Study to Evaluate Mechanisms of Acquired Resistance to Panitumumab

Study Overview
=================
Brief 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.

Detailed Description
-----------------
In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2. In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.

Official Title
-----------------
Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin-or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance to Panitumumab

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Biological: Panitumumab
* Biological: Ganitumab
* Drug: Irinotecan


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panitumumab<br>Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W. | Biological: Panitumumab<br>* Panitumumab 6 mg/kg administered via IV infusion over 60 minutes<br>* Other names: Vectibix;Biological: Ganitumab<br>* AMG 479 12 mg/kg adminstered by IV infusion over 60 minutes<br>* Other names: AMG 479;Drug: Irinotecan<br>* Irinotecan starting dose of 180 mg/m² adminstered via IV infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Emergence of Mutant KRAS | Mutation in Kirsten rat sarcoma-2 virus oncogene (KRAS) status was determined by examining KRAS exons 2, 3, and 4. The emergence of mutant KRAS was defined as a change in KRAS mutation status from wild-type at Baseline in KRAS exons 2, 3, and 4 to mutant in any of KRAS exons 2, 3, and 4 at the time of the second biopsy following the radiographic evidence of acquired resistance to panitumumab when given in combination with irinotecan. | From first dose of study drug until the 2nd biopsy at the time of disease progression/entry into Part 2; median duration of treatment in Part 1 was 16 weeks. | 
| Part 2: Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression (increase in size) of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) and no new lesions. | From the first dose of study drug in Part 2 until the end of treatment in Part 2; median duration of treatment in Part 2 was 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective Response Rate | Objective response rate is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified RECIST version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. | From first dose of study drug until the end of treatment in Part 1; median duration of treatment was 16 weeks. | 
| Progression-free Survival (PFS) | Progression-free survival was defined as the interval from the first dose of study therapy to the earlier date of disease progression (per modified RECIST version 1.0) or death prior to the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in Part 2 where applicable. Participants who had not progressed or died during this period were censored at their last evaluable disease assessment date. Progressive Disease (PD): At least a 20% increase in the size of target or non-target lesions, significant increase in pleural effusions, ascites, or other fluid collections with cytologic proof of malignancy, or any new lesions. | From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2. | 
| Overall Survival (OS) | Overall survival was defined as the time from the first dose of study therapy in Part 1 or Part 2 to the date of death. Participants who had not died by the analysis data cutoff date were censored at their last contact date. | From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2. | 
| Time to Objective Response | Time to objective response was defined as the time from first dose of study drug to the first confirmed objective response. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. | From the first dose of study drug until the end of treatment in each Part; median duration of treatment was 16 weeks in Part 1 and 8 weeks in Part 2. | 
| Duration of Response | Duration of response is defined as the time from the first confirmed objective response to the earlier date of disease progression or death. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. | From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2. | 
| Number of Participants Who Developed Antibodies to Panitumumab | Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. Postive samples were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay. | From first dose date to 30 days since the last dose date. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2. | 
| Number of Participants Who Developed Antibodies to Ganitumab | Two validated assays were used to detect the presence of anti-ganitumab antibodies. First, an eletrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding ganitumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against ganitumab. | From first dose of ganitumab until 30 days after last dose; median time frame was 2.4 months. | 
| Number of Participants With Adverse Events | The severity of each adverse event (AE) was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (where 1 = Mild [aware of sign or symptom, but easily tolerated]; 2 = Moderate [discomfort enough to cause interference with usual activity]; 3 = severe [incapacitating with inability to work or do usual activity]; 4 = life-threatening; 5 = fatal), with the exception of selected skin toxicities that were graded using a modified version of CTC. Treatment-related adverse events were those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by panitumumab (Part 1) and by panitumumab and/or ganitumab (Part 2). Discontinuation includes AEs leading to discontinuation of panitumumab (Part 1) and panitumumab, ganitumab (Part 2) or removal from the study. | From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2. | 
| Number of Subjects With Worst Post-baseline Grade 3 or Higher Laboratory Toxicities | The severity of laboratory toxicities was graded using CTCAE v3.0. | From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
wild-type KRAS, panitumumab, biomarker, mechanisms of acquired resistance, metastatic colorectal cancer