Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003888

Trial Description

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Title

A Randomised Double-blind Cross-over Patient Preference Study of Pazopanib Versus Sunitinib in Treatment naïve Locally Advanced or Metastatic Renal Cell Carcinoma.

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Trial Acronym

PISCES

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URL of the Trial

[---]*

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Brief Summary in Lay Language

This is a randomised, double-blind, cross-over study of pazopanib versus sunitinib in
patients with locally advanced or metastatic renal cell carcinoma (mRCC) who have received
no prior systemic therapy for advanced or metastatic RCC. Approximately 160 eligible
patients will be stratified based on the ECOG performance status (0 vs. 1) and number of
metastatic sites of disease (0 and 1 vs. >=2). The study consists of two treatment periods
of 10 weeks with a 2-week wash-out period between the two treatment periods. Patients will
receive pazopanib and sunitinib treatment sequentially in a double-blinded fashion. The
primary objective of the study is to assess how the tolerability and safety differences
between pazopanib and sunitinib translate into patient preference, defined by the patient's
stated preference for which drug they may prefer to continue treatment with at end of study.
The secondary objectives are to evaluate the reason for patient preference as assessed by a
patient preference questionnaire; to evaluate fatigue as assessed by FACIT-Fatigue and
quality of life as assessed by EuroQoL EQ-5D; to evaluate dose modifications and time to
dose modification; and to evaluate safety.

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Brief Summary in Scientific Language

This is a randomised, double-blind, cross-over study to evaluate the patient preference of
pazopanib versus sunitinib in patients with locally advanced or metastatic RCC who have
received no prior systemic therapy for advanced or metastatic RCC. Approximately 160
eligible patients will be stratified based on the ECOG performance status (0 vs. 1) and
number of metastatic sites of disease (0 and 1 vs. 2+).

The study consists of two 10-weeks treatment periods with a two-week wash-out period between
the treatment periods. Patients will receive pazopanib and sunitinib treatment sequentially.
At the end of the second treatment period, patient preference and disease assessment are
evaluated and the patients are unblinded. Further treatment is at the discretion of the
physician. Further treatment with pazopanib is available within the study. Patients
requiring other treatments will complete the study at this point.

Patients will be randomized in a 1:1 ratio to receive blinded (overencapsulated) study drug:
either 800mg pazopanib orally for 10 weeks followed by 50mg sunitinib orally for 10 weeks or
50mg sunitinib orally for 10 weeks followed by 800mg pazopanib orally for 10 weeks. A
two-week washout period will separate the treatment periods (the medical monitor should be
consulted if ongoing AEs need to be resolved and the wash-out period needs to be extended).
The regimen for sunitinib is 4 weeks of treatment followed by 2 weeks off treatment. To
maintain the double-blind during the two weeks off drug for patients on sunitinib
('Treatment Holiday'), patients will be taking matching placebo. No study drug will be taken
during the wash-out period in either arm.

Following the two-week wash-out period and disease assessment, all patients are planned to
cross over to the second treatment. Patients will be informed of their disease assessment
result and any patient that wishes to come off study at this point due to a very significant
response, defined as more than a 50% reduction in tumour size (or complete response if
non-measurable disease), will have the option to be unblinded to continue with whichever
treatment they were on, however each patient case will need to be discussed with the medical
monitor prior to unblinding. Patients who were on sunitinib will leave the study and
continue treatment outside the study. Patients who were on pazopanib will continue on
pazopanib within the pazopanib open-label part of the study. Conversely, should a patient
have a very significant response and wish to cross over or complete the study, this must be
documented in the patients notes.

Patients crossing over with progressive disease will follow the same visit schedule and
assessments and investigators will have the option for these patients to be unblinded or
not. The patients' preference will be collected and analysed but will not contribute to the
primary, but an exploratory analysis because of the bias caused by progressing on the first
treatment. Even if unblinded, patients may continue to receive the second treatment and may
receive open label pazopanib after the second treatment within the study if they did not
progress on pazopanib.

