ROPETAR: Rotating Pazopanib and Everolimus to Avoid Resistance

Sponsor

Netherlands Working Group on Immunotherapy of Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT01408004

Collaborator

(none)

101

Enrollment

Locations

Arms

Duration (Months)

5.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Carcinoma	Drug: Pazopanib Drug: Everolimus Drug: Pazopanib Drug: Everolimus Drug: Everolimus Drug: Pazopanib	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

101 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Nov 1, 2011

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Pazopanib tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus Other Names: Votrient L01XE11 Drug: Everolimus tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus Other Names: Afinitor L01XE10 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 Other Names: Afinitor L01XE10 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 Other Names: Votrient L01XE11
Active Comparator: 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.	Drug: Pazopanib Tablet 800mg qd til progression Other Names: Votrient L01XE11 Drug: Everolimus tablet 10 mg qd til progression Other Names: Afinitor L01XE10

Arm

Intervention/Treatment

Experimental: 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.

Drug: Pazopanib

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

Other Names:

Votrient

L01XE11

Drug: Everolimus

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

Other Names:

Afinitor

L01XE10

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

Other Names:

Afinitor

L01XE10

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

Other Names:

Votrient

L01XE11

Active Comparator: 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.

Drug: Pazopanib

Tablet 800mg qd til progression

Other Names:

Votrient

L01XE11

Drug: Everolimus

tablet 10 mg qd til progression

Other Names:

Afinitor

L01XE10

Outcome Measures

Primary Outcome Measures

Progression free survival [Randomization until earliest date of disease progression (according RECIST 1.1 criteria) or death, an expected average of one year]

Secondary Outcome Measures

Time to second progression [Time between first and second progression, an expected average of five months]
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.
Change in Quality of life assessed by the FKSI-DRS and EORTC QLQ-C30 questionnaires compared to baseline [From randomization until one month after ceasing study medication, an expected average of 18 months]
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).
Toxicity reported as number/percentage of patients with adverse events [From randomization until one month after ceasing study medication, an expected average of 18 months]
Adverse events will be reported according Criteria for Adverse Events v4.0 (NCI CTCAE v4)
Overall survival [Time between randomization and death, an estimated average of 2-5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

Cardiac angioplasty or stenting
Myocardial infarction
Stable or unstable angina pectoris.
Coronary artery bypass graft surgery.
Symptomatic peripheral vascular disease
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Franciscus Gasthuis	Rotterdam	Zuid-Holland	Netherlands
2	Medisch Centrum Alkmaar	Alkmaar		Netherlands
3	Acedemisch Medisch Centrum Amsterdam	Amsterdam		Netherlands
4	NKI-AVL	Amsterdam		Netherlands
5	Amphia ziekenhuis Breda	Breda		Netherlands
6	Haga Ziekenhuis	Den Haag		Netherlands
7	Maxima Medisch Centrum	Eindhoven		Netherlands
8	UMC Groningen	Groningen		Netherlands
9	Atrium Medisch Centrum Heerlen	Heerlen		Netherlands
10	Medische Centrum Leeuwarden	Leeuwarden		Netherlands
11	Acedemisch ziekenhuis Maastricht	Maastricht		Netherlands
12	St. Antonius ziekenhuis	Nieuwegein		Netherlands
13	Erasmus Medisch Centrum	Rotterdam		Netherlands
14	Orbis Medisch Centrum	Sittard-Geleen		Netherlands
15	St. Elisabeth ziekenhuis	Tilburg		Netherlands
16	UMC Utrecht	Utrecht		Netherlands	3508 GA
17	Isala klinieken	Zwolle		Netherlands