Study of Everolimus and Low-dose Cyclophosphamide in Patients With Metastatic Renal Cell Cancer

May 9, 2017 updated by: Hans J. van der Vliet, MD, PhD

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

In the present phase 1-2 study the investigators aim to determine whether depletion of Tregs using metronomic cyclophosphamide can enhance the antitumor efficacy of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase 1 part of the study the investigators will determine the optimal CD4+CD25+ regulatory T cell-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with a fixed dose (10 mg daily) of everolimus. In the phase 2 part of the study the investigators will subsequently evaluate whether the number of patients who are cancer progression free at 4 months can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase 1 part) to everolimus. In addition to efficacy, the investigators will evaluate treatment toxicity to determine whether this combination strategy is feasible and safe.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

96

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Alkmaar, Netherlands
        • Medisch Centrum Alkmaar
      • Amsterdam, Netherlands, 1081 HV
        • VU University Medical Center
      • Amsterdam, Netherlands
        • NKI-AvL
      • Den Haag, Netherlands
        • Haga Ziekenhuis
      • Den Haag, Netherlands
        • Medisch Centrum Haaglanden
      • Groningen, Netherlands
        • Universitair Medisch Centrum Groningen
      • Hoofddorp, Netherlands
        • Spaarne Ziekenhuis Hoofddorp
      • Leeuwarden, Netherlands
        • Medisch Centrum Leeuwarden
      • Maastricht, Netherlands
        • University Hospital Maastricht
      • Nieuwegein, Netherlands
        • St. Antonius Ziekenhuis
      • Nijmegen, Netherlands
        • UMC St Radboud Nijmegen
      • Rotterdam, Netherlands
        • Sint Franciscus Gasthuis Rotterdam
      • Zwolle, Netherlands
        • Isala Klinieken Zwolle

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 mmol/L.
  • 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 arrhythmia.
  • 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 everolimus).
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: from 28 days up to 2 years
Outcome measure in Phase 1 and 2 part
from 28 days up to 2 years
Number of patients progression-free at 4 months.
Time Frame: 4 months
Outcome measure in phase 2 part
4 months
Depletion of circulating CD4+CD25+ regulatory T cells
Time Frame: 28 days
Treatment schedule that most selectively induces CD4+CD25+ Treg depletion in phase 1 part will be selected for phase 2.
28 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall survival
Time Frame: 2 years
2 years
Response rate
Time Frame: 2 years
2 years
Frequency of tumor infiltrating CD4+CD25+FOXP3+ regulatory T cells.
Time Frame: 2 years
2 years
Peripheral blood drug levels of everolimus and cyclophosphamide
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hans J. van der Vliet, MD, PhD

Collaborators

Novartis
Dutch Cancer Society

Investigators

  • Study Director: Hans J. van der Vliet, MD, PhD, Amsterdam Umc, Location Vumc

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2011

Primary Completion (Actual)

January 1, 2017

Study Completion (Actual)

January 1, 2017

Study Registration Dates

First Submitted

October 10, 2011

First Submitted That Met QC Criteria

October 26, 2011

First Posted (Estimate)

October 31, 2011

Study Record Updates

Last Update Posted (Actual)

May 10, 2017

Last Update Submitted That Met QC Criteria

May 9, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11/016

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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