E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with metastatic or inoperable renal cell cancer |
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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 |
1.1 Objectives phase I study 1 To determine the recommended dosing for the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma. 2 To evaluate safety and tolerability for the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma. 3 To determine early signs of clinical activity of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
1.2 Primary Objectives phase II study 1 To determine the proportion of patients with metastatic renal cell carcinoma receiving the combination of Sunitinib and Dalteparin as first line treatment, that is progression-free at 11 months. 2 To determine the safety of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
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E.2.2 | Secondary objectives of the trial |
1.3 Secondary Objectives for phase I and phase II studies 1 To determine the clinical response rate of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma. 2 To determine time-to-progression (TTP) and overall survival amongst patients with metastatic renal cell carcinoma receiving Sunitinib and Dalteparin. 3 To determine the effect of Sunitinib alone and Dalteparin alone compared to the combination of Dalteparin plus Sunitinib on plasma coagulation parameters. 4 To determine the effect of Sunitinib alone and Dalteparin alone compared to the combination of Dalteparin plus Sunitinib on angiogenesis parameters in blood. 5 To evaluate the modulation of tumor blood volume and vascular permeability in patients treated with Sunitinib and Dalteparin by DCE-MRI.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
3.1 Inclusion Criteria
1) Patients must have histologically confirmed metastatic or unresectable renal cell carcinoma. 2) Clear cell and non-clear renal carcinoma patients are eligible. Oncocytoma, collecting duct tumors and transitional cell carcinoma are NOT eligible. 3) No prior systemic treatments for metastatic disease are permitted, including antiangiogenic therapy, immunotherapy, chemotherapy and investigational therapy. 4) Patients with their primary tumor in place who are appropriate surgical candidates should be strongly encouraged to undergo nephrectomy prior to treatment initiation, based on the potential effect on survival. 6) Prior palliative radiation to metastatic lesion(s) is permitted, provided there is at least one measurable and/or evaluable lesion(s) that has not been radiated. 7) Radiation therapy must be completed >4 weeks prior to registration 8) Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as >20 mm with conventional techniques or as >10 mm with spiral CT scan (RECIST criteria). 9) Age > 18 years. 10) ECOG performance status ≤ 2. 11) Patients must have normal organ and marrow function as defined below: • leukocytes >3,000/mm3 • absolute neutrophil count >1,500/mm3 • platelets >100,000/mm3 • total bilirubin <1.5 x laboratory upper limit of normal • AST(SGOT)/ALT(SGPT) <2.5 x laboratory upper limit of normal • creatinine <1.5 x laboratory upper limit of normal or measured Creatinine clearance of >50 ml/min/1.73m2 • PT/INR <1.5 • Urine protein <1+; if >1+, 24 hour urine protein should be obtained and should be <1000 mg
12) The effects of Sunitinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because angiogenesis inhibitors are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 13) Ability to understand and the willingness to sign a written informed consent document. 14) The effect of this combination treatment on the risk for hemorrhage is unknown, but it is possible that it is increased. Therefore, except for Dalteparin that will be administered as a study drug, the patients should not take any other anticoagulants or anitiplatelet agents during the study, including but not limited to NSAID (any dose of aspirin), warfarin or other anticoagulants.
