NCT01462214

Brief Summary

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
96

participants targeted

Target at P75+ for phase_1

Timeline
Completed

Started Oct 2011

Longer than P75 for phase_1

Geographic Reach
1 country

13 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

October 1, 2011

Completed
9 days until next milestone

First Submitted

Initial submission to the registry

October 10, 2011

Completed
21 days until next milestone

First Posted

Study publicly available on registry

October 31, 2011

Completed
5.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 1, 2017

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2017

Completed
Last Updated

May 10, 2017

Status Verified

May 1, 2017

Enrollment Period

5.3 years

First QC Date

October 10, 2011

Last Update Submit

May 9, 2017

Conditions

Metastatic Renal Cell Cancer

Outcome Measures

Primary Outcomes (3)

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

    Outcome measure in Phase 1 and 2 part

    from 28 days up to 2 years

  • Number of patients progression-free at 4 months.

    Outcome measure in phase 2 part

    4 months

  • Depletion of circulating CD4+CD25+ regulatory T cells

    Treatment schedule that most selectively induces CD4+CD25+ Treg depletion in phase 1 part will be selected for phase 2.

    28 days

Secondary Outcomes (4)

  • Response rate

    2 years

  • Frequency of tumor infiltrating CD4+CD25+FOXP3+ regulatory T cells.

    2 years

  • Peripheral blood drug levels of everolimus and cyclophosphamide

    2 years

  • Overall survival

    2 years

Interventions

EverolimusDRUG

Patients will be treated with low-dose oral cyclophosphamide (8 different dose levels and schedules) in combination with fixed dose (10 mg) everolimus in patients with mRCC.

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (13)

Medisch Centrum Alkmaar

Alkmaar, Netherlands

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

NKI-AVL

Amsterdam, Netherlands

Location

Universitair Medisch Centrum Groningen

Groningen, Netherlands

Location

Spaarne Ziekenhuis Hoofddorp

Hoofddorp, Netherlands

Location

Medisch Centrum Leeuwarden

Leeuwarden, Netherlands

Location

University Hospital Maastricht

Maastricht, Netherlands

Location

St. Antonius Ziekenhuis

Nieuwegein, Netherlands

Location

UMC St Radboud Nijmegen

Nijmegen, Netherlands

Location

Sint Franciscus Gasthuis Rotterdam

Rotterdam, Netherlands

Location

Haga Ziekenhuis

The Hague, Netherlands

Location

Medisch Centrum Haaglanden

The Hague, Netherlands

Location

Isala Klinieken Zwolle

Zwolle, Netherlands

Location

Related Publications (2)

  • Huijts CM, Werter IM, Lougheed SM, Goedegebuure RS, van Herpen CM, Hamberg P, Tascilar M, Haanen JB, Verheul HM, de Gruijl TD, van der Vliet HJ; Dutch WIN-O Consortium. Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2019 Feb;68(2):319-329. doi: 10.1007/s00262-018-2248-3. Epub 2018 Nov 9.

    PMID: 30413837DERIVED

  • Huijts CM, Santegoets SJ, van den Eertwegh AJ, Pijpers LS, Haanen JB, de Gruijl TD, Verheul HM, van der Vliet HJ. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer. BMC Cancer. 2011 Nov 30;11:505. doi: 10.1186/1471-2407-11-505.

    PMID: 22129044DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Everolimus

Condition Hierarchy (Ancestors)

AdenocarcinomaCarcinomaNeoplasms, Glandular and EpithelialNeoplasms by Histologic TypeNeoplasmsKidney NeoplasmsUrologic NeoplasmsUrogenital NeoplasmsNeoplasms by SiteFemale Urogenital DiseasesFemale Urogenital Diseases and Pregnancy ComplicationsUrogenital DiseasesKidney DiseasesUrologic DiseasesMale Urogenital Diseases

Intervention Hierarchy (Ancestors)

SirolimusMacrolidesLactonesOrganic Chemicals

Study Officials

  • Hans J. van der Vliet, MD, PhD

    Amsterdam UMC, location VUmc

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Medical Oncologist, Department of Medical Oncology

Study Record Dates

First Submitted

October 10, 2011

First Posted

October 31, 2011

Study Start

October 1, 2011

Primary Completion

January 1, 2017

Study Completion

January 1, 2017

Last Updated

May 10, 2017

Record last verified: 2017-05

Locations

NL(13)