Rotating Pazopanib and Everolimus to Avoid Resistance (ROPETAR)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Prof. dr. E.E. Voest, Netherlands Working Group on Immunotherapy of Oncology
ClinicalTrials.gov Identifier:
NCT01408004
First received: April 7, 2011
Last updated: July 15, 2014
Last verified: July 2014
  Purpose

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 Intervention Phase
Clear Cell Renal Carcinoma
Drug: Pazopanib
Drug: Everolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Netherlands Working Group on Immunotherapy of Oncology:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: Randomization until earliest date of disease progression (according RECIST 1.1 criteria) or death, an expected average of one year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to second progression [ Time Frame: Time between first and second progression, an expected average of five months ] [ Designated as safety issue: No ]
    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 [ Time Frame: From randomization until one month after ceasing study medication, an expected average of 18 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: From randomization until one month after ceasing study medication, an expected average of 18 months ] [ Designated as safety issue: Yes ]
    Adverse events will be reported according Criteria for Adverse Events v4.0 (NCI CTCAE v4)

  • Overall survival [ Time Frame: Time between randomization and death, an estimated average of 2-5 years ] [ Designated as safety issue: No ]

Enrollment: 101
Study Start Date: November 2011
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01408004

Locations
Netherlands
St. Franciscus Gasthuis
Rotterdam, Zuid-Holland, Netherlands
Medisch Centrum Alkmaar
Alkmaar, Netherlands
NKI-AVL
Amsterdam, Netherlands
Acedemisch Medisch Centrum Amsterdam
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
Orbis Medisch Centrum
Sittard-Geleen, Netherlands
St. Elisabeth ziekenhuis
Tilburg, Netherlands
UMC Utrecht
Utrecht, Netherlands, 3508 GA
Isala klinieken
Zwolle, Netherlands
Sponsors and Collaborators
Netherlands Working Group on Immunotherapy of Oncology
Investigators
Principal Investigator: E.E. Voest, MD/PhD UMC Utrecht
  More Information

Additional Information:
No publications provided

Responsible Party: Prof. dr. E.E. Voest, Netherlands Working Group on Immunotherapy of Oncology
ClinicalTrials.gov Identifier: NCT01408004     History of Changes
Other Study ID Numbers: NL35303.041.11
Study First Received: April 7, 2011
Last Updated: July 15, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Netherlands Working Group on Immunotherapy of Oncology:
Renal carcinoma
Resistance
Reversible
Translational

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 26, 2014