Download CASE #4808 TITLE: An Observational Study of Metastatic Renal

CASE #4808
TITLE: An Observational Study of Metastatic Renal Cell Carcinoma Patients Prior to
Initiation of Initial Systemic Therapy
Principal Investigator:
Brian I. Rini, M.D.
Department of Solid Tumor Oncology
Cleveland Clinic Taussig Cancer Institute
9500 Euclid Avenue/Desk R35
Cleveland, Ohio 44195
Phone: 216-445-9567
Fax: 216-444-9464
E-mail: [email protected]
Co-Investigators:
Mellar Davis, M.D.
Robert Dreicer, M.D.
Jorge Garcia, M.D.
Petros Grivas, M.D.
Tim Gilligan, M.D.
Statistician:
Paul Elson, Sc.D.
The Cleveland Clinic Foundation
Taussig Cancer Center
Cancer Biostatistics/Desk R41
9500 Euclid Avenue
Cleveland, OH 44195
Phone: (216) 444-7775
Fax: (216) 636-2498
Email: [email protected]
Responsible Research
Nurse:
Laura Wood, RN
The Cleveland Clinic Foundation
Taussig Cancer Center
9500 Euclid Avenue, R 35
Cleveland, OH 44195
Phone:(216) 444-9822
Fax: (216) 444-0114
Email: [email protected]
Responsible Data
Manager:
Donna Company
The Cleveland Clinic Foundation
Taussig Cancer Center
9500 Euclid Avenue, JJN2
Cleveland, OH 44195
Phone:(216) 636-5649
Fax: (216) 444-9302
Email: [email protected]
Approvals:
Protocol Review and Monitoring Committee: 04/08/2008
CASE IRB: 05/22/2008
PROTOCOL DATE:
VERSION 1: 2/6/08
VERSION 2: 9/29/08
Version 3: 10/4/10
Version 4: 3/30/2011
Version 5: 7/25/2011
Version 6: 2/26/2013
Version 7: 5/21/2013
Version 8: 2/4/2014
Version 9: 6/15/2015
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TABLE OF CONTENTS
1
OBJECTIVES ........................................................................................................................ 4
2
BACKGROUND AND RATIONALE ...................................................................................... 5
3
ELIGIBILITY CRITERIA ....................................................................................................... .9
4
REGISTRATION PROCEDURES ...................................................................................... .10
5
TREATMENT PLAN ............................................................................................................ 10
5.1 STUDY DESIGN AND METHODS............................................................................................. 10
5.2 DURATION OF THERAPY ...................................................................................................... 10
5.3 STUDY CALENDAR .............................................................................................................. 11
6
ANCILLARY THERAPY ...................................................................................................... 12
7
CRITERIA FOR TUMOR BURDEN EVALUATION ............................................................. 12
8
CORRELATIVE STUDIES................................................................................................... 16
9
STATISTICAL CONSIDERATIONS .................................................................................... 18
10 REFERENCES .................................................................................................................... 20
APPENDIX 1............................................................................................................................... 21
APPENDIX 2............................................................................................................................... 22
APPENDIX 3............................................................................................................................... 23
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1
OBJECTIVES
1.1
Primary Objective: To characterize the clinical outcome of patients with metastatic renal
cell carcinoma (RCC) who defer initial systemic treatment.
1.2
Secondary Objectives:
1.2.1 To describe the quality of life changes over time in patients with metastatic RCC who
defer initial systemic treatment according to the FKSI-DRS.
1.2.2 To describe the anxiety and depression changes over time in patients with metastatic
RCC who defer initial systemic treatment according to the Hospital Anxiety and
Depression Score (HADS).
1.2.3 To describe changes in immune cell populations over time in an untreated metastatic
RCC cohort.
