P h a s e I I I T r i a l o f I n t e r f e r o n A l f a - 2 a W i t h o r W i t h o u t
`1 3 - cis- R e t i n o i c A c i d f o r P a t i e n t s W i t h A d v a n c e d
`R e n a l C e l l C a r c i n o m a
`
`By Robert J. Motzer, Barbara A. Murphy, Jennifer Bacik, Lawrence H. Schwartz, David M. Nanus, Tania Mariani,
`Patrick Loehrer, George Wilding, Diane L. Fairclough, David Cella, and Madhu Mazumdar
`
`Purpose: A randomized phase III trial was con-
`ducted to determine whether combination therapy with
`13-cis-retinoic acid (13-CRA) plus interferon alfa-2a
`(IFNa2a) is superior to IFNa2a alone in patients with
`advanced renal cell carcinoma (RCC).
`PatientsandMethods: Two hundred eighty-four pa-
`tients were randomized to treatment with IFNa2a plus
`13-CRA or treatment with IFNa2a alone. IFNa2a was
`given daily subcutaneously, starting at a dose of 3
`million units (MU). The dose was escalated every 7 days
`from 3 to 9 MU (by increments of 3 MU), unless > grade
`2 toxicity occurred, in which case dose escalation was
`stopped. Patients randomized to combination therapy
`were given oral 13-CRA 1 mg/kg/d plus IFNa2a. Qual-
`ity of life (QOL) was assessed.
`responses were
`Results: Complete or partial
`achieved by 12% of patients treated with IFNa2a plus
`13-CRA and 6% of patients treated with IFNa2a (P 5
`.14). Median duration of response (complete and par-
`tial combined) in the group treated with the combina-
`
`tion was 33 months (range, 9 to 50 months), versus 22
`months (range, 5 to 38 months) for the second group
`(P 5 .03). Nineteen percent of patients treated with
`IFNa2a plus 13-CRA were progression-free at 24
`months, compared with 10% of patients treated with
`IFNa2a alone (P 5 .05). Median survival time for all
`patients was 15 months, with no difference in survival
`between the two treatment arms (P 5 .26). QOL de-
`creased during the first 8 weeks of treatment, and a
`partial recovery followed. Lower scores were associ-
`ated with the combination therapy.
`Conclusion: Response proportion and survival did
`not improve significantly with the addition of 13-CRA to
`IFNa2a therapy in patients with advanced RCC. 13-CRA
`may lengthen response to IFNa2a therapy in patients
`with IFNa2a-sensitive tumors. Treatment, particularly
`the combination therapy, was associated with a de-
`crease in QOL.
`J Clin Oncol 18:2972-2980. © 2000 by American
`SocietyofClinicalOncology.
`
`METASTATIC RENAL CELL carcinoma (RCC) is
`
`characterized by a high level of resistance to sys-
`temic treatment.1-3 Cytotoxic chemotherapy and hormonal
`therapy are ineffective treatments for advanced RCC.4
`Interest in biologic response modifiers has been fostered by
`a low rate of response to interferon alfa-2a (IFNa2a) and
`interleukin-2 therapy.5,6
`13-cis-retinoic acid (13-CRA) increased the antiprolifera-
`tive effects of IFNa2a in several interferon-sensitive renal
`
`From the Genitourinary Oncology Service, Division of Solid Tumor
`Oncology, and the Departments of Medical Imaging and Biostatistics
`and Epidemiology, Memorial Sloan-Kettering Cancer Center; Joan
`and Sanford I. Weill Medical College of Cornell University; and New
`York Presbyterian Hospital, New York, NY; Vanderbilt University,
`Nashville, TN; Indiana University, Indianapolis, IN; University of
`Wisconsin, Madison, WI; AMC Cancer Research Center, Denver, CO;
`and Evanston Northwestern Healthcare and the Robert H. Lurie
`Comprehensive Cancer Center of Northwestern University, Chicago,
`IL.
`Submitted January 31, 2000; accepted April 26, 2000.
`Supported by grant no. CA 05826 from the National Cancer Institute
`and by Hoffman-La Roche, Nutley, NJ.
