anti-neoplastic<br>Drug: Cetuximab<br>* Epidermal growth factor receptor inhibitor, anti-neoplastic<br>|
| Experimental: Cohort B: Retreatment<br>Participants with treatment refractory disease who have previously benefitted (greater than or equal to 4 months ago) from anti-EGFR therapy. Panitumumab (6mg/kg) or Cetuximab 500mg (per treating physician) on day 1 and 15 of a 28-day cycle, +/- Irinotecan (180mg/m^2) every 2 two weeks per standard of care | Drug: Panitumumab<br>* Epidermal growth factor receptor inhibitor, anti-neoplastic<br>Drug: Cetuximab<br>* Epidermal growth factor receptor inhibitor, anti-neoplastic<br>Drug: Irinotecan<br>* anti-neoplastic, chemotherapy drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A Objective Response Rate (ORR) | Objective responses which will include all confirmed complete responses (CR) and confirmed partial responses (PR) determined as per RECIST v1.1 on treatment with panitumumab in metastatic, left-sided, non-bulky colorectal cancer. | up to 1 year | 
| Cohort B Progression Free Survival (PFS) | PFS will be defined as the duration (in months) from the date of study enrollment to date of disease progression (or death). If no progression (or death) event is observed during the follow-up period of the study, then PFS will be censored at the last date of follow-up per standard RECIST vs. 1.1 evaluation. | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A Progression Free Survival (PFS) | PFS will be defined as the duration (in months) from the date of study enrollment to date of disease progression (or death). If no progression (or death) event is observed during the follow-up period of the study, then PFS will be censored at the last date of follow-up per standard RECIST vs. 1.1 evaluation. | up to 4 years | 
| Cohort B Objective Response Rate (ORR) | Objective responses which will include all confirmed complete responses (CR) and confirmed partial responses (PR) determined as per RECIST v1.1 on treatment with panitumumab in metastatic, left-sided, non-bulky colorectal cancer. | up to 1 year | 
| Type and Severity of Toxicities | Toxicities will be graded using the most recent version of the CTCAE criteria. Toxicities will be summarized by type and severity in tabulator format. | up to 1 year (adverse events collected to 30 days post treatment) | 
| Rate of Retreatment with EGFRi | The rate of retreatment with EGFRi will be defined as the proportions of all eligible subjects who are retreated with EGFRi among all eligible subjects. | up to 4 years | 
| Overall Survival (OS) | OS will be defined as the duration (in months) from the date of study enrollment to the date of death (of any case). If no death event is observed during the follow-up period in a subject, then OS for that subject will be censored at the date of the last known survival status. | up to 4 years |