| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Metastatic Clear Cell Carcinoma of the Kidney |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Renal Cell Carcinoma |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 estimate the efficacy as measured by progression free survival (PFS) of subjects receiving AMG 386 (either 3mg/kg or 10mg/kg IV QW) in combination with sorafenib (400mg PO BID) compared to subjects receiving sorafenib (400mg PO BID) plus placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of the combination regimen of AMG 386 and sorafenib.
To estimate the efficacy (by parameters other than PFS) of subjects receiving AMG 386 (either 3 mg/kg or 10 mg/kg IV QW) in combination with sorafenib (400 mg PO BID) compared to the subjects receiving sorafenib (400 mg PO BID) plus placebo
To evaluate the pharmacokinetics (pK) of AMG 386 and sorafenib when used in combination.
To determine the incidence of occurrence of anti-AMG386 antibody formation.
To evaluate patient reported outcomes (PRO) using the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15) and EQ-5D.
To evaluate the efficacy of subjects receiving AMG 386 10.0 mg/kg QW in combination with sorafenib after treatment failure with sorafenib plus placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease Related:
• Subjects must have a histologically confirmed metastatic RCC with a clear cell component
• Low or intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification defined as meeting between 0 and 2 of the following risk factors:
- Karnofsky performance status < 80%
- Serum lactate dehydrogenase > 1.5 x upper limit of normal (ULN)
- Serum hemoglobin < lower limit of normal (LLN) for their institutions
- Serum Calcium (corrected) > 10 mg/dL
- Time from diagnosis of RCC to first systemic treatment < 1 year
• Measurable disease with at least one unidimensionally measurable lesion per RECIST.
Complete radiology and tumor measurement within 28 days prior to
randomization:
o Chest: CT / MRI scan with intravenous contrast if the contrast is not
medically contraindicated
o Abdomen: CT / MRI scan with intravenous contrast if the contrast is
not medically contraindicated
o Pelvis: CT / MRI scan with intravenous contrast if the contrast is not
medically contraindicated
o Brain or Head: CT / MRI scan
o Bone: Whole body Bone Scintigraphy
Demographic:
• Men or women≥ 18 years old
Laboratory:
• Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days of randomization:
• Hematological function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L
- Platelet count ≥ 100 x 10e9/L
- Hemoglobin≥9 g/dL
• Renal function, as follows:
- Calculated creatinine clearance > 50 mL/min according to the
Cockcroft-Gault formula
- Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample
• Hepatic function, as follows:
- Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN)
- Alanine aminotransferase (ALT) ≤ 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
- Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver metastases are present, ≤ 5 x ULN)
- Bilirubin≤ 2.0 x ULN
• Hemostatic function, as follows:
- International Normalized Ratio (INR) < 1.5 per institutional laboratory range
- Partial thromboplastin time (PTT) or activated partial thromboplastin (aPTT) ≤ 1.5 x ULN per institutional laboratory range
General:
• Able to tolerate infusions and self-administer oral medications
• Competent to comprehend, sign, and date an institutional review board (IRB) or
Independent Ethics Committee (IEC) -approved informed consent form
• ECOG of 0 or 1
• Subject plans to begin protocol directed therapy within 7 days of randomization |
|
| E.4 | Principal exclusion criteria |
Disease Related:
• Primary tumor in situ
- Subjects must have their primary tumor resected to be eligible for this study
• Known history of central nervous system metastases. An MRI or CT scan of the brain or head will be performed within 28 days of randomization.
• History of arterial or venous thrombosis within 6 months prior to randomization
• History of bleeding diathesis or clinically significant bleeding within 14 days of randomization
• Previous treatment (excluding surgery and palliative radiotherapy) for advanced or metastatic renal cell carcinoma
• Focal radiation therapy for palliation of pain from bony metastases within 14 days of randomization.
• Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to randomization
Medications:
• Currently or previously treated with sorafenib or other small molecule inhibitors of VEGF including, but not limited to AMG 706 (motesanib), SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788
• Currently or previously treated with bevacizumab
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor including but not limited to, AZD-5180, XL-820, CEP 11981/SSR-106462, BSF-466,895, CGI-1842, LOC-590, XL-184, or CP-8681596
• Concomitant or use within 30 days prior to randomization of any strong inducer of CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital and dexamethasone
General Medical:
• Known ongoing pancreatitis
• Myocardial infarction, cerebrovascular accident, transient ischemic attack, percutaneous transluminal coronary angioplasty/stent, congestive heart failure, grade 2 or greater peripheral vascular disease, arrhythmias not controlled by outpatient medication, or unstable angina within 1 year prior to randomization
• Major surgery within 4 weeks before randomization or still recovering from prior surgery
• History of allergic reactions to bacterially produced proteins
• Pregnant (i.e., positive beta-human chorionic gonadotropin test) or is breast feeding
• Exclude subjects with a history of prior malignancy, except:
o 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 treating physician
o Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
o Adequately treated cervical carcinoma in situ without evidence of disease
o Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Minor surgical procedures, placement of access device, or fine needle
aspiration within 7 days of first dose
• Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic >150 mmHg. Anti-hypertensive medications are permitted.
• Known active or ongoing infection within 14 days before randomization
• Subject known to have tested positive for HIV
• Subject known to have chronic hepatitis
• Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
• History of pulmonary hemorrhage or gross hemoptysis (1/2 teaspoon or more of bright red blood) within 6 months before randomization
• Concurrent or prior (within 1 week before randomization) anticoagulation therapy, excluding Aspirin. The concurrent use of low molecular weight heparin or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis against central venous catheter thrombosis is acceptable
Other:
• Other investigational procedures are excluded
• Subject not consenting to the use of highly effective contraceptive, e.g. double barrier method (i.e. condom plus diaphragm) precautions during the course of the study and for 6 months after administration of the last study medication
• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s)
• Subject has known sensitivity to any of the products to be administered during dosing.
• Subject has previously been randomized onto this study
• Subject will not be available for follow-up assessment
• 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) |
Progression-free survival (PFS): time from randomization date to date of disease progression per the modified RECIST criteria or death. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after the 75th subject is enrolled |
|
| E.5.2 | Secondary end point(s) |
Objective Response Rate (ORR): The incidence of either a confirmed complete response (CR) or partial response (PR) per modified RECIST criteria (responder). A confirmed CR requires 2 assessments of CR at least 28 days apart. A confirmed PR requires 2 assessments at least 28 days apart of PR or CR. 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 (DOR): (calculated only for those subjects with an objective response) time from first confirmed objective response to disease progression or death due to any cause. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
• Change in continuous measures of tumor burden
• Time-adjusted area under the curve (AUC) for the FACT-Kidney Cancer Symptom Index (FKSI-15) scale score from baseline through disease progression with imputation for missing data.
• Incidence of AEs and significant laboratory changes
• Incidence of the occurrence of anti-AMG 386 antibody formation
• Pharmacokinetic parameters for AMG 386 (Cmax and Cmin) and sorafenib (Cmin) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 16 weeks after the 75th subject is enrolled. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Subjects in Arm C have option to go to sorafenib + open label AMG 386 following disease progression. |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 0 |
| 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 |
| Austria |
| Belgium |
| France |
| Poland |
|
| 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 is when all subjects have completed the treatment period or safety follow-up or long-term follow-up (maximum 48 months from the date the last subject was 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 | 5 |
| 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 | 5 |
| 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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