| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Wild-Type KRAS Metastatic Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
Colon Cancer
Colorectal Cancer
Gastrointestinal Cancer
Metastatic Colorectal Cancer
Rectal Cancer
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1:
To identify a tolerable dose of AMG 102 in combination with panitumumab based on the incidence of dose-limiting toxicities (DLTs)
Part 2:
To evaluate the efficacy as assessed by the overall objective response rate (ORR) of AMG 102 (tolerable dose selected from part 1) in combination with panitumumab and AMG 479 in combination with panitumumab versus panitumumab alone |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
To evaluate the safety of AMG 102 in combination with panitumumab.
Pharmacokinetics (PK) exposure of AMG 102 and panitumumab when given in
combination.
Part 2:
To evaluate the safety and efficacy of AMG 102 (tolerable dose selected from
part 1) in combination with panitumumab and AMG 479 in combination with panitumumab versus panitumumab alone.
• PK exposure of AMG 102 and panitumumab when given in combination
• PK exposure of AMG 479 and panitumumab when given in combination
• PK exposure of panitumumab when given alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Parts 1 and 2
Disease related:
-Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum.
Wild-type KRAS tumor status of archival tumor tissue confirmed by an Amgen approved central laboratory or an experienced laboratory (local laboratory) per local regulatory guidelines using a validated test method (see Section 7.1.1 for information on KRAS testing and Section 7.5.1.1 for tumor tissue requirements)
-Radiographic evidence of disease progression during or following prior treatment with irinotecan and/or oxaliplatin based chemotherapy for mCRC.
-At least 1 uni-dimensionally measurable lesion ≥ 20 mm (CT or MRI) or≥ 10 mm (spiral CT) in one dimension per modified RECIST v1.0 (Appendix F). 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.
-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix E)
Demographic:
-Man or woman ≥ 18 years of age
-A life expectancy estimate of ≥ 3 months
Laboratory:
To be performed ≤ 7 days before enrollment, unless otherwise specified:
Hematologic function within the following limits:
-Absolute neutrophil count (ANC) ≥ 1.0 x 10*9 cells/L
-Platelets ≥ 100 x 10*9/L
Renal function within the following limits:
-Creatinine < 2.0 mg/dL
Hepatic function within the following limits:
-Aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if liver
metastases)
-Alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver
metastases)
-Bilirubin ≤ 2 x ULN
Magnesium ≥ lower limit of normal
Subjects with known diabetes (Type 1 or 2) must have adequate glycemic
function, as follows:
-Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0%
-Documented fasting blood sugars < 160 mg/dL
Negative pregnancy test ≤ 3 days before enrollment (for woman of childbearing potential only)
Inclusion Criteria for Part 3:
Unless otherwise specified, subjects must meet the following criteria before unblinding in the IVRS may occur (see Section 7.2 for details and time between part 2 and 3).
Disease Related:
•Radiographic evidence of disease progression per modified RECIST v1.0, clinical
progression, or intolerability during treatment (cohort 3 confirmed upon unblinding)
• ECOG 0 or 1
Laboratory:
• Hematologic function within the following limits:
-Hemoglobin ≥ 8 g/dL
-Absolute neutrophil count (ANC) ≥ 1.0 x 10*9 cells/L
-Platelets ≥ 100 x 10*9/L
•Renal function within the following limits:
-Creatinine < 2.0 mg/dL
•Hepatic function within the following limits:
-Aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases)
-Alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases)
-Bilirubin ≤ 1.5 x ULN
•Magnesium: For subjects presenting with hypomagnesemia, hypomagnesemia must be ≤ Grade 2
-Glycosylated hemoglobin (HgbA1c) of ≤ 8.0%
General
• No history or evidence of thrombosis or vascular ischemic events within the last 12 months before enrollment into part 3, such as deep venous thrombosis, pulmonary embolism, transient ischemic attack, cerebral infarction, or myocardial infarction. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria - Parts 1&2
Disease Related:
History of prior or concurrent central nervous system (CNS) metastases
History of other primary cancer, unless:
-Curatively resected non-melanomatous skin cancer
-Curatively treated cervical carcinoma in situ
-Other primary solid tumor treated with curative intent and no known active disease present for ≥ 5 years before enrollment
Medications:
-Participation in a phase 3 randomized study of panitumumab in combination with chemotherapy, regardless of treatment assignment
-Prior treatment with anti-EGFr inhibitors (eg, panitumumab, cetuximab, erlotinib, gefitinib), unless treatment was received in the adjuvant setting ≥ 6 months before enrollment
-Prior treatment with c-Met, IGF-IR, or IGF-IIR inhibitors
-Prior treatment with either AMG 102 or AMG 479
