E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chemorefractory, Wild-type Kirsten rat sarcoma viral oncogene homolog (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 | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To evaluate the effect of panitumumab and best supportive care (BSC) versus BSC alone on overall survival (OS) in subjects with chemorefractory wild-type codons 12 and 13 Kirsten rat sarcoma viral oncogene homolog (KRAS) mCRC |
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E.2.2 | Secondary objectives of the trial |
To evaluate the treatment effect of panitumumab and BSC versus BSC alone in chemorefractory mCRC for:
Efficacy:
- OS among subjects with wild-type RAS tumors (without mutation in KRAS codon 12, 13, 61, or neuroblastoma RAS viral oncogene [NRAS]).
- Progression-free survival (PFS) among subjects with wild-type codons 12 and 13 KRAS tumors.
- PFS among subjects with wild-type RAS tumors (without mutation in KRAS codon 12, 13, 61, or NRAS).
- Objective response rate (ORR) among subjects with wild-type codons 12 and 13 KRAS tumors.
- ORR among subjects with wild-type RAS tumors (without mutation in KRAS codon 12, 13, 61, or NRAS).
- Safety: Subject incidence of adverse events (AEs), significant laboratory changes, and immunogenicity.
- To evaluate the electrocardiographic profile in a subset of subjects treated with panitumumab as an indicator of effect on cardiac repolarization. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
QTc Evaluation, date and version same as main protocol: To evaluate the electrocardiographic profile in a subset of subjects treated with
panitumumab as an indicator of effect on cardiac repolarization.
Pharmacogentic, date and version same as main protocol:To investigate the effect of genomic deoxyribonucleic acid (DNA) polymorphism in EGFR signaling pathway genes, drug metabolism genes, cancer genes, and drug target genes on efficacy. |
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E.3 | Principal inclusion criteria |
4.1.1 Disease Related
• Histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum
- Metastatic disease
• Wild-type (without mutation in codons 12 and 13) KRAS gene in tumor tissue confirmed by a central laboratory (see Section 7.2)
- KRAS mutational analysis may have been performed by the central
laboratory prior to obtaining consent for study
- Formalin-fixed paraffin-embedded tumor tissue from either the primary tumor or a metastatic lesion must be available and submitted to Amgen approved central laboratory for KRAS testing and/or other biomarker testing
• ECOG performance status of 0, 1 or 2
• At least 1 measurable or non-measurable lesion per RECIST version 1.1 guidelines. Lesion must not be chosen from a previously irradiated field unless there had been documented tumor progression in that lesion prior to randomization. All sites of disease must be evaluated ≤ 28 days prior to randomization
• Treatment failure (defined as failure due to either disease progression [clinical or radiological] or toxicity [treatment intolerance]) of 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.
- Disease relapse within 6 months after completing adjuvant chemotherapy (with either an irinotecan or oxaliplatin containing regimen) will also be considered as treatment failure of a prior regimen for metastatic disease
• Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of CRC
4.1.2 Demographic
• Man or woman ≥ 18 years of age
4.1.3 Laboratory
• Hematologic function, as follows: (≤ 10 days prior to randomization)
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 75 x 109/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)
4.1.4 Ethical
• Subject or subject’s legally acceptable |
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E.4 | Principal exclusion criteria |
4.2.1 Disease Related
• 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
4.2.2 Medications
• 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) ≤ 21 days before randomization. Subjects must have recovered from any acute toxicity
• Radiotherapy ≤ 14 days before randomization. Subjects must have recovered from any acute radiotherapy-related toxicities
4.2.3 General
• Subject previously randomized to this study
• Other investigational procedures ≤ 30 days before randomization
• Subject currently 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
• Minor surgical procedure (eg, open biopsy) ≤ 7 days before randomization, or not yet recovered from prior minor surgery
Note:uncomplicated placement of vascular access device, fine needle aspiration, thoracocentesis or paracentesis ≥ 3 days prior to randomization is acceptable
• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months prior to randomization
• History of interstitial lung disease (ILD) eg, interstitial pneumonitis, pulmonary fibrosis or evidence of ILD 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 administration or may interfere with the interpretation of the results
• Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event ≤ 30 days before randomization. If on anticoagulation, subject must be on stable therapeutic dose prior to randomization.
• Subject pregnant or breast feeding, or planning to become pregnant during treatment and within 2 months after the end of treatment
• Female subject of childbearing potential is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for at least an additional 2 months 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 infection ≤ 14 days prior to randomization (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection)
• 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
4.2.4 Exclusion Criteria for QTc Evaluation Subpart of the Study
The following exclusion criteria will only apply to subjects who are being considered for inclusion into the QTc evaluation subpart of the study. Subjects who meet the following criteria will not be eligible to participate in QTc evaluation subpart of the study.
• Prolongation of QT/QTc interval > 450 milliseconds at screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival: time from randomization date to date of death for subjects with wild-type codons 12 and 13 KRAS |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When approximately 250 deaths are anticipated to be observed and at 24 months after last subject randomised if this occurs after 250 deaths observed |
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E.5.2 | Secondary end point(s) |
Efficacy:
- OS: Time from randomization date to date of death for subjects with wild-type RAS (without mutation in KRAS codon 12, 13, 61, or NRAS)
- PFS: time from randomization date to date of disease progression per
RECIST version 1.1 or death for subjects with wild-type codons 12 and 13 KRAS
- PFS: time from randomization date to date of disease progression per
RECIST version 1.1 or death for subjects with wild-type RAS (without
mutation in KRAS codon 12, 13, 61, or NRAS)
- ORR: The incidence of either a complete response (CR) or partial response (PR) per RECIST version 1.1 for subjects with wild-type codons 12 and 13 KRAS
- ORR: The incidence of either a CR or PR per RECIST version 1.1 for
subjects with wild-type RAS (without mutation in KRAS codon 12, 13, 61, or NRAS)
• Safety: Incidence of AEs, significant laboratory changes, and immunogenicity
• QTc evaluation related endpoint:
- QTc interval for the subjects at the measured time points. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
When approximately 250 deaths are anticipated to be observed and at 24 months after last subject randomised if this occurs after 250 deaths 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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best Supportive Care alone |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Canada |
China |
Croatia |
Estonia |
Greece |
India |
Korea, Republic of |
Latvia |
Lithuania |
Malaysia |
Mexico |
Peru |
Philippines |
Romania |
Serbia |
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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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End of Study: The end of study will be the later of the Primary Completion (see definition below) or when the last subject discontinues the study treatment phase and has had the opportunity to complete the safety follow-up visit. (Primary Completion: The final analysis will occur approximately 24 months after the date the last subject is randomized or when approximately 250 deaths are observed, whichever is later) |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |