Rotating Pazopanib and Everolimus to Avoid Resistance

NCT ID: NCT01408004

Last Updated: 2014-07-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-30
• Study Completion Date: 2014-04-30

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.

Conditions

Clear Cell Renal Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Alternating regimen

In the experimental arm (Arm A) alternating treatment will consist of 8 weeks of Pazopanib 800 mg qd alternated by 8 weeks of Everolimus 10 mg qd until first progression(PD per RECIST 1.1)followed thereafter by Pazopanib (when PD after 8 weeks of Everolimus)or Everolimus (when PD after 8 weeks of Pazopanib) monotherapy until second progression.

Group Type: EXPERIMENTAL

Pazopanib

Intervention Type: DRUG

tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

Everolimus

Intervention Type: DRUG

tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

Everolimus

Intervention Type: DRUG

Everolimus 10mg qd monotherapy until second progression (PD per RECIST 1.1)when first progression after 8 weeks of Pazopanib in alternating regimen

Pazopanib

Intervention Type: DRUG

Pazopanib 800mg qd monotherapy until second progression (PD per RECIST 1.1) when first progression after 8 weeks of Everolimus in alternating regimen

Sequential treatment

The comparative arm (Arm B) will be the standard regimen of Pazopanib (800 mg qd continuously) until progression, followed thereafter by Everolimus (10 mg qd continuously) until progression.

Group Type: ACTIVE_COMPARATOR

Pazopanib

Intervention Type: DRUG

Tablet 800mg qd til progression

Everolimus

Intervention Type: DRUG

tablet 10 mg qd til progression

Interventions

Pazopanib

Tablet 800mg qd til progression

Intervention Type: DRUG

Everolimus

tablet 10 mg qd til progression

Intervention Type: DRUG

Pazopanib

tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

Intervention Type: DRUG

Everolimus

tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus

Intervention Type: DRUG

Everolimus

Everolimus 10mg qd monotherapy until second progression (PD per RECIST 1.1)when first progression after 8 weeks of Pazopanib in alternating regimen

Intervention Type: DRUG

Pazopanib

Pazopanib 800mg qd monotherapy until second progression (PD per RECIST 1.1) when first progression after 8 weeks of Everolimus in alternating regimen

Intervention Type: DRUG

Other Intervention Names

Votrient; L01XE11; Afinitor; L01XE10; Votrient; L01XE11; Afinitor; L01XE10; Afinitor; L01XE10; Votrient; L01XE11

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Netherlands Working Group on Immunotherapy of Oncology

OTHER

Sponsor Role: lead

Responsible Party

Prof. dr. E.E. Voest

Prof. dr. E.E. Voest

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

E.E. Voest, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Locations

St. Franciscus Gasthuis

Rotterdam, South Holland, Netherlands

UMC Utrecht

Utrecht, Utrecht, Netherlands

Medisch Centrum Alkmaar

Alkmaar, , Netherlands

Acedemisch Medisch Centrum Amsterdam

Amsterdam, , Netherlands

NKI-AVL

Amsterdam, , Netherlands

Amphia ziekenhuis Breda

Breda, , Netherlands

Maxima Medisch Centrum

Eindhoven, , Netherlands

UMC Groningen

Groningen, , Netherlands

Atrium Medisch Centrum Heerlen

Heerlen, , Netherlands

Medische Centrum Leeuwarden

Leeuwarden, , Netherlands

Acedemisch ziekenhuis Maastricht

Maastricht, , Netherlands

St. Antonius ziekenhuis

Nieuwegein, , Netherlands

Erasmus Medisch Centrum

Rotterdam, , Netherlands

Orbis Medisch Centrum

Sittard-Geleen, , Netherlands

Haga Ziekenhuis

The Hague, , Netherlands

St. Elisabeth ziekenhuis

Tilburg, , Netherlands

Isala klinieken

Zwolle, , Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 27918762 (View on PubMed)

Related Links

http://www.win-o.nl

Dutch Immunotherapy consortion for oncology

Other Identifiers

NL35303.041.11

Identifier Type: -

Identifier Source: org_study_id