Patients who withdraw from treatment due to unacceptable toxicity or progression during the
first treatment period will cross-over directly to the second treatment following a 2-week
wash-out period.

Actual further treatment at the end of the study will be at the discretion of the
investigator taking into account both disease assessments results, laboratory results and
the patient preference. Choice and rationale for continuing treatment will be documented.

Patients who did not progress on pazopanib and who prefer to continue with pazopanib may
continue on pazopanib and will be followed up for safety until the patient comes off
pazopanib due to disease progression, toxicity, death or patient choice, which ever is the
earliest.

Those patients that may benefit from further treatment with sunitinib for the same reasons
as above will receive it off study and will not be followed up, as will patients who receive
any other treatment.

Patients are permitted to receive supportive care throughout the study including transfusion
of blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrhoeal
agents, analgesics, erythropoietin or bisphosphonates, when appropriate. The study treatment
will continue until the end of the two treatment periods or unacceptable toxicity or consent
withdrawal or death, whichever occurs first.

The patient preference will be ascertained prior to the second disease assessment result
being shared with the patient to avoid bias.

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Organizational Data

  •   DRKS00003888
  •   2012/04/30
  •   2010/02/04
  •   no
  •   [---]*
  •   [---]*
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Secondary IDs

  •   NCT01064310  (ClinicalTrials.gov)
  •   113046  (GlaxoSmithKline)
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Health Condition or Problem studied

  •   Carcinoma, Renal Cell
  •   C64 -  Malignant neoplasm of kidney, except renal pelvis
  •   C65 -  Malignant neoplasm of renal pelvis
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Interventions/Observational Groups

  •   Drug: pazopanib
  •   Drug: sunitinib
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, caregiver, investigator/therapist, assessor
  •   Active control (effective treament of control group)
  •   Treatment
  •   Crossover
  •   III
  •   [---]*
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Primary Outcome

- Number of Participants With Preference for Pazopanib Versus Sunitinib as Assessed by the Patient Preference Questionnaire (PPQ); time frame: End of treatment of both study drugs (maximum of 22 weeks); The PPQ is used to measure participants' preference for pazopanib or sunitinib for renal cell carcinoma management and is used to determine a participant's preference for 1 of the 2 drugs given in the 2 double-blind treatment periods. Participants were asked to select 1 of the following: 1. prefer the drug taken as the first treatment; 2. prefer the drug taken as the second treatment; or 3, no preference. Those participants who indicated a preference were asked to select the factors that had an influence on their treatment preference, as well as the most important reason for their preference.
- Number of Participants Answering "Yes," "no," or Not Applicable (N/A) to the Question of Whether the Indicated Factors Influenced Their Preference for Sunitinib or Pazopanib Treatment as Assessed by the Patient Preference Questionnaire; time frame: End of treatment of both study drugs (maximum of 22 weeks); The PPQ is used to measure participants' preference for pazopanib or sunitinib for renal cell carcinoma management and is used to determine a participant's preference for 1 of the 2 drugs given in the 2 double-blind treatment periods. Participants were asked to select 1 of the following: 1. prefer the drug taken as the first treatment; 2. prefer the drug taken as the second treatment; or 3, no preference. Those participants who indicated a preference were asked to select the factors that had an influence on their treatment preference, as well as the most important reason for their preference.

