Rotating Pazopanib and Everolimus to Avoid Resistance

Clear Cell Renal Carcinoma Clinical Trial

— ROPETAR  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01408004
• Other study ID #: NL35303.041.11
• Status: Completed
• Phase: Phase 2
• First received: April 7, 2011
• Last updated: July 15, 2014
• Start date: November 2011
• Est. completion date: April 2014

Study information

• Verified date: July 2014
• Source: Netherlands Working Group on Immunotherapy of Oncology
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Clear Cell Renal Carcinoma
• Kidney Neoplasms

Intervention

Drug:
• Pazopanib
Tablet 800mg qd til progression
• Everolimus
tablet 10 mg qd til progression
• Pazopanib
tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus
• Everolimus
tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus
• Everolimus
Everolimus 10mg qd monotherapy until second progression (PD per RECIST 1.1)when first progression after 8 weeks of Pazopanib in alternating regimen
• Pazopanib
Pazopanib 800mg qd monotherapy until second progression (PD per RECIST 1.1) when first progression after 8 weeks of Everolimus in alternating regimen

Locations

Country	Name	City	State
Netherlands	Medisch Centrum Alkmaar	Alkmaar
Netherlands	Acedemisch Medisch Centrum Amsterdam	Amsterdam
Netherlands	NKI-AVL	Amsterdam
Netherlands	Amphia ziekenhuis Breda	Breda
Netherlands	Haga Ziekenhuis	Den Haag
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	St. Franciscus Gasthuis	Rotterdam	Zuid-Holland
Netherlands	Orbis Medisch Centrum	Sittard-Geleen
Netherlands	St. Elisabeth ziekenhuis	Tilburg
Netherlands	UMC Utrecht	Utrecht
Netherlands	Isala klinieken	Zwolle

Sponsors (1)

Lead Sponsor	Collaborator
Netherlands Working Group on Immunotherapy of Oncology

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival		Randomization until earliest date of disease progression (according RECIST 1.1 criteria) or death, an expected average of one year	No
Secondary	Time to second progression	Time between first progression and second progression (PD) per RECIST 1.1 on Everolimus monotherapy (when PD after 8 weeks Pazopanib) or Pazopanib monotherapy (when PD after 8 weeks Everolimus) as second line treatment in experimental arm and time to progressive disease on Everolimus as second line treatment in comparative arm.	Time between first and second progression, an expected average of five months	No
Secondary	Change in Quality of life assessed by the FKSI-DRS and EORTC QLQ-C30 questionnaires compared to baseline	Quality of life will be assessed bi-monthly by using the FACT Kidney Symptom Index (FKSI)-Disease Related Symptom (DRS)and the EORTC QLQ-C30 questionnaire. The symptoms covered by the FKSI-DRS include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. The EORTC QLQ-C30 questionnaire evaluates five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact).	From randomization until one month after ceasing study medication, an expected average of 18 months	No
Secondary	Toxicity reported as number/percentage of patients with adverse events	Adverse events will be reported according Criteria for Adverse Events v4.0 (NCI CTCAE v4)	From randomization until one month after ceasing study medication, an expected average of 18 months	Yes
Secondary	Overall survival		Time between randomization and death, an estimated average of 2-5 years	No

External Links

•   Dutch Immunotherapy consortion for oncology