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

This study is currently recruiting participants.
Verified February 2014 by VU University Medical Center
Sponsor:
Collaborators:
Dutch Cancer Society
Novartis
Information provided by (Responsible Party):
Hans J. van der Vliet, MD, PhD, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01462214
First received: October 10, 2011
Last updated: February 19, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Metastatic Renal Cell Cancer
Drug: Everolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1-2 Study of Everolimus and Low-dose Cyclophosphamide in Patients With Metastatic Renal Cell Cancer.

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: from 28 days up to 2 years ] [ Designated as safety issue: Yes ]
    Outcome measure in Phase 1 and 2 part

  • Number of patients progression-free at 4 months. [ Time Frame: 4 months ] [ Designated as safety issue: No ]
    Outcome measure in phase 2 part

  • Depletion of circulating CD4+CD25+ regulatory T cells [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Treatment schedule that most selectively induces CD4+CD25+ Treg depletion in phase 1 part will be selected for phase 2.


Secondary Outcome Measures:
  • Response rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Frequency of tumor infiltrating CD4+CD25+FOXP3+ regulatory T cells. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Peripheral blood drug levels of everolimus and cyclophosphamide [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 96
Study Start Date: October 2011
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Everolimus
    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.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01462214

Contacts
Contact: Hans J van der Vliet, MD, PhD +31-20-4441295 jj.vandervliet@vumc.nl
Contact: Henk M Verheul, MD, PhD +31-20-4441295 h.verheul@vumc.nl

Locations
Netherlands
Medisch Centrum Alkmaar Recruiting
Alkmaar, Netherlands
Contact: Dr. Smorenburg         
Principal Investigator: Dr. Smorenburg         
VU University Medical Center Recruiting
Amsterdam, Netherlands, 1081 HV
Contact: Hans J van der Vliet, MD, PhD    +31-20-4441295    jj.vandervliet@vumc.nl   
Contact: Henk M Verheul, MD, PhD    +31-20-4441295    h.verheul@vumc.nl   
Principal Investigator: Hans J. van der Vliet, MD, PhD         
NKI-AVL Recruiting
Amsterdam, Netherlands
Contact: Prof. Dr. Haanen         
Principal Investigator: Prof. Dr. Haanen         
Medisch Centrum Haaglanden Recruiting
Den Haag, Netherlands
Contact: Dr. Helgason         
Principal Investigator: Dr. Helgason         
Haga Ziekenhuis Recruiting
Den Haag, Netherlands
Contact: Dr. Portielje         
Principal Investigator: Dr. Portielje         
Universitair Medisch Centrum Groningen Active, not recruiting
Groningen, Netherlands
Spaarne Ziekenhuis Hoofddorp Recruiting
Hoofddorp, Netherlands
Contact: Dr. Beeker         
Principal Investigator: Dr. Beeker         
Medisch Centrum Leeuwarden Recruiting
Leeuwarden, Netherlands
Contact: Dr. Polee         
Principal Investigator: Dr. Polee         
University Hospital Maastricht Recruiting
Maastricht, Netherlands
Principal Investigator: Dr. Soetekouw, MD         
St. Antonius Ziekenhuis Recruiting
Nieuwegein, Netherlands
Contact: Dr. Los         
Principal Investigator: Dr. Los         
UMC St Radboud Nijmegen Recruiting
Nijmegen, Netherlands
Contact: Dr. van Herpen         
Principal Investigator: Dr. van Herpen         
Sint Franciscus Gasthuis Rotterdam Recruiting
Rotterdam, Netherlands
Contact: Dr. Hamberg         
Principal Investigator: Dr. Hamberg         
Isala Klinieken Zwolle Recruiting
Zwolle, Netherlands
Contact: Dr. Tascilar         
Principal Investigator: Dr. Tascilar         
Sponsors and Collaborators
Hans J. van der Vliet, MD, PhD
Dutch Cancer Society
Novartis
Investigators
Study Director: Hans J. van der Vliet, MD, PhD VU University Medical Center
  More Information

No publications provided by VU University Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hans J. van der Vliet, MD, PhD, Medical Oncologist, Department of Medical Oncology, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01462214     History of Changes
Other Study ID Numbers: 11/016
Study First Received: October 10, 2011
Last Updated: February 19, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Cyclophosphamide
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on April 17, 2014