| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic 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 | 17.0 |
| 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 |
| The primary objective is to determine the safety and tolerability of AMG 386 in combination with sunitinib in subjects with metastatic renal cell carcinoma |
|
| E.2.2 | Secondary objectives of the trial |
• To estimate the efficacy (as measured by objective response rate [ORR], disease control rate [DCR], duration of response [DOR], progression free survival [PFS], overall survival [OS]) and change in continuous measures of tumor burden) of AMG 386 15 mg/kg IV QW in combination with sunitinib (50 mg PO QD) in subjects with metastatic renal cell cancer.
• To evaluate the pharmacokinetics (PK) of AMG 386 and sunitinib and its primary active metabolite when used in combination (only in a sub-group of subjects at selected sites outside of Europe for sunitinib and its primary active metabolite)
• To determine the incidence of occurrence of anti-AMG386 antibody formation |
|
| 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:
o Karnofsky performance status < 80%
o Time from diagnosis of RCC to first systemic treatment < 1 year
o Serum lactate dehydrogenase > 1.5 x upper limit of normal (ULN)
o Serum hemoglobin < lower limit of normal (LLN) for their institution
o Serum calcium (corrected) > 10 mg/dL
*For the corrected calcium value, the following formula should be used:
Corrected calcium = Total serum calcium [mg/dL] + (0.8 x (4 – serum albumin [g/dL]))
Note: If the units of calcium measurement are in mmol/L (or mmoles/L or mM), then the conversion to mg/dL is as follows:
Calcium (mmol/L) x 4 = Calcium (mg/dL)
Calcium (mg/dL) x 0.25 = Calcium (mmol/L)
• Measurable disease with at least one unidimensionally measurable lesion per RECIST (see Appendix E).
• Left ventricular ejection fraction (LVEF) ≥ 45% as measured by Muga scan or ECHO within 28 days prior to enrollment
Demographic
• Men or women > 18 years old
• ECOG of 0 or 1
Laboratory
• Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days of enrollment:
• Hematological function, as follows:
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
o Platelet count ≥ 100 x 109/L
o Hemoglobin ≥ 9 g/dL
• Renal function, as follows:
o Creatinine clearance > 40 mL/min per 24 hour urine collection or calculated according to the Cockcroft- Gault formula
(140-age) x actual body weight (kg) ( x 0.85 for
CrCl (mL/min) 72 x serum creatinine (mg/dL) females)
Or
CrCl (140-age) x actual body weight (kg) ( x 0.85 for
(mL/min) 0.8136 x serum creatinine (umol/L) females)
o 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:
o Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN)
o Alanine aminotransferase (ALT) < 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
o Alkaline phosphatase < 2.0 x ULN (if bone or liver metastases are present, ≤ 5 x ULN)
o Bilirubin < 2.0 x ULN
• Hemostatic function, as follows:
o International Normalized Ratio (INR) < 1.5 per institutional laboratory range
o 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)/ Independent Ethics Committee (IEC) -approved informed consent form
• Subject plans to begin protocol directed therapy within 7 days of enrollment |
|
| E.4 | Principal exclusion criteria |
Disease Related
• Primary tumor in situ
o Subjects must have their primary tumor resected to be eligible for this study
• Any existing tumor thrombus must be removed before enrollment
• Known history of central nervous system metastases. An MRI or CT scan of the brain or head will be performed within 28 days of enrollment.
• History of arterial or venous thromboembolism within 12 months prior to enrollment
• History of clinically significant bleeding within 6 months prior to enrollment
• Previous treatment (excluding surgery, prior cytokine-based immunotherapy and palliative radiotherapy) for advanced or metastatic renal cell carcinoma
• Focal radiation therapy for palliation of pain from bony metastases within 14 days of enrollment.
• Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to enrollment
Medications
• Currently or previously treated with sunitinib or other small molecule inhibitors of VEGF including, but not limited to AMG 706 (motesanib), SU11248 (sunitinib), sorafenib, PTK787 (vatalinib), AZD 2171 (recentin), AEE-788
• Currently or previously treated with agents that neutralizing VEGF such as bevacizumab, or VEGF-TRAP
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor including but not limited to, XL-820, XL-184, or CVX- 060/PF-4856884
• Currently or previously treated with agents inhibiting the mammalian target of rapamycin (mTOR)
• Current or within 30 days prior to enrollment treatment with immune modulators such as systemic cyclosporine and tacrolimus
• Concomitant or previous use within 30 days prior to enrollment of any strong inducer of CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital and dexamethasone.
Dexamethasone as bolus injection or premedication is allowed.
• Concomitant or previous use within 30 days prior to enrollment of any strong inhibitors of CYP3A4 including, but not limited to, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit, and grapefruit juice
• Concomitant or previous use of amiodarone within 6 months prior to enrollment
General Medical
• Known ongoing pancreatitis
• Clinically significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
• History of allergic reactions to bacterially produced proteins
• Pregnant (i.e., positive beta-human chorionic gonadotropin test) or is breast feeding
• Subjects with history of prior malignancy, except:
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
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
• Major surgery within 28 days prior to enrollment or still recovering from prior surgery
• Minor surgical procedures, placement of tunneled central venous access device (except PICC or peripherally inserted central catheter), or fine needle aspiration within 7 days prior to enrollment
• Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic >150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted.
• Known active or ongoing infection (except uncomplicated UTI) within 14 days prior to enrollment
• Subject known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection
• 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 2.5 mL
of bright red blood) within 6 months before enrollment
• Non-healing wound, ulcer (including gastrointestinal) or fracture
For further exclusion criteria please see protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is safety and tolerability, as measured by the incidence of adverse events, dose interruptions due to adverse events, dose reductions of sunitinib during the first 12 weeks of study treatment and significant laboratory abnormalities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis of the primary endpoint will occur after the last subject enrolled has been followed up for at least 24 weeks
|
|
| 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 two consecutive assessments of CR at least 28 days apart. A confirmed PR requires two consecutive 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 subjects who had an objective response): The 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.
• Disease control rate (DCR): Defined as the percentage of subjects with confirmed CR or PR or have stable disease (SD), as defined by modified-RECIST (CRs or PRs will be confirmed at least 28 days after the criteria for response are first met).
• Progression-free survival (PFS): The time from enrollment date to date of disease progression (ie, radiographic 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. Radiological imaging to
assess disease status will be performed until subjects develop disease progression. Events of radiographic progression per RECIST 1.0 with modifications that occur after initiation of subsequent anticancer therapy will not be considered PFS events. Deaths occuring after initiation of subsequent anticancer therapy will be considered PFS events. Further details on events and censoring times of PFS are provided in the Statistical Analysis Plan. All imaging scans may be assessed by an independent central review group.
• Overall survival (OS): The time from enrollment date to date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
• Change in continuous measures of tumor burden
• Pharmacokinetic parameters (Cmax and Cmin) for AMG 386 when used in combination with sunitinib
• Pharmacokinetic parameter (Cmin) for sunitinib and its primary active metabolite when used in combination with AMG 386 in a sub-group of subjects at selected sites outside of Europe
• Incidence of the occurrence of anti-AMG 386 antibody formation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of secondary endpoints will be performed on each AMG 386 arm separately at the time of the analysis of the primary 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Sunitinib Malate historical data |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Belgium |
| France |
| Poland |
| 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 is when all subjects have completed the treatment period or long-term follow-up (maximum 48 months from the date the last subject was enrolled), 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