`Address reprint requests to Robert J. Motzer, MD, Memorial
`Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
`© 2000 by American Society of Clinical Oncology.
`0732-183X/00/1816-2972
`
`lines.7 The combination resulted in a 30%
`cancer cell
`response proportion in a phase II trial conducted at our
`center, which was higher
`than the proportion earlier
`achieved with IFNa2a alone.8 In three other phase II trials,
`treatment of RCC with IFNa2a plus retinoid was associated
`with relatively high response rates.9-11 One treatment pro-
`gram included interleukin-2 with 13-CRA and IFNa2a, and
`a 22% major response rate was reported.10 The combination
`of IFNa2a, 13-CRA, interleukin-2, and fluorouracil was
`associated with a 44% major response rate.11 The in vitro
`and clinical studies provided the rationale for the present
`randomized trial.
`The influence of cytokine treatment on quality of life
`(QOL) is an important aspect in the management of ad-
`vanced RCC. The Functional Assessment of Cancer Ther-
`apy (FACT) scale12 was used to assess QOL. Items were
`appended to the general questionnaire (Functional Assess-
`ment of Cancer Therapy-General [FACT-G]) to address the
`impact of side effects associated with treatment with
`IFNa2a and the retinoid.
`
`PATIENTS AND METHODS
`
`Patient Selection
`
`Between April 1994 and July 1996, 284 patients were entered onto
`this randomized trial. Participating centers were Memorial Sloan-
`Kettering Cancer Center (MSKCC) and member institutions of the
`
`2972
`
`Journal of Clinical Oncology, Vol 18, No 16 (August), 2000: pp 2972-2980
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 9
`
`

`

`IFNa2a AND 13-CRA IN RENAL CELL CARCINOMA
`
`Eastern Cooperative Oncology Group (ECOG). All patients gave
`informed consent. Eligibility requirements included the following:
`histologic confirmation of RCC, bidimensionally measurable disease,
`Karnofsky performance status (KPS) $ 70%, estimated life expectancy
`more than 3 months, WBC count $ 3,000/mL, platelet count $
`100,000/mL, serum total bilirubin level less than 1.5 mg/dL (normal, ,
`1.0 mg/dL), and serum creatinine level less than 2 mg/dL (normal, ,
`1.1 mg/dL) or creatinine clearance more than 50 mL/min. Patients were
`excluded if they had received prior systemic chemotherapy or immu-
`notherapy, had received radiation within 4 weeks of study entry, or had
`brain metastases.
`Each patient was evaluated before initiation of treatment. A history
`was obtained and a physical examination, chest radiography, ECG,
`automated complete blood cell count, comprehensive blood chemistry
`panel including determination of cholesterol and triglyceride levels,
`and appropriate radiographic imaging of measurable disease were
`performed. A negative pregnancy test result was required for women
`with childbearing potential.
`
`Treatment Plan
`
`Recombinant human IFNa2a (Roferon-A) and 13-CRA (Accutane)
`were obtained from Hoffmann-La Roche (Nutley, NJ) through the
`Division of Cancer Treatment, National Cancer Institute, Bethesda,
`MD. IFNa2a was provided in 3–million unit (MU) and 18-MU vials
`and was mixed with sterile water. 13-CRA was available in 10- and 40-
`mg tablets.
`Patients were randomized to daily treatment with IFNa2a plus
`13-CRA or IFNa2a alone. IFNa2a was given as a single daily
`subcutaneous injection, starting at a dose of 3 MU, and the dose was
`escalated every 7 days by increments of 3 MU, to 9 MU. During
`escalation, if $ grade 2 nonhematologic toxicity or grade 3 hemato-
`logic toxicity was noted, dose escalation was stopped. Patients ran-
`domized to combination therapy received oral 13-CRA 1 mg/kg/d in
`two divided doses (rounded to the nearest 10 mg) plus IFNa2a.
