Clinical trial NCT01408004: Rotating Pazopanib and Everolimus to Avoid Resistance
Official title: A Randomized Phase II Study to Explore the Efficacy and Feasibility of Upfront Bi-monthly Rotations Between Everolimus and Pazopanib in Patients With Advanced or Metastatic Clear Cell Renal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Clear Cell Renal Carcinoma
Keywords: Renal carcinoma
Resistance
Reversible
Translational
Lead sponsor: Netherlands Working Group on Immunotherapy of Oncology
Sponsor class: OTHER
First posted: 2011-08-02
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this study will be examined whether alternating treatment between two classes of drugs (TKI's and m-TOR inhibitors) postpones or prevents drug resistance in patients with renal cancer.

Detailed description: Current practice is to treat with VEGFR-TKI or mTOR inhibitors until progression and then continue with the next active agent. From a biological perspective, TKI's will most likely activate compensatory pathways which, may ultimately lead to the development of resistance. Recent studies suggest that resistance to treatment with TKI may be reversible after stopping treatment. There is therefore a rationale to alternate treatment to prevent or delay the occurrence of resistance.

Our hypothesis is that alternating active agents in clear cell renal carcinoma (ccRCC) may reduce side effects, improve tolerability and compliance of treatment and prolong progression free survival and overall survival compared to the standard of care.

Eligibility criteria: Inclusion Criteria:

* Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up.
* Age ≥ 18 years.
* Histologically confirmed diagnosis of progressive metastatic clear cell renal cell cancer defined as \>10% of the tumor cells having the clear cell phenotype.
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to AJCC staging).
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Measurable disease.
* No prior systemic anti-cancer treatment against clear cell renal carcinoma.
* Adequate organ system function.
* Non-childbearing potential.

Exclusion Criteria:

* Prior malignancy.
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
* Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding.
* Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product.
* Presence of uncontrolled infection.
* Known past or present infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV).
* Corrected QT interval (QTc) \> 480 msecs using Bazett's formula.
* History of one or more of the following cardiovascular conditions within the past 6 months:

  1. Cardiac angioplasty or stenting
  2. Myocardial infarction
  3. Stable or unstable angina pectoris.
  4. Coronary artery bypass graft surgery.
  5. Symptomatic peripheral vascular disease
  6. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
* Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg\].
* History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any nonhealing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Evidence of active bleeding or bleeding diathesis.
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
* Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
* Unable or unwilling to discontinue use of prohibited medications or modify the dosing of interacting drugs for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
* Pregnant or lactating female.
* Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of Pazopanib OR Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy.

Primary outcomes:
measure: Progression free survival
timeFrame: Randomization until earliest date of disease progression (according RECIST 1.1 criteria) or death, an expected average of one year
Secondary outcomes:
measure: Time to second progression
timeFrame: Time between first and second progression, an expected average of five months
measure: Change in Quality of life assessed by the FKSI-DRS and EORTC QLQ-C30 questionnaires compared to baseline
timeFrame: From randomization until one month after ceasing study medication, an expected average of 18 months
measure: Toxicity reported as number/percentage of patients with adverse events
timeFrame: From randomization until one month after ceasing study medication, an expected average of 18 months
measure: Overall survival
timeFrame: Time between randomization and death, an estimated average of 2-5 years
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: St. Franciscus Gasthuis
state: Zuid-Holland
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Amsterdam
country: Netherlands
facility: Acedemisch Medisch Centrum Amsterdam
city: Amsterdam
country: Netherlands
facility: NKI-AVL
city: Breda
country: Netherlands
facility: Amphia ziekenhuis Breda
city: Den Haag
country: Netherlands
facility: Haga Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Heerlen
country: Netherlands
facility: Atrium Medisch Centrum Heerlen
city: Leeuwarden
country: Netherlands
facility: Medische Centrum Leeuwarden
city: Maastricht
country: Netherlands
facility: Acedemisch ziekenhuis Maastricht
city: Nieuwegein
country: Netherlands
facility: St. Antonius ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Sittard-Geleen
country: Netherlands
facility: Orbis Medisch Centrum
city: Tilburg
country: Netherlands
facility: St. Elisabeth ziekenhuis
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Zwolle
country: Netherlands
facility: Isala klinieken
Study officials:
affiliation: UMC Utrecht
name: E.E. Voest, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klumpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating Treatment With Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients With Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. doi: 10.1001/jamaoncol.2016.5202.