Sunniforecaststudie


Protocolnummer:
NL35150.029.11; AVL studienummer M12ECR

Ziekenhuizen:
Amphia Ziekenhuis Breda
Amsterdam UMC locatie VUmc
Franciscus Gasthuis & Vlietland
Haaglanden Medisch Centrum
Haga ziekenhuis
Isala Zwolle
Maastricht UMC+
Medisch Centrum Leeuwarden
NKI / A.v.L ziekenhuis Amsterdam
Noordwest Ziekenhuisgroep Alkmaar & Den Helder
RadboudUMC Nijmegen
Spaarne Gasthuis Hoofddorp
St. Antonius ziekenhuis Nieuwegein
Tergooiziekenhuizen Blaricum & Hilversum
Universitair Medisch Centrum Groningen

Titel:

Phase 1-2 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

Rationale of combining everolimus and metronomic cyclophosphamide:

Inhibition of mTOR has been shown to result in the expansion of immunosuppressive Tregs that play a detrimental rol in many malignancies, including RCC. Furthermore, available data suggest that the use of clinical agents that can eliminate Treg could be an important adjunct in cancer immunotherapy. As low-dose oral (metronomic) cyclophosphamide has the capacity to selectively deplete Tregs, while restoring T and NK cell effector functions in end stage cancer patients, it is our hypothesis that the antitumor efficacy of mTOR inhibitors can be enhanced by the simultaneous administration of low-dose oral cyclophosphamide.

Ofwel: In dit onderzoek bestuderen we of de behandelingsresultaten van patiënten met uitgezaaide niercelkanker verbeterd kunnen worden door patiënten met een combinatie van everolimus en cyclofosfamide te behandelen. Daarnaast wordt bestudeerd hoe deze behandeling verdragen wordt.


Behandeling:
Behandeling: Gedurende 28 dagen, één behandelcyclus, zult u eenmaal daags everolimus tabletten innemen. Deze behandeling met everolimus zal worden gecombineerd met tabletten cyclofosfamide, waarbij de cyclofosfamide afhankelijk van het behandelschema waarin u wordt ingedeeld elke dag moet worden ingenomen óf afwisselend één week wel en één week niet. Uw arts zal u vertellen in welk schema u bent ingedeeld. Tijdens de behandeling bezoekt u het ziekenhuis om de 2 tot 4 weken om onderzoeken te laten doen en nieuwe everolimus en cyclofosfamide tabletten te ontvangen. We zullen u vragen naar eventuele bijwerkingen en uw bloed zal worden gecontroleerd. Tevens wordt er elke 8 weken een CT scan van uw borstkas en buik gemaakt om veranderingen in de tumoromvang van te stellen. Deze bezoeken duren ongeveer 30 min. – 1 uur. De behandeling met everolimus en cyclofosfamide wordt voortgezet zolang u eventuele bijwerkingen kunt verdragen en er geen aanwijzingen zijn dat de ziekte verergert. Aan het einde van de behandeling vragen wij u om nog één keer naar het ziekenhuis te komen voor een bezoek van ongeveer 4 uur. Patienten met uitgezaaide niercelkanker

Stadium:

Belangrijkste in/exclusiecriteria:

Inclusion criteria

1. 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).

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

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

4. Aged 18 years or older.

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

6. WHO performance status 0-2.

7. Life expectancy of at least 12 weeks.

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

9. 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).

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

11. Measurable or evaluable disease as defined by RECIST 1.1.

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

13. Signed informed consent.

14. Able to receive oral medication.

Exclusion criteria

1. 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.

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

3. 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.

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

5. 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.

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

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

8. Macroscopic hematuria

9. Prior therapy with mTOR inhibitors.

10. Known hypersensitivity to everolimus or other rapamycins (sirolimus/temsirolimus) or to its excipients.

11. 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).

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

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

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

14. Drug or alcohol abuse.

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

Gesloten

Contactpersoon:
Coordinating investigator: dr. H.J. van der Vliet. Lokale onderzoeker AVL: J. Haanen

Alle niercelcarcinoom trials