`Treatment was continued until progression of disease, complete
`response, or development of toxicity occurred. Dose modifications
`during therapy were dictated by an attenuation schedule. The IFNa2a
`dose was attenuated by 3-MU increments in patients with $ grade 2
`nonhematologic toxicity and grade 3 or 4 leukopenia or thrombocyto-
`penia. In cases of grade 3 or 4 neurologic toxicity (except mood-
`affecting neurotoxicity), treatment was discontinued and the patient
`taken off study. In cases of grade 3 or 4 mood-affecting neurotoxicity,
`the IFNa2a dose was attenuated by 3-MU increments. Patients with
`fatigue that resulted in a decrease in KPS to # 50% underwent
`sequential dose reduction and were removed from the study if the
`participating investigator deemed removal appropriate. If toxicity
`resulted in an interruption of therapy, patients treated with IFNa2a plus
`13-CRA had both drugs withheld. The 13-CRA dose was reduced by
`50% in cases of grade 4 dermatologic toxicity or any other grade 3 or
`4 toxicity associated with 13-CRA administration.
`Patients were monitored weekly for the first 4 weeks of therapy and
`every 2 weeks thereafter (physical examination, complete blood cell
`count, and serum chemical analysis). All patients underwent reassess-
`ment of measurable disease every 4 weeks until maximum response
`and every 2 months thereafter. All patients kept daily logs in which
`they documented symptoms and medications taken.
`Standard response and toxicity criteria were used.13 Stable disease
`was defined as disease that remained stable for at least 3 months from
`the day of evaluation after the first cycle of therapy.
`
`2973
`
`Biostatistical Analysis
`
`This trial was designed with response proportion as the major end
`point. Two hundred eighty-four patients were accrued to detect a 15%
`difference in response proportion with a power of $ 85% and a
`significance level of 5%. The design included an O’Brien and Fleming
`stopping rule.14 As the data accumulated, two interim analyses were
`undertaken and the data were reviewed by an independent data and
`safety monitoring committee. Randomization was performed at a
`centralized office at MSKCC using the method of random permuted
`block, with center (MSKCC v ECOG),
`lung-only disease, prior
`nephrectomy, and KPS (70% or 80% v 90%) used as stratification
`factors.15 All analyses were intent-to-treat analyses. Fisher’s exact test
`was used to compare the response proportions in each treatment arm.
`Survival curves were estimated using the Kaplan-Meier method16 and
`were compared using the log-rank test. The Wilcoxon rank sum test17
`was used to compare the duration of response by treatment arm for
`patients who achieved a complete or partial response. Durations of best
`response and survival were measured from the date of initiation of
`therapy. Toxicity data are summarized as frequency tables, with each
`patient’s worst-grade toxicity over all cycles used in calculations.
`
`QOL Study
`
`Patients enrolled after February 1995 were asked to undergo assess-
`ment of QOL. The baseline assessment was performed before therapy,
`with other assessments performed 2, 8, 17, 34, and 52 weeks after
`initiation of therapy.
`The trial used FACT Version 3 as the tool for QOL assessment.12
`For this trial, 17 disease- and treatment-specific items were developed
`and appended to the core questionnaire to address symptoms related to
`treatment with interferon and retinoids. The composite questionnaire
`was titled the Functional Assessment of Cancer Therapy-Biologic
`Response Modifier (FACT-BRM). Using an approach combining
`conceptual input and principal components factor analysis followed by
`checks on internal consistency, the original pool of 17 statements was
`reduced to a 16-item measure to assess toxicity related to treatment
`with biologic response modifiers. The 16-item measure consisted of
`two subscales to assess toxicity having a physical effect (10 items) and
`toxicity affecting mood or cognition (six items) (Table 1).
`The Trial Outcome Index (TOI), calculated by adding the physical
`well-being score, functional well-being score, and the two biologic
`response modifier subscale scores, was used in the following analysis
`as a summary measure of physical and functional well-being. Time
`intervals around each scheduled assessment were defined so that each
`questionnaire received was included in an interval. The compliance rate
`for each interval was then calculated as the number of questionnaires
`received divided by the number expected.
`A joint mixed-effects and survival model that accounts for unignor-
`able missing data was used to capture changes in QOL over time.18
`Estimates of QOL at baseline and at 2, 8, 17 and 34 weeks were
`obtained for each arm, and differences between the arms were tested.
