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Phase 1-2 Study of Everolimus and Low-dose Cyclophosphamide in Patients With Metastatic Renal Cell Cancer.

Phase 1/Phase 2
18 Years
Open (Enrolling)
Metastatic Renal Cell Cancer

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Trial Information

Phase 1-2 Study of Everolimus and Low-dose Cyclophosphamide in Patients With Metastatic Renal Cell Cancer.

This is a phase I/II, national multi-center study of different doses and schedules of
low-dose oral cyclophosphamide in combination with fixed dose everolimus in patients with
mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor
containing treatment regimen. Phase I part: Patients will be enrolled in cohorts of 5 per
dose level. The first 5 patients enrolled will be assigned to dose level 0 in order to
assess immune and angiogenic effects caused by everolimus monotherapy. The second 5 patients
enrolled will be assigned to dose level 1. 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. Entry of patients
into the expansion cohort will not occur until at least 28 days after the last patient in
the escalation phase received his/her first study treatment. At the final dose level
recommended for the phase II study a minimum of 10 patients will be treated. Phase II part:
In the phase 2 part of the study up to 56 patients will be treated at the dose level that
has been selected based on its capacity to most selectively deplete circulating Treg levels
in the phase 1 part of the study. Based on data of patients with mRCC treated with
everolimus monotherapy after previous treatment with sunitinib ± sorafenib, the
investigators aim to increase the number of patients who are alive and cancer progression
free at 4 months from 50% to 70% by adding metronomic cyclophosphamide. In addition, the
investigators consider this increase meaningful as long as the combination treatment does
not cause combination treatment related toxicity ≥ grade 3 in ≥ 30% of patients.

Inclusion Criteria:

- 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).

- Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors
(i.e. bevacizumab) is permitted.

- Patients with brain metastases are eligible if they have been stable for at least two
months post-radiation therapy or surgery.

- Aged 18 years or older.

- No other current malignant disease, except for basal cell carcinoma of the skin.

- WHO performance status 0-2.

- Life expectancy of at least 12 weeks.

- Adequate hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, Hb ≥ 6.0

- 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).

- Adequate renal function: calculated creatinine clearance ≥ 50 ml/min.

- Measurable or evaluable disease as defined by RECIST 1.1.

- Patients with reproductive potential must use effective contraception. Female
patients must have a negative pregnancy test.

- Signed informed consent.

- Able to receive oral medication.

Exclusion Criteria:

- 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.

- Known human immunodeficiency virus (HIV) or other major immunodeficiency.

- 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.

- Patients with an active bleeding diathesis or on oral anti-vitamin K medication.

- 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.

- Active infection or serious intercurrent illness, except asymptomatic bacteriuria.

- Presence of unstable angina, recent myocardial infarction (within the previous 6
months), or use of ongoing maintenance therapy for life-threatening ventricular

- Macroscopic hematuria

- Prior therapy with mTOR inhibitors. 10. Known hypersensitivity to everolimus or other
rapamycins (sirolimus/temsirolimus) or to its excipients.

- 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

- Presence of any significant central nervous system or psychiatric disorder(s) that
would hamper the patient's compliance.

- Uncontrolled diabetes as defined by fasting serum glucose > 2 ULN, severely impaired
lung function.

- Cirrhosis/chronic active hepatitis/chronic persistent hepatitis, history of HCV
infection (for hepatitis screening indications see section 3.3).

- Drug or alcohol abuse.

- Any other major illness that, in the investigator's judgment, substantially increased
the risk associated with the subject's participation in the study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Outcome Description:

Outcome measure in Phase 1 and 2 part

Outcome Time Frame:

from 28 days up to 2 years

Safety Issue:


Principal Investigator

Hans J. van der Vliet, MD, PhD

Investigator Role:

Study Director

Investigator Affiliation:

VU University Medical Center


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

October 2011

Completion Date:

March 2013

Related Keywords:

  • Metastatic Renal Cell Cancer
  • Carcinoma, Renal Cell