Primary objectivesThe primary objective is to assess the progression-free survival (PFS) of patients who receive bi-monthly rotations of Pazopanib and Everolimus versus patients who receive Pazopanib as a first line treatment. Secondary…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression-free survival: PFS is defined as time to progressive disease per
RECIST 1.1 or death whichever comes first in arm A (alternating schedule) and
after Pazopanib monotherapy in arm B. Comparing time to first PD with time to
first PD.
Patients who have not progressed or died at the date of the analysis cut-off or
when they receive any further anticancer therapy will have their disease status
censored at the time of the last adequate tumor assessment before the cut-off
date or the anticancer therapy date.
Secondary outcome
Time to second progression or death: defined as time to progressive disease per
RECIST 1.1 on Everolimus monotherapy (when PD after 8 weeks Pazopanib) or on
Pazopanib monotherapy (when PD after 8 weeks Everolimus) as second line
treatment in arm A and time to progressive disease on Everolimus in arm B.
Comparing time to 2nd PD with time to 2nd PD.
Quality of life and toxicity. Quality of life assessments and Common Toxicity
Criteria will be used.
Overall survival
Pharmacodynamic measurements and pharmacokinetic assessments at the switch of
Pazopanib and Everolimus and vice versa.
Genetic analysis of tumorbioppsies (optional).
Background summary
(Protocol chapter 1)The introduction of targeted agents in the treatment of
clear cell renal cancer (ccRCC) has made a significant impact on survival of
these patients. However, the optimal use of these agents is presently unclear.
Current practice is to treat with VEGFR-TKI or mTOR inhibitors until
progression and then continue with the next active agent. Although this
strategy prolongs survival, side effects are substantial. Patient compliance to
oral anti-cancer agents is an important issue and side effects are a factor in
adherence to the prescribed treatment. 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 Pazopanib and Everolimus in 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. Pazopanib is registered as first line treatment of locally advanced or
metastatic ccRCC. The continuous dosing schedule of Pazopanib provides a
concomitant continuous therapeutic pressure on tumor cells. This makes
Pazopanib the targeted agent of choice in this trial. In the current design it
is avoided to start the alternating regimen with Everolimus because there are
no data on Everolimus in first line treatment.
Study objective
Primary objectives
The primary objective is to assess the progression-free survival (PFS) of
patients who receive bi-monthly rotations of Pazopanib and Everolimus versus
patients who receive Pazopanib as a first line treatment.
Secondary objectives
The secondary objectives are time to second progression or death, overall
survival, quality of life, toxicity of randomized patients receiving treatment
as defined in arm A compared to arm B.
Other secondary objectives include pharmacodynamic measurements and
pharmacokinetic assessments at the switch of Pazopanib and Everolimus and vice
versa.
To develop biomarkers that may predict responsiveness to either of the agents
used.
Study design
This is an open-label, randomized phase II study to determine the feasibility
of alternating cycles of treatment with Pazopanib and Everolimus compared to
sequential treatment of Pazopanib followed by Everolimus.
The purpose of the study is to determine the progression free survival,
feasibility and tolerability of the experimental arm compared to standard of
care.
In the experimental arm (Arm A) alternating treatment will consist of repeating
periods of 16 weeks of treatment consisting of 8 weeks of Pazopanib 800 mg qd
followed by 8 weeks of Everolimus 10 mg qd until progression followed
thereafter by Pazopanib or Everolimus monotherapy until second progression. 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.
Intervention
In the experimental arm (Arm A) alternating treatment will consist of repeating
periods of 16 weeks of treatment consisting of 8 weeks of Pazopanib 800 mg qd
followed by 8 weeks of Everolimus 10 mg qd until progression followed
thereafter by Pazopanib or Everolimus monotherapy until second progression. 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.
Study burden and risks
The side effects of Pazopanib and Everolimus used as single agents have been
well described. Outside study participation patients will be offered similar
agents. The additive risk, for half of the participating patients, results from
the alternating dosing schedule. The side effects of alternating Everolimus and
Pazopanib is still unknown. The current guideline recommends starting with a
TKI in the first line followed by a mTOR inhibitor when progressive disease
develops. This switch is generally well tolerated.
If the patient accepts tumorbiopsies at baseline and when progressive disease
occurs the punction related complicationrate varies between 0-1,6% (Protocol
chapter 12.6). Most common complications are bruising, bleeding which required
bloodtransfusion and pneumothorax. This part is optional. It*s an invasive
procedure in which the burden will greatly depend on the patient*s perception.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
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 cancer.;- Adequate organ system function.;- A female is eligible to enter and participate in this study if she is of: Non-childbearing potential (physiologically or by using adequate contraception) .
Exclusion criteria
- Malignancy within the previous 5 years.;- 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 including, but not limited to:
1)Active peptic ulcer disease.
2)Known intraluminal metastatic lesions with risk of bleeding.
3) Inflammatory bowel disease (e.g. ulcerative colitis, Crohn*s disease), or other gastrointestinal conditions with increased risk of perforation.
4)History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.;-Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
1)Malabsorption syndrome.
2)Major resection of the stomach or small bowel.;-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 as listed in Section 6.8.1. and 6.8.2 of the protocol.;- 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-000127-32-NL |
| ClinicalTrials.gov | NCT01408004 |
| CCMO | NL35303.041.11 |