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Metastatic Renal Cell CancerPhase 1/2NCT01462214

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

A Phase 1/2 study testing Everolimus in people with Metastatic Renal Cell Cancer, run by Hans J. van der Vliet, MD, PhD at 13 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Renal Cell Cancer
What is being tested?
Everolimus
Type of treatment
Pill or oral medicine
How many people
96 participants
Where
13 sitesNetherlands
Study dates
Oct 2011to Jan 2017
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

Netherlands13 sites

  • Medisch Centrum Alkmaar

    Alkmaar

  • VU University Medical Center

    Amsterdam, 1081 HV

  • NKI-AVL

    Amsterdam

  • Universitair Medisch Centrum Groningen

    Groningen

  • Spaarne Ziekenhuis Hoofddorp

    Hoofddorp

  • Medisch Centrum Leeuwarden

    Leeuwarden

  • University Hospital Maastricht

    Maastricht

  • St. Antonius Ziekenhuis

    Nieuwegein

  • UMC St Radboud Nijmegen

    Nijmegen

  • Sint Franciscus Gasthuis Rotterdam

    Rotterdam

  • Haga Ziekenhuis

    The Hague

  • Medisch Centrum Haaglanden

    The Hague

  • Isala Klinieken Zwolle

    Zwolle

Other trials in Netherlands

About this study

Official title: 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.

Read the 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.

Being tested
Everolimus
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 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.

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Outcome measure in Phase 1 and 2 part

    Measured: from 28 days up to 2 years

  2. Number of patients progression-free at 4 months.

    Outcome measure in phase 2 part

    Measured: 4 months

  3. 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.

    Measured: 28 days

Secondary outcomes (4)

  1. Response rate

    Measured: 2 years

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

    Measured: 2 years

  3. Peripheral blood drug levels of everolimus and cyclophosphamide

    Measured: 2 years

  4. Overall survival

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Oct 2011 (estimated)
  2. Study startOct 2011
  3. Primary completionJan 2017
  4. Study completionJan 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
96 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01462214
Sponsor's protocol ID
11/016
Status last verified
May 2017
First submitted
10 Oct 2011
Last updated
10 May 2017
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 30413837

  • 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.

    PubMed 22129044

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Everolimus in people with Metastatic Renal Cell Cancer, run by Hans J. van der Vliet, MD, PhD at 13 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants with Adverse Events as a Measure of Safety and Tolerability (time frame: from 28 days up to 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01462214, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2017.

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