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Secondary Outcome

- Change From Period Baseline (BL) in Fatigue as Assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score; time frame: Day 1 (Period [P] 1 Pre-dose); Weeks 2, 4, 6, 8, and 10 of P 1; during 2-week Wash-out Period (Study Weeks 11 and 12); Weeks 2, 4, 6, and 8 of P 2 (Study Weeks 14, 16, 18, 20, and 22, respectively); End of Study (Week 10 of P 2 [Study Week 22]); Change from period (P) BL is computed as participants' (par.) average post-BL fatigue score within each P minus their P-specific BL score. P 1 BL is the P 1 Pre-Dose assessment; P 2 BL is the wash-out assessment. Crossover analyses compared par. average scores on each treatment, adjusting for sequence. FACIT-Fatigue Scale: overall score (0 to 52)=the sum of scores for 13 questions. For each question, par. rated their condition for the past week on a 5-point scale: 0 (not at all) to 4 (very much). A high score indicates low fatigue. A negative change from BL represents a worsening of condition.
- Quality of Life as Assessed by the EuroQoL-5 Dimensions (EQ-5D) Thermometer and Utility Scores; time frame: Day 1 (Period 1 Pre-dose); during 2-week Wash-out Period (Study Weeks 11 and 12); and End of Study (Week 10 of Period 2 [Study Week 22]); The EQ-5D is a participant-answered questionnaire measuring 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D has two separate components: utility score and thermometer score. The EQ-5D total utility score ranges from 0 (worst health state) to 1 (perfect health state); 1 reflects the best outcome. The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).
- Time to Dose Modification; time frame: End of second treatment period (maximum of 22 weeks); For the subset of participants who had a dose modification, time to dose modification was defined as the time from the first dose in each period until the first reduction in dose within a period.
- Number of Participants With the Indicated Number of Dose Reductions; time frame: End of second treatment period (maximum of 22 weeks); Participants are recorded under the treatment they were receiving at the time the dose reduction was reported.
- Number of Participants With the Indicated Reason for Receiving a Dose Reduction; time frame: End of second treatment period (maximum of 22 weeks); Dose reduction of study drug was a stepwise reduction of the dose of the study drug: one less capsule was received at each step reduction. Participants were monitored for approximately 10 to 14 days at each dose level. Participants are recorded under the treatment they were receiving at the time the dose reduction was reported.
- Number of Participants With Grade 1 to Grade 5 Adverse Events (AEs); time frame: Baseline to end of study (maximum of 22 weeks); AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE.
- Number of Participants With the Indicated AEs Leading to Permanent Discontinuation of Study Treatment; time frame: Baseline to end of study (maximum of 22 weeks); An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE that spans more than one period is considered to be an AE for each period during which the AE increased in grade. There is only one action with respect to study drug recorded for the whole event. As such, it is not always possible to determine in which study period treatment was discontinued due to the AE.
- Change From Baseline (BL) in Systolic Blood Pressure (SBP) and Diastolic BP (DBP); time frame: Baseline of Period (P) 1 (Screening); Period 1 Weeks 2 and 6 (Study Weeks 2 and 6); Baseline of Period 2 (Washout=Study Week 12); Period 2 Weeks 2, 6, and 10 (Study Weeks 14, 18, and 22); When the heart beats, it contracts and pushes blood through the arteries to the rest of body. This force creates pressure on the arteries called SBP. DBP is the pressure in the arteries when the heart rests between beats. Normal levels: SBP (120 mmHg or less); DBP (80 mmHg or less). Mean change from BL for each assessment week was calculated as the average change from period BL at the specified visits (combining data across P 1 and 2 for Weeks 2 and 6). Study weeks are approximate; participants could have crossed over from P 1 to P 2 at earlier time points than specified in the protocol.
- Change From Baseline (BL) in Heart Rate; time frame: Baseline of Period (P) 1 (Screening); Period 1 Weeks 2 and 6 (Study Weeks 2 and 6); Baseline of Period 2 (Washout=Study Week 12); Period 2 Weeks 2, 6, and 10 (Study Weeks 14, 18, and 22); Heart rate (HR) is the number of heartbeats per unit of time, typically expressed as beats per minute. HR can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep. A normal resting HR ranges from 60 to 100 beats per minute. Mean change from BL for each assessment week was calculated as the average change from period BL at the specified visits (combining data across P 1 and 2 for Weeks 2 and 6). Study weeks are approximate; participants could have crossed over from P 1 to P 2 at earlier time points than specified in the protocol.

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Countries of Recruitment

  •   Finland
  •   France
  •   Germany
  •   Italy
  •   United Kingdom
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Locations of Recruitment

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Recruitment

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  •   2010/05/31
  •   169
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Patients must provide written informed consent prior to performance of any
study-specific procedures or assessments and must be willing to comply with treatment
and follow up. Procedures conducted as part of the patient's routine clinical
management (e.g. blood count, imaging study) and obtained prior to signing of
informed consent may be utilised for screening or baseline purposes provided these
procedures are conducted as specified in the protocol.

- Received no prior systemic therapy (including interleukin-2, interferon-alpha,
chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI)
for advanced or metastatic RCC. Patients who received adjuvant treatment with a
cancer vaccine are eligible.

- Locally advanced (defined as disease not amenable to curative surgery or radiation
therapy) or metastatic renal cell carcinoma of any histology (equivalent to Stage IV
RCC according to AJCC staging). Patients with non-measurable disease are allowed if
metastatic disease can be confirmed.

- ECOG PS of 0 or 1

- Age >= 18 years

- A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e. physiologically incapable of becoming pregnant)
Childbearing potential, including any female who has had a negative serum pregnancy test
within two weeks prior to the first dose of study treatment, preferably as close to the
first dose as possible and agrees to use adequate contraception.

- Adequate organ system functions

- Total serum calcium concentration <12.0mg/dL

- Left ventricular ejection fraction (LVEF) >=lower limit of institutional normal (LLN)
as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan. The
same modality used at baseline must be applied for subsequent evaluations.

- Patient is able to swallow and retain oral tablets

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Exclusion Criteria

- Poor MSKCC risk group

- History of another malignancy. Note: Patients who have had another malignancy and
have been disease-free for 3 years or patients with a history of completely resected
non-melanomatous skin carcinoma or successfully treated in situ carcinoma are
eligible.

- History or clinical evidence of central nervous system (CNS) metastases.

Note: Patients who have previously-treated CNS metastases (surgery +/- radiotherapy,
radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

- Are asymptomatic,

- Have had no evidence of active CNS metastases for >=6 months prior to enrolment ,

- Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC).

- Any clinically significant gastrointestinal abnormalities that may increase the risk
for gastrointestinal bleeding or affect absorption of investigational product
including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel that could affect the absorption of
study drug

- Active peptic ulcer disease

- Inflammatory bowel disease

- Ulcerative colitis, or other gastrointestinal conditions with increased risk of
perforation

- History of abdominal fistula, gastrointestinal perforation, or intra abdominal
abscess within 28 days prior to beginning study treatment.

- Presence of uncontrolled infection.

- 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

- Unstable angina

- 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 > 150mmHg
or diastolic blood pressure (DBP) of > 90mmHg) at baseline.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. Blood pressure must be re-assessed on two occasions that are separated by a
minimum of 1 hour within a visit. The mean SBP/DBP values from each blood pressure
assessment must be <=150/90mmHg in order for a patient to be eligible for the study.

- History of cerebrovascular accident (CVA) including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Patients with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks are eligible.

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major).

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

- Evidence of active bleeding or bleeding diathesis.

- Significant haemoptysis within 6 weeks prior to first dose of study drug.

- Any serious and/or unstable pre-existing medical, psychiatric, or other conditions
that could interfere with patient's safety, obtaining informed consent or compliance
to the study.

- Use any prohibited medications within 14 days of the first dose of study medication.

- Use of an investigational agent, including an investigational anti-cancer agent,
within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study
drug.

- Radiation therapy, surgery or tumour embolisation within 14 days prior to the first
dose of study treatment.

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib or sunitinib.

- Pregnant or lactating female Female patients who are lactating should discontinue
nursing prior to the first dose of study drug and should refrain from nursing
throughout the treatment period and for 14 days following the last dose of study
drug.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • GlaxoSmithKline
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  • start of 1:1-Block address scientific-contact
    • GlaxoSmithKline
    • GSK Clinical Trials 
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  • start of 1:1-Block address public-contact
    • GlaxoSmithKline
    • GSK Clinical Trials 
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    •   [---]*
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    •   [---]*
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   8
  •   2016/01/14


* This entry means the parameter is not applicable or has not been set.