Phase 1-2 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer.

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 96

Inclusion Criteria

1. Patients with histologically or cytologically confirmed clear-cell mRCC with progressive disease and not amenable to or progressive on or within 6 months of stopping treatment with a VEGF receptor tyrosine kinase inhibitor (sunitinib (or pazopanib) ± sorafenib).
2. Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors (i.e. bevacizumab) is permitted.
3. Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery.
4. Aged 18 years or older.
5. No other current malignant disease, except for basal cell carcinoma of the skin.
6. WHO performance status 0-2.
7. Life expectancy of at least 12 weeks.
8. Adequate hematologic function: ANC >= 1.5 x 109/L, platelets >= 100 x 109/L, Hb >= 6.0 mmol/L.
9. Adequate hepatic function: serum bilirubin <= 1.5 x ULN, ALT and AST <= 2.5 x ULN (or <= 5 times ULN if liver metastases are present).
10. Adequate renal function: calculated creatinine clearance >= 50 ml/min.
11. Measurable or evaluable disease as defined by RECIST 1.1.
12. Patients with reproductive potential must use effective contraception. Female patients of child baring potential must have a negative pregnancy test.
13. Signed informed consent.
14. Able to receive oral medication.

Exclusion Criteria

1. Patients currently receiving chemotherapy, immunotherapy, or radiotherapy or who have received these <= 4 weeks prior to visit 1. Radiotherapy on a non-target lesion is allowed >= 2 weeks prior to visit 1.The wash-out period for sunitinib or sorafenib is at least 2 weeks from the first dose of the study medication.
2. Known human immunodeficiency virus (HIV) or other major immunodeficiency.
3. Immunosuppressive agents within 3 weeks of study entry, except for low dose corticosteroids with a maximum daily dose of 10mg prednisone or equivalent. Topical or inhaled corticosteroids are permitted.
4. Patients with an active bleeding diathesis or on oral anti-vitamin K medication.
5. Patients with untreated CNS metastases with clinical symptoms or who have received treatment for CNS metastases within 2 months of study entry. Patients with treated CNS metastases, who are neurologically stable and off of corticosteroids for more than 2 months prior to study entry are eligible to enter the study.
6. Active infection or serious intercurrent illness, except asymptomatic bacteriuria.
7. Presence of unstable angina, recent myocardial infarction (within the previous 6 months), or use of ongoing maintenance therapy for life-threatening ventricular arrhythmia.
8. Macroscopic hematuria
9. Prior therapy with mTOR inhibitors.
10. Known hypersensitivity to everolimus or other rapamycins (sirolimus/temsirolimus) or to its excipients.
11. Pregnant or nursing women, or women who were of childbearing potential and who were not utilizing an effective contraceptive method. A woman of childbearing potential is defined as a female who is biologically capable of becoming pregnant. Men with partners of childbearing potential not using an effective method of contraception. (Use of effective contraceptives must continue for 3 months after the last dose of everolimus).
12. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient*s compliance.
13. Uncontrolled diabetes as defined by fasting serum glucose > 2 ULN, severely impaired lung function.
14. Cirrhosis/chronic active hepatitis/chronic persistent hepatitis, history of HCV infection (for hepatitis screening indications see section 3.3).
15. Drug or alcohol abuse.
16. Any other major illness that, in the investigator*s judgment, substantially increased the risk associated with the subject*s participation in the study.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary objectives Phase I<br /><br>1) Assessment of the recommended dosing and schedule for metronomic<br /><br>cyclophosphamide when administered in combination with fixed dose (10 mg) oral<br /><br>everolimus in patients with mRCC with respect to the selective induction of<br /><br>CD4+CD25+ regulatory T cell depletion.<br /><br>2) Assessment of safety and tolerability for the combination of metronomic<br /><br>cyclophosphamide and fixed dose oral everolimus in patients with mRCC.<br /><br><br /><br>Primary objectives Phase II<br /><br>1) To investigate the proportion of patients with mRCC receiving everolimus and<br /><br>metronomic cyclophosphamide that is alive and progression-free at 4 months.<br /><br>2) Assessment of safety and tolerability for the combination of metronomic<br /><br>cyclophosphamide and fixed dose oral everolimus in patients with mRCC.</p><br>

Secondary Outcome Measures

Name	Time	Method

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