Metastatic renal cell cancer.
Conditions
Interventions
Patients with mRCC will be treated with low-dose oral cyclophosphamide (8 different dose levels and schedules) in combination with fixed dose (10 mg) everolimus.
Dose levels of oral cyclophosphamide
1. 50 mg cyclo
o.d., week on, week off
2. 50 mg cyclo
o.d., continuous
3. 50 mg cyclo
bid, week on, week off
4. 50 mg cyclo
bid, continuous
5. 100 mg cyclo
6. 100 mg cyclo
7. 150 mg cyclo
8. 150 mg cyclo
bid, continuous.
Patients will be enrolled in cohorts of 5 per dose level. The first 5 patients enrolled will be assigned to dose level 0. If there are <= 1 dose-limiting toxicities (DLTs) experience
Sponsors
VU University Medical Center
Eligibility
Inclusion criteria
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) ¡À 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 must have a negative pregnancy test; 13. Signed informed consent; 14. Able to receive oral medication.
Exclusion criteria
Exclusion criteria: 1. Patients currently receiving chemotherapy, immunotherapy, or radiotherapy or who have received these 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase I: 1. Assessment of the recommended dosing and schedule for metronomic cyclophosphamide when administered in combination with fixed dose (10 mg) oral everolimus in patients with mRCC with respect to the selective induction of CD4+CD25+ regulatory T cell depletion; 2. Assessment of safety and tolerability for the combination of metronomic cyclophosphamide and fixed dose oral everolimus in patients with mRCC. Phase II: 1. To investigate the proportion of patients with mRCC receiving everolimus and metronomic cyclophosphamide that is alive and progression-free at 4 months; 2. Assessment of safety and tolerability for the combination of metronomic cyclophosphamide and fixed dose oral everolimus in patients with mRCC. | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase I and II study: 1. To assess the response rate, time to progression, and overall survival of the combination of metronomic cyclophosphamide and fixed dose oral everolimus in patients with mRCC; 2. Assessment of the immunological effects of combining metronomic cyclophosphamide with everolimus; 3. Assessment of the effect of the combination of metronomic cyclophosphamide and everolimus on selected angiogenesis parameters; 4. To assess whether intrapatient changes in thrombocyte numbers correlate with response rate and/or time to progression in patients using the combination of metronomic cyclophosphamide and fixed dose oral everolimus; 5. To asess the effects of the combination of metronomic cyclophosphamide and everolimus on tumor-infiltrating leukocytes, including CD4+CD25+FOXP3+ regulatory T cells; 6. To assess the effects of cyclophosphamide administration on the pharmacokinetics of everolimus. | — |
Contacts
Public ContactJ.J. Vliet, van der
De Boelelaan 1117
Outcome results
None listed