1.2.4 To examine tissue-based assays in metastatic RCC who defer initial systemic treatment.
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2
BACKGROUND AND RATIONALE
2.1 Renal Cell Carcinoma
Metastatic renal cell carcinoma (RCC) is an incurable disease at present with limited treatment
options. VEGF-targeted agents have recently demonstrated robust anti-tumor activity and
changed the therapeutic landscape of RCC.1 Although several active agents now exist for
metastatic RCC, their inability to produce durable complete responses necessitates chronic
therapy in the majority of patients, and thus any benefits must be weighted against the overall
burden of treatment including toxicity, time commitment and cost. There is growing evidence that
treatment benefit is preserved even if therapy is delayed. For example, Ratain et al. reported on
patients who were randomized to placebo on the sorafenib randomized discontinuation trial,
where sorafenib was readministered upon disease progression.2 These patients continued on
sorafenib until further progression (a median of 24 weeks), identical to the PFS for patients
initially randomized to continue sorafenib. These data are further supported by a lack of
significantly different overall survival in a phase III trial (n=905) of sorafenib versus placebo in
treatment-refractory RCC in which placebo patients crossed over to receive sorafenib.3 These
data suggests that some asymptomatic patients may be able to have treatment delayed without
compromising the ability to achieve clinical benefit with deferred therapy.
In addition, it has not been demonstrated that tumor burden impacts response to subsequent
therapy. It may therefore be possible to monitor patients without therapy until the attainment of
significant tumor burden and/or development of symptoms. This approach would spare patients
toxicity for a period of time, and then allow them to benefit from therapy when needed.
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Metastatic RCC can be an indolent disease in a substantial proportion of patients, highlighting
the variable underlying biology. Many patients with indolent disease choose to defer therapy. No
prospective observation of such patients has yet been undertaken. Prospective study is needed
to more clearly define the clinical phenotype of patients in whom such an approach is feasible,
and the outcome of such patients over time.
2.2 Quality of life measurement in RCC
Patient-reported outcomes are a valuable tool in assessing the overall burden of cancer, and
treatment if applicable. The Functional Assessment of Cancer Therapy – Kidney Cancer Index
(FKSI) is a validated tool developed to measure both disease-related and treatment-related
toxicity.4 Further refinement of this tool to limit it to the 9 items that are most disease-related has
recently been undertaken. This new tool, the FKSI-Disease-Related Symptoms (FKSI-DRS), has
been validated on a sample of 141 RCC patients with additional input from RCC experts.5 This
test is reliable with internal consistency of 0.78 and intraclass correlation of 0.85. This
questionnaire will be used in this observational study to characterize changes in disease-related
symptoms over time in the absence of treatment.
2.3 Hospital Anxiety and Depression Score (HADS)
There is a need to assess the contribution of mood disorder, especially anxiety and depression,
in order to understand the experience in advanced cancer patients. The Hospital Anxiety And
Depression Scale, or HADS, was designed to provide a simple yet reliable tool for use in
medical practice (Appendix 2).6 The term 'hospital' in its title suggests that it is only valid in such
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a setting but many studies conducted throughout the world have confirmed that it is valid when
used in community settings and primary care medical practice. The questionnaire responses
estimate the severity of both anxiety and of depression. The number of items in the
questionnaire is seven reflecting anxiety and seven reflecting depression. Each item had been
answered by the patient on a four point (0–3) response category so the possible scores ranged
from 0 to 21 for anxiety and 0 to 21 for depression. A score of 0 to 7 for either subscale is
regarded as being in the normal range, a score of 11 or higher indicating probable presence
('caseness') of the mood disorder and a score of 8 to 10 being just suggestive of the presence of
the respective state. Further work indicated that the two subscales, anxiety and depression,
were independent measures. Subsequent experience enabled a division of each mood state into
four ranges: normal, mild, moderate and severe and it is in this form that the HADS is now
issued by its publisher
2.4
Immune dysregulation in RCC
Immune dysfunction is well documented in renal cell carcinoma (RCC) patients, and likely
contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T cell
cytokine response and enhanced T-regulatory (Treg) cell expression. We have characterized
type-1 (IFNγ) and type-2 (IL-4) responses in T cells at baseline and day 28 of treatment with an
RCC therapeutic, sunitinib, by measuring intracellular cytokines after in vitro stimulation with
anti-CD3/anti-CD28 antibodies (Finke et al. Clinical Cancer Research, submitted). After one
cycle of treatment there was a significant increase in the percentage of IFNγ producing T cells
(CD3+ p<.001, CD3+CD4+, p<.001), a reduction in IL-4 production (CD3+ cells, p=.05) and a
diminished type-2 bias (p= .001). The increased percentage of Treg cells noted in metastatic
RCC patients over healthy donors (p= <.001), was reduced after treatment, although not
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reaching statistical significance. While noteworthy, there is no data regarding potential variability
over time of these immune parameters in an untreated metastatic RCC population. Such data
would provide important information to compare to other data sets which have investigated
changes induced by therapy.
