| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 Phase 2 study is to compare the progression-free survival in enzastaurin and sunitinib therapy versus sunitinib and placebo in the first-line setting for patients with metastatic clear-cell RCC |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• to compare the following time-to-event efficacy variables between treatment arms:
- time to tumor progression (TTP)
- overall survival (OS)
- to estimate duration of overall response in each treatment arm
• to compare the objective response rate (complete response [CR] + partial response [PR]) between treatment arms
• to compare the rate of clinical benefit (CR + PR + stable disease [SD]) between treatment arms
• to assess the safety and adverse events in both treatment arms
• to characterize the pharmacokinetics (PK) of enzastaurin and sunitinib when administered in combination
• to assess biomarkers (for example, PKCβ, GSK3β, S6K, PTEN, CREB) relevant to enzastaurin and disease state, and their correlation to clinical outcome.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Patients with metastatic RCC who have not received prior treatment with systemic (adjuvant or neoadjuvant) therapy for RCC (including targeted therapy such as tyrosine kinase inhibitors or bevacizumab, immunotherapy, chemotherapy, hormonal, or investigational therapy)
[2] Histologically confirmed RCC with metastases with a component of clear (conventional) cell histology
[3] Evidence of unidimensionally measurable disease (≥1 malignant tumor mass that can be accurately measured in at least 1 dimension ≥20 mm with conventional computed tomography (CT) or magnetic resonance imaging (MRI) scan, or ≥10 mm with spiral CT scan. (If spiral CT scan is used, minimum lesion size should be twice the reconstruction interval used. For example, if reconstruction size is 7 mm, lesion size should be ≥14 mm). CT/MRI should be performed within 4 weeks prior to study entry
Note: Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable.
[4] Primary tumor has been surgically removed by nephrectomy or nephron-sparing surgery
[5] ECOG performance status score of 0 or 1 (see Protocol Attachment S061.5)
[6] Have adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements, to be conducted within 7 days prior to treatment: (ULN/LLN = upper/lower limit of normal)
○ Hemoglobin >9.0 g/dL
○ Absolute neutrophil count (ANC) ≥1.5 x 103 μL
○ Platelet count ≥100 x 103/μL
○ Total bilirubin ≤1.5 x ULN
○ Serum calcium within 10% of normal range
○ Serum creatinine ≤2 x ULN
○ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN (or <5 x ULN for patients with liver involvement of their cancer)
○ Prothrombin Time (PT) or International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN
○ Left ventricular ejection fraction (LVEF) ≥ LLN as defined by the institution performing the scan, as assessed by Multiple Gated Acquisition (MUGA) scan, or from echocardiogram
[7] Estimated life expectancy of at least 12 weeks
[8] Patient compliance and geographic proximity that allow for adequate follow-up
[9] Patients must sign an informed consent document
[10] Patients must be at least 18 years of age
[11] Women of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopause) must test negative for pregnancy within 7 days prior to or at the time of enrollment, based on either a serum or urine pregnancy test. Both male and female patients of reproductive potential must agree to use a reliable method of birth control, as determined by the patient and his or her health-care team, during the study and for 3 months following the last dose of study treatment
[12] No prior malignancies for ≥5 years with the exception of cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated ≥5 years prior to study entry.
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| E.4 | Principal exclusion criteria |
[13] Have received prior treatment with sunitinib or enzastaurin
[14] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
[15] Have had any of the following within 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF), cerebrovascular accident, transient ischemic attack, or pulmonary embolism
Note: Ongoing treatment with therapeutic doses of Coumadin (warfarin) or a derivative of Coumadin or phenprocoumon is not allowed, but prophylactic, low-dose Coumadin (≤ 2 mg daily) for deep vein thrombosis is allowed. In such cases, PT/INR should be very closely monitored as clinically indicated.
[16] Ongoing cardiac arrhythmias >New York Health Association Class II (Protocol Attachment S061.6), atrial fibrillation of any grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females
[17] Have uncontrolled hypertension (>150/100 mm/Hg despite optimal medical therapy), or history of poor compliance with antihypertensive treatment
[18] Have active, clinically serious bacterial or fungal infection more than NCI CTCAE Grade 2
[19] Have known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B/C
[20] Have history of or known brain metastases, spinal cord compression, carcinomatous meningitis, or evidence of brain or leptomeningeal disease on screening CT or MRI scan
[21] Have history of documented central nervous system disease unrelated to cancer; for example, uncontrolled seizures, unless adequately treated with standard medical therapy
[22] Have evidence of bleeding diathesis, NCI CTCAE Grade 3 hemorrhage <4 weeks of starting the study treatment, coagulopathy, or thromboembolic event
[23] Have medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results or have a history of substance abuse
[24] Have known or suspected allergy to any agent given in association with this trial
[25] Have any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study (for example, uncontrolled diabetes mellitus, pancreatitis, acute or chronic liver disease), and preexisting thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
[26] Require concomitant use of potent CYP3A4 inducer, for example, rifampicin or potent CYP3A inhibitors, such as ketoconazole.
Note: Protocol Attachment S061.4 provides an extensive list of CYP3A4 inhibitors or inducers
[27] Significant surgery or radiation therapy <4 weeks of starting study treatment. Prior palliative radiotherapy to metastatic lesion(s) is/are permitted, provided there is at least 1 measurable lesion that has not been irradiated
[28] Patients who are pregnant or breast feeding
[29] Have impairment of the gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
[30] Current or recent (within 10 days of first dose of study treatment) daily use of aspirin (>325 mg/day)
[31] Have serious nonhealing wounds, acute or nonhealing ulcers, or bone fractures
[32] Are unable or unwilling to discontinue use of carbamazepine, phenobarbital, or phenytoin at least 14 days prior to study therapy
[33] Are unable to swallow tablets.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for Part 1 (Safety lead in) is to evaluate the safety of the combination of enzastaurin plus sunitinib.
The primary endpoint for Part 2 is to compare progression-free survival (PFS) between the two arms of treatment.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| 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 | No |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1 of the trial : Open /// Part 2 of the trial : Randomised, Double Blind, Parrallel group |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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