Study to Evaluate Mechanisms of Acquired Resistance to Panitumumab
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Panitumumab; Ganitumab; Irinotecan
Intervention description: Panitumumab 6 mg/kg administered via IV infusion over 60 minutes; AMG 479 12 mg/kg adminstered by IV infusion over 60 minutes; Irinotecan starting dose of 180 mg/m² adminstered via IV infusion
Intervention MeSH terms: Irinotecan; Panitumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: wild-type KRAS; panitumumab; biomarker; mechanisms of acquired resistance; metastatic colorectal cancer

Summary:

      This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal
      growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in
      metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus
      oncogene (KRAS) tumor status at the time of initial diagnosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or
             rectum;

          -  Subjects with wild-type KRAS tumor status confirmed by an Amgen approved central
             laboratory assessment or an experienced local laboratory assessment of archival tumor
             tissue (preferably from the primary tumor);

          -  Radiographic evidence of disease progression while on or ≤ 6 months after completion
             of treatment with irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for
             mCRC;

          -  Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of
             treatment with investigational product);

          -  At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional computed
             tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm by spiral CT scan per
             modified RECIST v1.0. Lesion must not be chosen from a previously irradiated field,
             unless there has been documented disease progression in that field after irradiation
             and prior to enrollment. All sites of disease must be evaluated;

          -  At least 1 tumor (preferably a metastasis or unresected primary tumour) that is
             amenable to core biopsy, as determined by the clinician who will perform the biopsy;

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

          -  A life expectancy estimate of ≥ 3 months;

          -  Willing to undergo two serial core biopsy procedures of tumors (metastasis or
             unresected primary);

          -  other criteria may apply

        Exclusion Criteria:

          -  History of other primary cancer, unless:

               -  Malignancy treated with curative intent and with no known active disease present
                  for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the
                  treating physician,

          -  Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of
             disease,

               -  Adequately treated cervical carcinoma in situ without evidence of disease,

               -  Prostatic intraepithelial neoplasia without evidence of prostate cancer;

          -  History of prior or concurrent central nervous system (CNS) metastases;

          -  Prior treatment with anti-EGFR (eg, panitumumab, cetuximab or small molecule
             inhibitors (eg, erlotinib, gefitinib);

          -  Prior treatment with monoclonal antibodies directed against insulin-like growth
             factor-1 receptor (IGF-1R) or small molecule inhibitors directed against IGF-1R;

          -  Use of systemic chemotherapy or radiotherapy ≤ 21 days before enrollment. Subjects
             must have recovered from acute toxicities related to radiotherapy;

          -  Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrolment;

          -  Use of anti-tumor therapies including prior experimental agents or approved anti-tumor
             small molecules ≤ 30 days before enrolment;

          -  Known allergy or hypersensitivity to any component of panitumumab, irinotecan, or AMG
             479;

          -  Known uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms
             predisposing to increased irinotecan toxicity;

          -  History of irinotecan intolerance that may interfere with planned treatment;

          -  History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence
             of interstitial lung disease on baseline chest CT scan;

          -  Clinically significant cardiovascular disease (including myocardial infarction,
             unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac
             arrhythmia) ≤ 1 year before enrolment;

          -  Active inflammatory bowel disease or other active bowel disease causing chronic
             diarrhea (defined as ≥ grade 2 per Common Terminology Criteria for Adverse Events
             (CTCAE) version 3.0);

          -  Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C
             virus, acute or chronic active hepatitis B infection;

          -  Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14
             days before enrollment. Subjects must have recovered from surgery related toxicities.
             Core biopsy, central venous catheter placement, fine needle aspiration, thoracentesis,
             or paracentesis is not considered a major or minor surgical procedure; - Other
             investigational procedures or drugs (ie, participation in another clinical study) ≤ 30
             days before enrolment;

          -  other criteria may apply