-Use of experimental or approved systemic chemotherapy or radiotherapy ≤ 21 days before enrollment
-Use of experimental or approved targeted therapies ≤ 30 days before enrollment
-Known allergy or hypersensitivity to any component of panitumumab, AMG 102, or AMG 479
General:
-History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computerized tomography (CT) scan
-Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrollment
-Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea (defined as ≥ grade 2 per CTCAE version 3.0)
-Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection
Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant ascites, significant pleural effusion)
-Serious or non-healing wound ≤ 35 days before enrollment
-Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any medical condition that may interfere with the interpretation of the study results
-Major surgical procedure ≤ 35 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. 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) are excluded ≤ 30 days before enrollment
-Subject of child-bearing potential is evidently pregnant (eg, positive HCG
test) or is breast feeding
-Man or woman of childbearing potential who is not willing to use adequate contraceptive precautions during treatment and for 6 months after the last dose of the last investigational product (men and women). Adequate contraceptive precautions includes double barrier contraceptive methods (eg, diaphragm and condom) or abstinence
-Previously enrolled into this study
-Subject unwilling or unable to comply with study requirements
-Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 – Dose-limiting Toxicity (DLT): Subject incidence of selected adverse and laboratory abnormalities as defined in Section 6.7.1 of the Protocol
Part 2 – Overall Objective Response Rate (ORR): The incidence during the treatment
phase of either a confirmed CR or PR per modified RECIST criteria (responder).
Responses must be confirmed by 2 assessments no less than 28 days apart. All
subjects that do not meet the criteria for a confirmed CR or PR by the analysis cut-off
date will be considered non-responders |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumour assessments at weeks 8 (+1 week) and within +/- 1 week at weeks 12, 16, 24, 32, 40, and 48, and every 12 weeks thereafter until radiographic disease progression or the subject begins another treatment |
|
| E.5.2 | Secondary end point(s) |
Duration of response: The interval in days from the confirmed objective response to disease progression per the modified RECIST v1.0 criteria. Subjects that have not progressed by the analysis cutoff date will be censored at their last evaluable disease assessment date. Calculated only for subjects with a confirmed objective response.
• Time to response: The interval in days from the first dose of investigational product to the date of first confirmed objective response. Calculated only for subject with a confirmed objective response
• Disease control: The incidence of confirmed objective response or stable disease. Stable disease cannot be established prior to study day 49 (calculated from the date of first dose of investigational product), ie, the earliest protocol scheduled tumor assessment.
• Progression-free survival (PFS): The interval in days from the first dose of investigational product to the date of disease progression per the modified RECIST v1.0 criteria or death. Subjects that have not progressed or died by the analysis cutoff date will be censored at their last evaluable disease assessment date.
• On-treatment progression-free survival (PFS): The interval in days from the first dose of investigational product to the date of disease progression per the modified RECIST v1.0 criteria or death during the treatment period (from the first to last dose of investigational product). Subjects who have not progressed or died by the analysis cutoff date will be censored at their last evaluable disease
assessment date prior to ending their treatment
• Overall survival: The interval in days from the first dose of investigational product to the date of death. Subjects who have not died by the analysis cutoff date will be censored at their last contact date.
• Incidence of all AEs and clinical laboratory abnormalities
• Incidence of antibody formation to panitumumab, AMG 102, and AMG 479
• Cmin, Cmax, and AUC for panitumumab and AMG 102 (part 1)
• Cmin and Cmax for panitumumab, AMG 102, and AMG 479 (part 2) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint is as described in each secondary endpoint.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label in Part 1 of the study, randomised, double blind in Parts 2 and 3 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will occur when all subjects have completed or have had the opportunity to complete the 30-day safety follow up and 60-day follow up visits or 2 years after the last subject is enrolled in Part 2, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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