`No estimate of QOL at 52 weeks was obtained for the treatment arms,
`because there was a paucity of data from that assessment time.
`
`MSKCC Prognostic Model
`
`A prognostic factor model was previously developed using data from
`670 patients with advanced RCC treated in 24 MSKCC clinical trials of
`immunotherapy and chemotherapy between 1975 and 1996.19 Pretreat-
`ment features associated with shorter survival
`in the multivariate
`analysis were low KPS (, 80%), high lactate dehydrogenase level (.
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 9
`
`

`

`2974
`
`Table 1.
`
`Two BRM Subscales Formed From Items Appended to the FACT-
`G Scale*
`
`Physical Toxicity
`I get tired easily.
`I feel weak all over.
`I have a good appetite.
`I have pain in my joints.
`I am bothered by chills.
`I am bothered by fevers.
`I am bothered by dry skin.
`I am bothered by dry mouth.
`I am bothered by dry eyes.
`I am bothered by sweating.
`Mood-/Cognition-Affecting Toxicity
`I have trouble concentrating.
`I have trouble remembering things.
`I get depressed easily.
`I get annoyed easily.
`I have emotional ups and downs.
`I feel motivated to do things.
`
`*“My thinking is clear” was an additional item in the FACT-BRM, but it was
`not included in either of the subscales because there was a decrease in the
`subscales’ alpha coefficients when the item was included.
`
`1 5 times upper limit of normal), low hemoglobin level (below lower
`limit of normal), high corrected serum calcium level (. 10 mg/dL), and
`absence of nephrectomy. These prognostic factors were used to
`categorize patients by risk into three groups: those with no risk factors
`(favorable risk), those with one or two risk factors (intermediate risk),
`and those with three or more risk factors (poor risk).19 This risk
`categorization was applied to the patients on our trial.
`
`RESULTS
`
`Patient Characteristics
`
`Two hundred eighty-four patients were registered onto
`the trial: 145 received IFNa2a alone and 139 received
`IFNa2a and 13-CRA. The two treatment arms were similar
`in terms of patient characteristics (Table 2). Overall median
`age was 60 years, and 61% of study patients had a KPS of
`90%. One hundred seventy-eight patients (63%) had two or
`more metastatic sites, and 144 (51%) had undergone ne-
`phrectomy. Twenty-nine patients
`(20%)
`treated with
`IFNa2a both had undergone nephrectomy and had lung-
`only metastases, compared with 33 patients (24%) treated
`with IFNa2a plus 13-CRA. One hundred nine (38%) were
`registered by MSKCC and 175 (62%) by ECOG.
`
`Response and Survival
`
`Twenty-five (9%) of the 284 patients registered onto the
`trial had a complete or partial response (Table 3). Complete
`or partial responses were achieved by 12% of patients
`treated with IFNa2a plus 13-CRA (five complete responses,
`11 partial responses) and 6% of patients treated with
`IFNa2a (one complete response, eight partial responses;
`
`MOTZER ET AL
`
`P 5 .14). Five patients (4%) treated with IFNa2a plus
`13-CRA achieved a complete response, compared with one
`(1%) treated with IFNa2a alone (P 5 .11). Median duration
`of response (complete and partial combined) from the start
`of treatment in the group treated with the combination was
`33 months (range, 9 to 50 months), versus 22 months
`(range, 5 to 38 months) for the group treated with IFNa2a
`alone (P 5 .03).
`Thirty-seven patients remained progression-free after fol-
`low-up: 21 after treatment with IFNa2a plus 13-CRA and
`16 after treatment with IFNa2a alone. The median progres-
`sion-free survival time was 5 months, with no difference in
`progression-free survival between the two arms (P 5 .13;
`Fig 1). However,
`the progression-free survival curves
`started to separate after 1 year of follow-up. Nineteen
`percent of patients treated with IFNa2a plus 13-CRA were
`progression-free at 24 months, compared with 10% of
`patients treated with IFNa2a alone (P 5 .05).
`Fifty-six of 284 patients remained alive, and the median
`survival time for all patients was 15 months (95% confi-
`dence interval, 12 to 17 months). The median follow-up for
`survivors was 38 months (range, 1 to 62 months); one of
`these patients was lost to follow-up at 1 month, another at 2
`months. There was no difference in survival between the
`two treatment arms (P 5 .26; Fig 2).
`
`Toxicity
`
`There was no difference in incidence of grade 2, 3, or 4
`toxicities between treatment arms (Table 4). Grade 2 tox-
`icities reported in 20% to 40% of patients were leukopenia,
`anemia, fever, and gastrointestinal toxicity. Grade 3 hema-
`tologic toxicities were reported in 60 patients (21%), and
`grade 4 hematologic toxicities were reported in three pa-
`tients (1%). A total of 82 grade 3 and 10 grade 4 nonhe-
`matologic toxicities were reported in 284 patients.
`
`QOL Analysis
`
`Two hundred thirty patients were asked to participate in
`the QOL assessment portion of the protocol. A total of 213
`patients completed and returned at least one questionnaire;
`735 questionnaires were received. The rate of compliance
`with baseline assessments was 81% in the IFNa2a treatment
`arm and 86% in the IFNa2a plus 13-CRA treatment arm
`(Table 5). Over time, compliance rates decreased; by the
`52-week assessment, the rates were 24% and 39% in the
`IFNa2a and IFNa2a plus 13-CRA treatment arms, respec-
`tively. There were similar dropout rates in the two arms at
`each of the assessment times.
`The estimates of change in TOI scores are displayed in
`Fig 3. There was a pattern of decrease in QOL from baseline
`to 2 weeks and a smaller decrease from 2 to 8 weeks,
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 9
`
`

`

`IFNa2a AND 13-CRA IN RENAL CELL CARCINOMA
`
`Table 2. Patient Characteristics
`
`IFNa2a
`(n 5 145)
`
`IFNa 1 13-CRA
`(n 5 139)
`
`No. of
`Patients
`
`%
`
`No. of
`Patients
`
`59
`22-80
`
`61
`27-81
`
`96
`49
`
`22
`36
`87
`
`75
`18
`0
`0
`
`1
`46
`46
`25
`27
`
`12
`37
`1
`26
`108
`15
`10
`45
`33
`4
`22
`15
`
`56
`89
`
`66
`34
`
`15
`25
`60
`
`52
`12
`
`1
`32
`32
`17
`18
`
`8
`26
`, 1
`18
`75
`10
`7
`31
`23
`3
`15
`10
`
`39
`61
`
`93
`46
`
`21
`33
`85
`
`69
`16
`0
`0
`
`1
`58
`37
`24
`19
`
`10
`31
`0
`27
`88
`9
`5
`31
`37
`4
`23
`18
`
`53
`86
`
`%
`
`67
`33
`
`15
`24
`61
`
`50
`12
`
`1
`42
`27
`17
`13
`
`7
`22
`
`19
`63
`6
`4
`22
`27
`3
`17
`13
`
`38
`62
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`KPS
`70%
`80%
`90%
`Prior treatment
`Nephrectomy
`Radiation therapy
`Immunotherapy
`Chemotherapy
`No. of metastatic sites
`Primary or local recurrence only
`1
`2
`3
`$ 4
`Sites of metastatic disease
`Adrenal
`Bone
`Breast
`Liver
`Lung
`Lymph nodes
`Kidney
`Mediastinum
`Retroperitoneum
`Skin
`Soft tissue
`Other
`Treatment center
`MSKCC
`ECOG
`
`2975
`
`All Patients
`(n 5 284)
`
`No. of
`Patients
`
`%
`
`60
`22-81
`
`189
`95
`
`43
`69
`172
`
`144
`34
`0
`0
`
`2
`104
`83
`49
`46
`
`22
`68
`1
`53
`196
`24
`15
`76
`70
`8
`45
`33
`
`109
`175
`
`67
`33
`
`15
`24
`61
`
`51
`12
`
`1
`37
`29
`17
`16
`
`8
`24
`, 1
`19
`69
`8
`5
`27
`25
`3
`16
`12
`
`38
`62
`
`especially in the IFNa2a plus 13-CRA treatment arm,
`making the difference between the arms significant at 8
`weeks (P 5 .02). After 8 weeks, there was some recovery of
`scores in the IFNa2a treatment arm and stabilization of
`scores in the IFNa2a plus 13-CRA treatment arm, with TOI
`scores significantly lower at 17 and 34 weeks in the IFNa2a
`plus 13-CRA treatment arm (P , .001 and P 5 .01,
`respectively). However, scores never recovered to baseline
`values in either arm.