2.5 Genomic Analysis of Tumor Tissue
The study of alterations in the genetic and molecular makeup of tumors, as well as the
integration of such data into the care of cancer patients, is becoming routine. For example,
identification of mutations of the anaplastic lymphoma kinase (ALK) gene in lung cancer leads to
a departure from standard chemotherapy to specific therapy directed at the mutation, which
provides greater clinical benefit. Similarly, the presence of a KRAS mutation in colorectal cancer
precludes the clinical efficacy of EGFR antibodies. The analysis of gene mutation and
gene/protein expression in indolent RCC has not been previously undertaken and will be
explored in this study.
3. ELIGIBILITY CRITERIA
1) Patients must have clinically-evident metastatic renal cell carcinoma of any histologic
subtype. Histologic documentation of RCC in a primary and/or metastatic tumor is
required.
a. Patients may have had first documentation (radiographic or histologic) of
metastatic RCC up to12 months prior to registration on study. Baseline CT scans
must be accessible to record tumor measurements.
2) Patients must not have received any prior systemic therapy for renal cell carcinoma in the
metastatic or neo/adjuvant setting. Prior radiotherapy (including radiotherapy for CNS
metastases) and prior nephrectomy/metastasectomy is permitted but not required.
3) Patients must be currently asymptomatic from their disease.
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4) Patients must currently have measurable or evaluable disease per RECIST criteria.7
5) Age ≥18 years.
6) Patients may not be concurrently receiving any therapy given with the intent of treating
RCC.
7) Ability to understand and the willingness to sign a written informed consent document.
3.1
Inclusion of Women and Minorities
Men, women and members of all ethnic groups are eligible for this trial.
4
REGISTRATION PROCEDURES
To enter eligible patients on study, contact the study coordinator at the Cancer Center Clinical
Trials Unit. All patients enrolled on study will be entered into the ONCORE database.
5
TREATMENT PLAN
5.1 Study Design and Methods
This is an observational study of metastatic RCC patients prior to initiation of first systemic
therapy. Patients will undergo radiographic disease assessment as per Section 5.3.
Patients will undergo clinic visits for H/P, QOL assessment and procurement of blood for
standard and correlate assays. Total tumor burden over time, time to initiation of systemic
treatment, time to disease progression and overall survival will be recorded. In addition,
clinical outcome (e.g. objective response rate, progression-free survival) following first
systemic therapy will be recorded.
5.2 Duration
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Patients may continue on study until one of the following criteria applies:
•
Initiation of systemic therapy for metastatic RCC (Patients will not be required to have
labs or MD/radiographic follow up per this study calendar, but type of initial therapy
received and clinical outcome (objective response, tumor shrinkage, PFS) to that
therapy will be recorded.)
•
Patient decides to withdraw from the study, OR
•
General or specific changes in the patient’s condition that render the patient
unacceptable for further observation in the judgment of the investigator.
5.2.1 Reason(s) for initiation of systemic therapy
The reason(s) for initiation of systemic therapy will be recorded including one or more of the
following (record all applicable reasons):
1. Radiographic progression of disease
2. Development of disease-related symptoms (note specific signs and/or symptom(s))
3. Patient and/or MD decision.
5.3 Study Calendar
Pre-study evaluations are to be conducted within 30 days prior to enrollment except for the
following: tumor measurement must be done within 12 weeks prior to protocol enrollment,
informed consent may be obtained anytime prior to enrollment. Pre-study laboratory evaluations
do not need to be repeated if done within 30 days of protocol enrollment. All post-baseline
laboratory and radiographic evaluation timepoints are +/- 14 days.
Patients who will no longer be coming to the Cleveland Clinic Cancer Institute for care, may
remain on study. Patients will have CT imaging done at their local hospital, scans and radiology
reports will be reviewed here by the treating oncologist. Lab, physical exam, weight, history,
concurrent medications, and QOL questionnaires will not be collected on this group of patients.
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Pre-Study
a
b
c
d
e
f
g
Month 3 and q 3
months thereafter
during year 1a
Month 4 of year 2
and q 4 months
during year 2a
Off Study f
Informed consent
Medical history
X
X
X
X
X
Concurrent Meds
Physical exam incl. vital
signs
Performance status
(Karnofsky and ECOG)
Height
Weight
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry b
Tumor measurement c
X
X
X
X
X
X
X
X
FKSI-DRS questionnaire
X
X
Xg
X
g
HADS questionnaire
X
X
X
X
Correlative study blood
collection (optional) d
Tumor block or 10
unstained slides
(optional) e
X
(X)
(X)
X
X
MD visits and radiographic evaluation may occur more or less frequently at the discretion of the treating physician.
. For pts that have a metastasectomy, their next f/u will be 3 months following the surgery, then every 3 months
according to year 1 of the study calendar and so on for year 2.. Note – during year 3 and beyond, imaging is only
required every 6 months.
Albumin, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, SGOT[AST],
SGPT[ALT], sodium.
CT scan of the chest, abdomen and pelvis are required at all timepoints; bone scan is required within 12 months of
baseline, then afterwards only if consistent with metastatic disease at baseline or if signs or symptoms suggestive
of bone metastases develop. Brain imaging (CT or MRI) is required within 12 months of baseline, then afterwards
only if consistent with metastatic disease at baseline or if signs or symptoms suggestive of brain metastases
develop. See Appendix 3 for tumor measurement sheet.
6 x 10 cc green top tubes of peripheral blood (CCF and Fox Chase only). Page the Research RN to coordinate
blood collection and delivery to laboratory of Dr. James Finke.
Patients may enroll on study before the block/slides are at CCF
Upon initiation of systemic therapy, patients will not be required to have labs or radiographic follow up per this
study calendar, but type of initial therapy received and clinical outcome to that therapy will be recorded.
Effective with IRB approval of protocol version 9, FKSI-DRS and HADS questionnaires will be discontinued.
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6 ANCILLARY THERAPY
Patients may not receive any ancillary therapy that is given to alleviate disease-related
symptoms. The requirement for such treatment would indicate symptomatic progression (as all
patients must be asymptomatic at baseline), and thus indicate disease progression requiring
treatment.
In addition, standard or investigational therapy given with the intent of treating RCC is prohibited
on study.
7 CRITERIA FOR EVALUATION OF TUMOR BURDEN
7.1 Definitions
Tumor burden will be evaluated in this study using the international criteria proposed by the
Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Changes in only the
largest diameter (unidimensional measurement) of the tumor lesions are used in the
RECIST criteria.
7.1.1 Measurable disease
Measurable lesions are defined as those that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >20 mm with conventional techniques
(PET, CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be
recorded in millimeters (or decimal fractions of centimeters).
7.1.2 Non-measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm
with conventional techniques or <10 mm using spiral CT scan), are considered nonmeasurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial
effusions, lymphangitis cutis/pulmonis, abdominal masses (not followed by CT or MRI),
and cystic lesions are all non-measurable.
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7.1.3 Target lesions
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total
representative of all involved organs should be identified as target lesions and recorded
and measured at baseline. Target lesions should be selected on the basis of their size
(lesions with the longest diameter) and their suitability for accurate repeated
measurements (either by imaging techniques or clinically). A sum of the longest diameter
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The
baseline sum LD will be used as reference by which to characterize tumor burden
changes.
7.1.4 Non-target lesions
All other lesions (or sites of disease) should be identified as non-target lesions and
should also be recorded at baseline. Non-target lesions include measurable lesions that
exceed the maximum numbers per organ or total of all involved organs as well as nonmeasurable lesions. Measurements of these lesions are not required, but the presence
or absence of each should be noted throughout follow-up.
7.2
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or
calipers. All baseline evaluations should be performed as closely as possible to the
beginning of treatment and never more than 6 weeks before the beginning of the
treatment.
Note: Tumor lesions that are situated in a previously irradiated area are not considered
measurable.
