E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously Untreated, KRAS Wild-Type, Unresectable, Metastatic Colorectal Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Colon Cancer, Colorectal Cancer, Rectal Cancer, Metastatic Colorectal 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 | 17.0 |
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 |
The primary objective of this study is to estimate the treatment effect on progression-free survival (PFS) of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy for mCRC in subjects with tumors expressing wildtype KRAS. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate overall survival (OS), objective response rate(ORR), duration of response (DOR), time to progression (TTP), time to response, resection rate, safety and tolerability of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy for mCRC in subjects with tumors expressing wild-type KRAS. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria
• Man or woman ≥ 18 years of age at the time the informed consent is obtained
• ECOG performance status of 0 or 1
• Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum in
subjects with unresectable metastatic (M1) disease
• At least 1 uni-dimensionally measurable lesion of at least 20 mm per modified
RECIST 1.0 guidelines using conventional techniques (CT scan or MRI) or at least 10 mm using spiral CT scan. 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 randomization. All sites of disease must be evaluated ≤ 28 days prior to randomization
• 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
• Adequate hematology, renal, hepatic, and coagulation function
• Magnesium ≥ lower limit of normal |
|
E.4 | Principal exclusion criteria |
Key Exclusion Criteria
• History of prior or concurrent central nervous system (CNS) metastases
• History of other malignancy, except:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 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
• Prior chemotherapy or other systemic anticancer therapy for the treatment of metastatic colorectal carcinoma including but not limited to bevacizumab and anti-EGFr therapy (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib)
• Prior adjuvant chemotherapy (including oxaliplatin therapy) or other adjuvant systemic anticancer therapy including but not limited to bevacizumab and anti-EGFr therapy (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) for the treatment of colorectal cancer ≤ 52 weeks prior to randomization with the following exceptions:
• Subjects may have received prior fluoropyrimidine therapy if administered solely for
the purpose of radiosensitization for the adjuvant or neoadjuvant treatment of
rectal cancer
• Radiotherapy ≤ 14 days prior to randomization. Subjects must have recovered from
all radiotherapy-related toxicities.
• Significant cardiovascular risk
• Significant bleeding risk
• History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline CT scan
• Active inflammatory bowel disease or other bowel disease causing chronic diarrhea
(defined as ≥ CTC grade 2, [CTCAE version 3.0])
• Peripheral sensory neuropathy (≥ CTC grade 2 [CTCAE version 3.0] |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) in subjects with wild-type KRAS tumors:
time from randomization to the date of first disease progression among subjects
with wild-type KRAS tumors per modified RECIST 1.0 criteria, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later). Subjects not meeting the criteria by the cutoff date are censored at the last evaluable tumor assessment date. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the study will be event-driven to coincide when 168 subjects have radiologic disease progression (per investigator assessment) or have died in the ITT Analysis Set which will include all consented and randomized subjects. |
|
E.5.2 | Secondary end point(s) |
The following efficacy endpoints will be analyzed for subjects with wildtype
KRAS tumors: OS, ORR, DOR, TTP, TTR, and resection rate.
The following efficacy endpoints will be analyzed for the subjects with
wild-type
RAS tumors (without activating mutations in the aggregate known RAS
family oncogenes); and wild-type RAS/BRAF tumors (without activating
mutations in the aggregate known RAS/BRAF family oncogenes): PFS,
OS, and ORR.
The following safety endpoints will be analyzed for the subjects with
wild-type
KRAS tumors:
• Incidence and severity of adverse events
• Incidence of on-treatment death (death on treatment or within 30
days after last
protocol-specified treatment)
• Protocol treatment delivery
• Incidence of concomitant medications
• Significant changes in laboratory values
The following safety endpoints will be analyzed for subjects with wildtype
RAS tumors (without activating mutations in the aggregate known RAS
family oncogenes); and wild-type RAS/BRAF tumors (without activating
mutations in the aggregate known RAS/BRAF family oncogenes):
• Incidence and severity of adverse events
• Protocol treatment delivery |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
As per primary analysis timepoint |
|
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 | No |
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) | 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 | 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) | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
|
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 visit or 3 years after the last subject is randomized, 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 | 5 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |