Een fase 1-2 studie van everolimus en lage dosis orale cyclofosfamide bij patiënten met uitgezaaide niercelkanker.

• Register: Netherlands Trial Register
• Last refreshed on: 28 April 2013
• Main ID: NTR3085
• Date of registration: 22/09/2011
• Primary sponsor: VU University Medical Center
• Public title: Een fase 1-2 studie van everolimus en lage dosis orale cyclofosfamide bij patiënten met uitgezaaide niercelkanker.
• Scientific title: Phase 1-2 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer. - Everolimus-LDcyclo
• Date of first enrolment: 1/10/2011
• Target sample size: 96
• Recruitment status: recruiting
• URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3085
• Study type: intervention
• Study design: Randomised: No; Masking: None; Control: Not applicable; Group: Parallel; Type: Single arm

Countries of recruitment

The Netherlands

Contacts

• Name: J.J. Vliet, van der

• Name: J.J. Vliet, van der

Key inclusion & exclusion 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: 1. Patients currently receiving chemotherapy, immunotherapy, or radiotherapy or who have received these <= 4 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 when given for disorders such as rheumatoid arthritis, asthma, or adrenal insufficiency. 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.

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Metastatic renal cell cancer

Intervention(s)

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 during the phase I part of the study are as follows:

0. No 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; bid, week on, week off;

6. 100 mg cyclo; bid, continuous;

7. 150 mg cyclo; bid, week on, week off;

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) experienced by the first 5 patients in a cohort during the first 28 days after the first study treatment, further patients will be entered in the next dose level. At the final dose level recommended for the phase II study a minimum of 10 patients will be treated.

Primary Outcome(s)

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 Outcome(s)

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.

Secondary ID(s)

11/016

Source(s) of Monetary Support

KWF Kankerbestrijding, Novartis