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E.4 | Principal exclusion criteria |
1) Prior therapy with Sunitinib. 2) Patients may not be receiving any other investigational agents. 3) Patients with known CNS metastases. Patients should have a head CT/MRI within 14 days prior to treatment initiation. Any imaging abnormality indicative of CNS metastases will exclude the patient from the study. 4) Patients with a “currently active” second malignancy other than non-melanoma skin cancers are not eligible. Patients are not considered to have a “currently active” malignancy if they have completed anti-cancer therapy and are considered by their physician to be at less than 30% risk of relapse. 5) Patients with a large (>2cm) pulmonary lesion involving the trachea or one of the main bronchus and any endobronchial lesion. 6) History of allergic reactions attributed to compounds of similar chemical or biologic composition to Dalteparin. 7) Evidence of bleeding diathesis within last 6 months. 9) Serious or non-healing wound, ulcer or bone fracture or active peptic ulceration. 10) Current therapeutic full-dose of anticoagulants, either warfarin or LMWH or unfractionated heparin. 11) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association Class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last 6 months), cardiac arrhythmia, history of CVA within 6 months (thrombotic or hemorrhagic), hypertension (defined as blood pressure of >160 mmHg systolic and/or >90 mmHg diastolic on medication), hemorrhagic retinopathy, history of peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements. 12) Patients with an ejection fraction <50% by MUGA scan are not eligible. 13) Pregnant women are excluded from this study because Sunitinib is an angiogenesis inhibitor agent with the potential for teratogenic or abortion inducing effects. 14) History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcess within 28 days prior to day 1 therapy. 15) Invasive procedures defined as: -Major surgical procedure, open biopsy, or significant traumatic injury within 6 weeks prior to day 1 therapy. -Anticipation of need for major surgical procedures during the course of the study. -Core biopsy within 7 days prior to start therapy.
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E.5 End points |
E.5.1 | Primary end point(s) |
7.1 Primary Objectives Phase I part
1 To determine the recommended dosing for the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma.
2 To evaluate safety and tolerability for the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma.
3. To determine early signs of clinical activity of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
The MTD will be determined as described in the design section 5. Sample size for the phase I portion of the study will be between 6 and 18 patients. Toxicities in both phase I and phase II parts will be summarized by tabulation. Summaries will be made across all types of toxicities and by grade and type.
7.2 Primary objectives Phase II
1 To determine the proportion of patients with metastatic renal cell carcinoma receiving the combination of Sunitinib and Dalteparin as first line treatment, that is progression-free at 11 months. The primary efficacy endpoint of the phase II portion of the trial is the progression free survival (PFS) receiving the combination therapy. For each patient, the time of progression will be recorded. Any patient who discontinues treatment due to adverse reactions, refusal, or who goes on to receive alternate therapy will be considered censored at their last visit and be counted as having progressed. The sample size was determined based upon a Bryant Day Phase II clinical trial design, taking into account both activity as well as toxicity. The proportion of patients with 11 month PFS will be calculated with exact 95% confidence intervals. A total of 56 enrolled patients gives 90% (1-) power to distinguish a proportion of 0.7 (P1) from the null value of 0.5 (p0), using Phase II Clinical Trial Design (BRYANT & DAY) with a one-sided test of proportion and an alpha level of 0.1 (). This design also takes into account toxicity and aims for a toxicity rate between 30 and 50%.
Interim analysis will be performed in this two stage design to analyze 11 month progression free survival and toxicity in 24 patients. (see detailed description of statistical analysis at paragraph 7.5). Kaplan-Meier curves will be used to summarize the pattern of PFS over time and the median time to progression will be calculated along with 95% confidence intervals.
2 To determine the toxicity of the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma. As described, toxicities will be tabulated and summarized overall and across grade and type according to CTC criteria. When grade 3 or 4 toxicity occurs in 50% of patients this will be evaluated as unacceptable toxicity and according to the two step evaluation design as described in paragraph 7.5 the study will be discontinued at an interim analysis of 24 patients. This relatively high percentage of toxicity is based on the details as given in the investigators brochure that Sunitinib monotherapy causes in 38% of patients toxicity that requires interruption of Sunitinib administration.
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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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety of combination treatment of two approved drugs |
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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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 | Information not present in EudraCT |
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 |
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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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The total accrual is expected to be 56 patients. The sample size in the Phase I portion of the study is expected to be 6-18 patients. For the phase II portion of the study, an additional maximum of 50 patients will be accrued resulting in 56 patients observed at the MTD for analysis with a planned interim analysis after 24 patients at the MTD. The sample size was determined based upon a Bryant Day Phase II clinical trial designs, taking into account both activity as well as toxicity.
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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 | 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 |