The same method of assessment and the same technique should be used to characterize
each identified and reported lesion at baseline and during follow-up. Imaging-based
evaluation is preferred to evaluation by clinical examination when both methods have
been used to assess the antitumor effect of a treatment.
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Clinical lesions. Clinical lesions will only be considered measurable when they are
superficial (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions,
documentation by color photography, including a ruler to estimate the size of the lesion, is
recommended.
Chest x-ray. Not permitted for evaluation of tumor burden
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm
or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and
pelvis. Head and neck tumors and those of extremities usually require specific protocols.
Ultrasound (US). US may not be used to measure tumor lesions.
7.3
Categorization of tumor burden changes
7.3.1 Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target
lesions, taking as reference the baseline sum LD
Progressive Disease (PD)
At least a 20% increase in the sum of he LD of target lesions, taking as
reference the smallest sum LD recorded since the treatment started
(including baseline LD) or the appearance of one or more new lesions
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, taking as reference the smallest sum LD since the
treatment started (including baseline LD)
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7.3.2 Evaluation of non-target lesions
Complete Response(CR)
Disappearance of all non-target lesions and normalization of tumor
marker level
Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of
tumor marker level above the normal limits
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal progression
of existing non-target lesions.
Although a clear progression of “non-target” lesions only is exceptional, in such
circumstances the opinion of the treating physician should prevail, and the progression
status should be confirmed at a later time by the study chair.
7.3.3 Evaluation of best overall response
The best overall response is the best response recorded from the start of enrollment until
disease progression (taking as reference for progressive disease the smallest
measurements recorded since the treatment started, including baseline; see table below).
The patient's best response assignment will depend on the achievement of both
measurement and confirmation criteria.
7.4 Time to Objective Progression
Time to objective progression will be measured from the date of the most recent
radiographic evaluation prior to protocol enrollment until the criteria for progression are
met.
8 CORRELATIVE STUDIES
8.1 FKSI—Disease-Related Symptoms (FKSI-DRS) and HADS questionnaire (Appendicies
1 and 2)
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The FKSI-DRS and HADS questionnaires will be administered to patients at baseline and at
every MD visit per the study calendar. Scores will be recorded and monitored over time for each
individual patient to correlate changes in tumor burden with changes in the FKSI-DRS and
HADS scores. Scores will also be looked at in aggregate to assess changes over time in an
untreated metastatic RCC population.
8.2 Peripheral Blood Assays (optional)
Correlative study blood collection will be performed at baseline, at each radiographic reassessment and the off study timepoint. The following assays will be performed:
8.2.1 T regulatory cells
T-regulatory (Treg) cells will be detected by first isolating peripheral blood mononuclear cells
(PBMC) via density gradient centrifugation over ficoll-paque. T cells will be isolated as previously
described by negative selection using StemSep antibody cocktail (StemCell technologies,
Vancouver, British Columbia). To detect Treg within the CD3+ population three-color flow
cytometry will be performed after staining with the following antibodies; anti-CD4 (Per C p), antiCD25 (PE) and FOXP3 (FITC).
T regulatory cells will also be quantified by RT-PCR. Following the positive selection of DC noted
above, Treg cells will be isolated and FOXP3 mRNA will be assessed as outlined above.
Aliquots of a standard cDNA prepared from PBMC collected from a healthy donor are used as
standards in each plate to normalize for inter-plate variability. Results for the expression of
FOXP3 are normalized using GAPDH signals, linearly transformed and readjusted to the
percentage of PBL in total PBMC. The final value reflects the expression level of FOXP3 within
total PBL.
8.2.1 Th1/Th2 phenotyping through intracellular cytokine staining
T cells will be isolated as described. Viable lymphocytes (1 x 106) will be stimulated or not for 72
hours with crosslinked anit-CD3 plus anti-CD28 antibodies in RMPI-1640 containing 10% FCS.
Cells will be labeled with APC-anti-CD3 Ab (BD) to define the T cell population or with PerCP16
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anti-CD4 (BD) to detect the major T helper subset. Cells will be fixed and permeabilized and
subsequently stained with antibodies to FITC-IFN-gamma (BD) and PE-IL-4 (BD). Cells will be
acquired on BD LSR and analysis performed using FLOJO software.
8.3 RCC tissue staining (optional)
The biology of metastatic RCC patients who have indolent disease is unique from all other
metastatic RCC patients. As such, examination of relevant protein expression in this cohort is of
interest. Baseline tumor tissue will be collected and stored. A panel of proteins will be assessed
by standard immunohistochemical methods including VEGF, PDGF, HIF alpha, CA IX, Glut-1,
Tregs, COX-2 and other markers relevant to RCC biology and/or current therapeutic targets.
8.4 Genomic Analysis
Currently, a number of assays are available to look at the genomic profile of a tumor, ranging
from DNA analysis of a candidate list of possibly mutated genes to whole exome sequencing, to
RNA analysis of gene expression, protein expression by IHC to NextGen sequencing providing a
more comprehensive profile of an individual tumor’s genome and expression. Baseline
nephrectomy (+/- metastatic tissue as available) will be collected from consenting patients and
stored for further analysis. As the technology of genomic profiling is rapidly changing, the precise
assy(s) used are not determined. Further, as this is exploratory, no set number of samples or
statistical assumptions are made. Data from this analysis will be reported using descriptive
statistics.
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9 STATISTICAL CONSIDERATIONS
The primary goal of this study is to characterize the clinical course of patients with metastatic
RCC who defer initial systemic treatment. Secondary goals are to characterize changes in
quality of life and changes in immune cell populations over time; and to characterize the
association between these parameters and changes in tumor burden. A sample size of 50
patients is recommended to achieve these goals.
The primary endpoint of the study is a description of metastatic RCC patients’ disease prior to
the initiation of systemic therapy. Secondary endpoints include changes over time in tumor
burden as determined using RECIST criteria; changes in quality of life assessed by the FKSIDRS and HADS instruments; changes in immune cell populations such as T-regulatory cells and
T-cells exhibiting a Th1 or Th2 response, characterization of protein expression in tumor tissue;
and outcome (response and progression-free survival) to the systemic therapy the patient
ultimately receives.
As described in section 5.2 systemic therapy can be started for a number of reasons; however
the predominate reasons are radiographic evidence of disease progression and/or development
of disease-related symptoms. The primary endpoint reflects this as an observational study of the
disease course for patients with initially asymptomatic, indolent metastatic RCC. Fifty patients is
a reasonable number to estimate important parameters such as the average pace of growth of
tumor burden and the proportion of patients who develop disease-related symptoms within 6
months of enrollment. This cohort size is also roughly the size of a phase II trial which could then
estimate clinical outcome for this cohort upon initiation of systemic therapy. Clinical and
radiographic assessments will be performed approximately every three months and therefore the
data will be analyzed using methods appropriate for interval censored data; however to estimate
the number of patients needed for the trial the binomial distribution can be used to determine
confidence intervals about key quantiles such as those described above. With 50 patients the
maximum half-width of a 95% confidence interval about a specific quantile, such as the
proportion of patients who develop disease-related symptoms within 6 months of enrollment, will
be 0.14. Fifty patients also provides good statistical power to detect meaningful changes in the
secondary endpoints (quality of life, anxiety/depression and immune cell populations). That is,
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with 50 patients there will be statistical power >.80 to detect changes from baseline at a
particular assessment that are >0.5 standard deviation (based on a two-sided p=.05 Wilcoxon
signed rank test). As an examples of what this means clinically, from the study by Cella et al (5)
that validated the FKSI-DRS instrument, the standard deviation of the change in scores from
baseline at a particular assessment can be conservatively estimated to be approximately 7
“points”. The present study therefore will have >.80 power to detect changes > 3.5 points; which
is slightly larger than the 2-3 point difference suggested by Cella et al. as the minimum
difference needed to signify a meaningful change, but smaller than the 4-5 point change needed
to signify a “clearly important difference”.
As discussed above the interval from diagnosis of metastatic disease to systemic treatment will
be analyzed using methods for interval censored data. Changes in quality of life and immune cell
populations will be assessed over time and at specific time points using parametric or nonparametric longitudinal methods and the Wilcoxon signed-rank test. Correlations between these
parameters and changes in tumor burden will primarily be assessed using Spearman rank
correlations. All tests of statistical significance will be two-sided and due to the exploratory
nature of these studies, no adjustment will be made for multiple comparisons.
