E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Renal cell carcinoma (RCC) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038414 |
E.1.2 | Term | Renal cell carcinoma stage IV |
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 compare overall survival (OS) between study arms in subjects treated with AGS-003 in combination with standard treatment (combination arm) versus active control of standard treatment alone (control arm). |
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E.2.2 | Secondary objectives of the trial |
Safety
• To compare safety assessments between study arms
Efficacy
• To compare progression free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST)1.1 between study arms
• To compare tumor responses based on RECIST 1.1 between study arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Advanced disease, histologically assessed as RCC, with predominatly clear cell histology
3. Metastatic disease (measureable or non-measurable) that can be monitored throughout the course of the study participation per RECIST 1.1
4. Subjects who are candidates for standard first-line therapy initiating with sunitinib
5. Time from diagnosis to treatment <1 year
6. Karnofsky Performance Status (KPS) ≥ 70%
7. Life expectancy of 6 months or greater
8. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to Grade ≤ 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
9. Adequate hematologic function, as defined by central laboratory values for all three of the following criteria:
a. Absolute neutrophil count (ANC) ≥ LLN, and
b. Platelets ≥ LLN, and
c. Hemoglobin (Hgb) ≥ 9.0 g/dL
10. Adequate renal function, as defined by either of the following criteria:
a. Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
b. OR, if serum creatinine > 1.5 x ULN, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min
11. Adequate hepatic function, as defined by both of the following:
a. Total serum bilirubin ≤ 1.5 x ULN
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
− or, AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy
12. Adequate coagulation function as defined by the following criteria:
a. INR <1.5 x ULN
b.For subjects receiving warfarin or LMWH, the subjets must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiveing anticoagulant therapy. The INR for these patietns may exceed 1.5 x ULN if that is the goal of anticoagulant therapy.
13. Negative serum pregnancy test for female subjects with reproductive potential, and agreement of all male and female subjects of reproductive potential to use a reliable form of contraception during the study and for 12 weeks after the last dose of study drug
14. Normal ECG or clinically non-significant finding(s) at Screening
15. Able to abstain from taking prohibited drugs, either prescription or non-prescription, during the treatment phase of the study
16. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
17. Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment |
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E.4 | Principal exclusion criteria |
1. Prior systemic therapy (including adjuvant or neoadjuvant) of any kind for RCC, including immunotherapy, chemotherapy, hormonal, or investigational therapy
2. Prior history of malignancy within the preceding 3 years, except for adequately treated in situ carcinomas or non-melanoma skin cancer, adequately treated early stage breast cancer, superficial bladder, and non-metastatic prostate cancer with a normal PSA.
3. History of or known brain metastases, spinal cord compression, or carcinomatous meningitis, or evidence of brain or leptomeningeal disease
4. Patients will be excluded if they have 5 or more of the following risk factors at Screening:
a. Hgb < LLN
b. Corrected calcium > 10.0 mg/dL
c. KPS < 80%
d. Neutrophils > ULN
e. Platelets > ULN
5. Planned or elective surgical treatment post-nephrectomy for the direct management of RCC within 28 days before Visit 1 (Day 0)
− NOTE: Palliative radiotherapy is permitted if it is completed > 28 14 days before Visit 1 (Day 0) 6. NCI CTCAE Grade 3 hemorrhage < 28 days before Visit 1 (Day 0)
7. Clinically significant cardiovascular conditions within 3 months prior to Randomization, including:
a. Cardiac angioplasty
b. Myocardial infarction
c. Unstable angina
d. Coronary artery by-pass graft or stenting
e. Class III or IV congestive heart failure (CHF)
f. Symptomatic peripheral vascular disease
g. Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
h. Sumptomatic or uncontrolled pulmonary embolism or deep vein thrombosis (DVT)
i. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, atrial fibrillation of any grade, or prolongation of the QTc for males > 450 msec and for females > 470 msec as corrected by either the Fridericia or Bazett formula
j. Left ventricular ejection fraction (LVEF) < LLN as assessed by either echocardiography or multiple gated acquisition (MUGA) scan
k. Poorly controlled hypertension, defined as a systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 90 mm Hg
− NOTE: Initiation of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on 2 occasions separated by at least 1 hour. The mean SBP/DBP values must be < 150/90 mm HGfor a subject to be eligible.
l. Evidence of active bleeding or a bleeding diathesis at Screening
8. Significant gastrointestinal abnormalities:
a. Any history of major resection of the stomach or small bowel
b. Malabsorption syndrome with active symptoms within 3 months prior to Randomization
c. Active peptic ulcer within 3 months prior to Randomization
d. Intra-luminal bleeding lesions within 3 months prior to Randomization
e. History of abdominal fistula or intra-abdominal abscess within 3 months prior to Randomization
9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
10. Active autoimmune disease or condition requiring chronic immunosuppressive therapy such as rheumatic arthritis, systemic lupus erythematous, multiple scleorsis, organ transplant recipient, etc.)
− NOTE: Abnormal laboratory values for autoimmunity markers in the absence of other signs/symptoms of autoimmune disease are not exclusionary.
11. Clinically significant infections, including human immunodeficiency virus (HIV), syphilis, and active hepatitis B or C
12. Current treatment with an investigational therapy on another clinical trial
13. Pregnancy or breastfeeding
14. Any serious medical condition or illness considered by the investigator to constitute an unwarranted high risk for investigational treatment |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy:
• Overall Survival (OS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of initial subject randomization until 290 deaths have accrued. |
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E.5.2 | Secondary end point(s) |
Safety:
• Treatment emergent adverse events (AEs)
• Changes from Baseline values in clinical laboratory tests (hematology, biochemistry, urinalysis)
• Changes in vital signs, physical examinations, and ECGs
• Treatment-emergent changes in autoimmunity evaluations as measured by clinical signs and symptoms and laboratory assessments
Efficacy:
• Progression-Free Survival (PFS)
− Progression-free survival from the date of subject randomization as assessed by the investigator per RECIST 1.1.
− Radiological evidence of progression
− Limited cases of protocol-defined clinical progression will also contribute to the PFS endpoint.
• Stable Disease and Tumor Response
− The clinical efficacy of AGS-003 in combination with standard treatment will be assessed based on tumor responses per RECIST 1.1 to determine the following:
o Overall response rate (ORR)
o Duration of overall response (DR)
o Disease control rate (DCR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety:
The safety of multiple administrations of AGS-003 in combination with standard treatment will be assessed by monitoring the following for all study subjects, starting at Visit 2 (Week 6), as this is the first dose of AGS-003 (for subjects randomized to the combination arm)
Radiological evidence of progression at baseline (Screening) and restaging scans at Weeks 8, 16, 24, 30, 36, 48, then every 12 weeks.
Efficacy
Overall survival from day of randomization |
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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 | Yes |
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) | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standard treatment initiating with sunitinib |
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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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Germany |
Israel |
Italy |
Spain |
United Kingdom |
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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Until 290 deaths have accrued |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |