E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously Treated, Wild-type KRAS, Metastatic Colorectal Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic Colorectal Cancer |
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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 |
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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 |
The primary objective is to compare the effect of panitumumab versus cetuximab on overall survival (OS) for chemorefractory mCRC among subjects with wild-type KRAS tumors. |
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E.2.2 | Secondary objectives of the trial |
To compare the treatment effect of panitumumab versus cetuximab as treatment for chemorefractory mCRC among subjects with wild-type KRAS tumors:
• Efficacy: progression-free survival (PFS), objective response rate (ORR), time to response, time to treatment failure, duration of response
• Safety: subject incidence of AEs, significant laboratory changes and immunogenicity
• Patient Reported Outcomes (PRO) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum Metastatic disease
-Wild-type KRAS tumor status by protocol-specified testing (see Section 7.10) Formalin-fixed paraffin-embedded tumor tissue from either the primary tumor or a metastatic lesion must be submitted for biomarker testing (see Section 7.10)
-ECOG performance status of 0, 1 or 2
-Measurable or non-measurable disease per RECIST version 1.1
-Must have failed a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease. Oxaliplatin and irinotecan may have been administered sequentially or in combination. Failure is defined as either disease progression (clinical or radiological) or intolerance to the regimen
-Subjects in whom relapse is diagnosed within 6 months after completing adjuvant chemotherapy (with either an irinotecan or oxaliplatin containing regimen) will be considered as having failed a prior regimen for metastatic disease
-Must have previously received a thymidylate synthase inhibitor (e.g. fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of CRC
-Man or woman ≥ 18 years of age
-Hematologic function, as follows: (≤ 10 days prior to randomization)
Absolute neutrophil count (ANC) ≥ 1.5 x 10 to the power of 9/L
Platelet count ≥ 75 x 10 to the power of 9/L
Hemoglobin ≥ 8.0 g/dL
Renal function, as follows: (≤ 10 days prior to randomization)
Creatinine ≤ 1.5 x ULN
Hepatic function, as follows: (≤ 10 days prior to randomization)
Aspartate aminotransferase (AST) ≤ 3 x ULN (if liver metastases
≤ 5 x ULN)
Alanine aminotransferase (ALT) ≤ 3 x ULN (if liver metastases ≤ 5 x ULN)
Total bilirubin ≤ 1.5 x ULN
Metabolic function, as follows: (≤ 10 days prior to randomization)
Magnesium ≥ lower limit of normal
-Negative pregnancy test ≤ 72 hours before randomization (for women of childbearing potential only)
-Competent to comprehend, sign, and date a written IEC/IRB approved informed consent form before any study-specific procedure |
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E.4 | Principal exclusion criteria |
-Symptomatic brain metastases requiring treatment
-History of other malignancy, except:
Malignancy treated with curative intent and with no known active disease present for ≥ 5 years prior to randomization 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
-Known hypersensitivity to any of the protocol-specified agents or their excipients
-Prior anti-EGFr antibody therapy (eg, panitumumab or cetuximab) or treatment with small molecule EGFr inhibitors (eg, gefitinib, erlotinib, lapatinib)
-Antitumor therapy (eg, chemotherapy, hormonal therapy, immunotherapy, antibody therapy, radiotherapy), or investigational agent or therapy ≤ 30 days before randomization. Subjects must have recovered from any acute toxicity
-Subject previously randomized to this study
-Other investigational procedures ≤ 30 days before randomization
-Subject currently is enrolled in or ≤ 30 days from ending other investigational device or drug study(s)
-Major surgery (eg, requiring general anesthesia) ≤ 28 days before randomization. Subjects must have recovered from any surgery related toxicities
-Clinically significant cardiovascular disease (as defined by: unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia)
-Myocardial infarction within last 6 months before randomization
-History of interstitial lung disease (ILD), eg, interstitial pneumonitis, pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT or MRI
-History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results
-Subject pregnant or breast feeding, or planning to become pregnant during treatment and within 6 months after the end of treatment
-Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for an additional 6 months (males and females) after the end of treatment
-Known positive test(s) for human immunodeficiency virus infection (testing is not required in the absence of clinical suspicion)
-Active infection requiring systemic treatment or any uncontrolled infections ≤14 days prior to randomization
-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 or is unwilling or unable to comply with study requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Survival (OS): time from randomization date to date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will occur when approximately 752 deaths are anticipated to be observed; |
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E.5.2 | Secondary end point(s) |
• Progression free survival (PFS): time from randomization date to date of disease progression per the RECIST version 1.1 or death. Subjects alive and not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
• Overall Response Rate (ORR): The incidence of either a complete response (CR) or partial response (PR) per RECIST version 1.1 (responder). All subjects that do not meet the criteria for an
objective response by the analysis cutoff date will be considered non-responders.
• Duration of response: (calculated only for those subjects with an objective response) time from first objective response to disease progression per the RECIST v1.1. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
• Time to response: time from randomization date to date of first objective response. Non-responders by the analysis data cutoff date with a best response of SD will be censored at their last assessment of SD, and subjects with all other categories of best response will be censored at the maximum observed time to a first confirmed
response among all responders.
• Time to treatment failure: time from randomization date to date that decision was made to end the treatment period for any reason; subjects who remain in the treatment period at the time of analysis will be censored at the date of the last on study assessment.
• Patient-reported outcomes (PRO):
− HRQOL:
EQ-5D Health Index Scale
EQ Visual Analog Scale
− CRC Symptomatology
NCCN FACT Colorectal Symptom Index (FCSI)
• Incidence of AEs, significant laboratory changes and immunogenicity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will occur when approximately 752 deaths are anticipated to be observed; |
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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 | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
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 |
Canada |
China |
Hong Kong |
India |
Israel |
Malaysia |
Mexico |
Peru |
Philippines |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
Turkey |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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Primary Completion: the time when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint of overall survival.
End of Study: the time when the last subject is assessed or receives an intervention for evaluation in the study (eg, safety follow up or survival assessment beyond the Primary Completion defined above).
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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 |