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10 REFERENCES
1. Rini BI, Small EJ: Biology and clinical development of vascular endothelial growth factortargeted therapy in renal cell carcinoma. J Clin Oncol 23:1028–43, 2005
2. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized
discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol
24:2505-12, 2006
3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell
carcinoma. N Engl J Med 356:125-34, 2007
4. Cella D, Yount S, Du H, et al: Development and validation of the Functional Assessment
of Cancer Therapy-Kidney Symptom Index (FKSI). J Support Oncol 4:191-9, 2006
5. Cella D, Yount S, Brucker PS, et al: Development and validation of a scale to measure
disease-related symptoms of kidney cancer. Value Health 10:285-93, 2007
6.
Zigmond AS, Snaith RP: The Hospital Anxiety And Depression Scale.
Acta Psychiatr Scand 1983, 67:361-70.
7.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response
to treatment in solid tumors. European Organization for Research and Treatment of Cancer,
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl
Cancer Inst 92:205-16., 2000
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Appendix 1: FKSI—Disease-Related Symptoms (FKSI-DRS) questionnaire
Date: __________
Below is a list of statements that other people with your illness have said are important. By
circling one (1) number per line, please indicate how true each statement has been for
you during the past 7 days.
Not at all A little bit Somewhat Quite a bit Very much
I have a lack of energy
0
1
2
3
4
I have pain
0
1
2
3
4
I am losing weight
0
1
2
3
4
I have bone pain
0
1
2
3
4
I feel fatigued
0
1
2
3
4
I have been short of breath
0
1
2
3
4
I have been coughing
0
1
2
3
4
I am bothered by fevers
0
1
2
3
4
I have had blood in my urine
0
1
2
3
4
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Appendix 2 (HADS):
Date: __________
The following questions are designed to measure anxiety and depression. Please respond to
each question regarding your feelings in the last 7 days. Circle the answer that best reflects
your feelings for each statement. Ignore the letters and numbers in the far left and right columns.
A
3
2
1
0
A
3
2
1
0
A
3
2
1
0
A
0
1
2
3
A
0
1
2
3
A
3
2
1
0
A
3
2
1
0
I feel tense or “wound-up”
I still enjoy the things I used to enjoy
Most of the time
A lot of the time
From time to time, occasionally
Not at all
I get a feeling something bad will occur
Definitely as much
Not quite as much
Only a little
Hardly at all
I can laugh and see the funny side of things
D
0
1
2
3
D
0
1
2
3
Very definitely
Yes, but not too badly
A little, but it doesn’t worry me
Not al all
Worrying thoughts go thru my mind
As much as I always could
Not quite so much now
Definitely not so much now
Not at all
I feel cheerful
A great deal of the time
A lot of the time
From time to time, but not too often
Only occasionally
I can sit at ease and feel relaxed
Not at all
Not often
Sometimes
Most of the time
I feel as if I am slowed down
Definitely
Usually
Not often
Not at all
I get a frightening feeling – “butterflies” in
the stomach
Nearly all the time
Very often
Sometimes
Not at all
I have lost interest in my appearance
Not at all
Occasionally
Quite Often
Very Often
I’m restless, I have to be on the move
Definitely
I don’t take as much care as I should
I may not take as much care
I take just as much care as ever
I look forward with enjoyment to things
Very much indeed
Quite a lot
Not very much
Not at all
I get sudden feelings of panic
As much as I ever did
Rather less than I used to
Definitely less than I used to
Hardly at all
I can enjoy a good book, radio or TV program
Very often indeed
Quite often
Not very often
Not at all
Often
Sometimes
Not often
Very seldom
D
3
2
1
0
D
3
2
1
0
D
3
2
1
0
D
0
1
2
3
D
0
1
2
3
**Total Anxiety Score __________________ Total Depression Score ____________________
22
6/15/2015
Appendix 3: Tumor measurement sheet
Name: _______________________
CCF # ____________________________
Tumor Measurements
Baseline
Date
Tumor Site
Bone Scan
CT/MRI
Brain
Total Tumor
Burden (cm)
% Change
from Baseline
n/a
23
6/15/2015