`TOI scores were compared according to risk group as
`classified by the MSKCC model.19 Each risk group had a
`dramatic decrease from baseline to 2 weeks, with the
`favorable- and intermediate-risk groups having a smaller
`decrease from 2 to 8 weeks (Fig 4). However, these two
`
`groups began to recover after 8 weeks, although a full
`recovery never occurred. In contrast, the poor-risk group
`experienced a decrease after 8 weeks, followed by a
`stabilization of scores at a very low level after 17 weeks.
`This group never experienced a recovery in scores, and
`although stabilization did occur after 17 weeks, it was at a
`level approximately 20 points lower than baseline. The
`differences between the intermediate- and poor-risk groups
`at 17 and 34 weeks were significant at the .05 level (P 5 .01
`and P 5 .03, respectively).
`
`DISCUSSION
`Response proportion and survival did not improve sig-
`nificantly with the addition of 13-CRA to IFNa2a therapy in
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 9
`
`

`

`2976
`
`Patients assessable for response
`Reasons for inassessable status
`Patient withdrawal
`Toxicity
`Protocol violation
`Other medical conditions
`Best response
`Complete
`Partial
`Minor
`Stable disease
`Disease progression
`Patient status
`Alive with no evidence of disease
`Alive with disease
`Dead
`Lost to follow-up
`
`Table 3. Response and Patient Status
`
`IFN-a2a
`(n 5 145)
`
`132 (91%)
`
`IFN-a2a 1 13-CRA
`(n 5 139)
`
`129 (93%)
`
`6
`3
`0
`4
`
`1
`8
`11
`69
`43
`
`1
`21
`121
`2
`
`2
`5
`2
`1
`
`5
`11
`7
`60
`46
`
`9
`23
`107
`0
`
`MOTZER ET AL
`
`All Patients
`(n 5 284)
`
`261 (92%)
`
`8
`8
`2
`5
`
`6
`19
`18
`129
`89
`
`10
`44
`228
`2
`
`patients with advanced RCC. The response proportion for
`patients treated with IFNa2a plus 13-CRA was greater than
`that for patients treated with IFNa2a, with more complete
`responses in the combination therapy arm. Moreover, the
`duration of response for patients who achieved a complete
`or partial response was longer after treatment with IFNa2a
`plus 13-CRA than after treatment with IFNa2a alone.
`However, the overall response proportion for all patients
`treated on the trial was low (9%), with no significant
`difference in major response proportion (complete and
`partial combined) between arms. Two phase III trials are
`being conducted by others20,21 and may provide further
`insight into the role of retinoid-cytokine combination ther-
`apy against RCC.
`
`Response proportions in individual phase II trials involv-
`ing patients with advanced RCC range from 0% to 30% for
`single-agent IFNatherapy,5 0% to 37% for combinations of
`IFNa2a plus interleukin-2,22 and 0% to 37% for the
`three-drug combination of IFNa, interleukin-2, plus flu-
`orouracil.23 Responsible factors include differences in treat-
`ment schedules, sample size, and patient selection. The
`impact of IFNa2a treatment on survival is controversial, but
`the two larger phase III trials found IFNa2a therapy to be
`associated with longer survival than vinblastine or me-
`droxyprogesterone therapy.24,25 In contrast, no randomized
`phase III trial has shown a survival benefit for combination
`therapy compared with treatment with IFNa2a or interleu-
`kin-2 alone in patients with advanced RCC.26-31 Each
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`Fig 1. Progression-free survival for patients with advanced RCC treated
`with IFNa2a versus IFNa2a plus 13-CRA.
`
`
`Fig 2. Survival for patients with advanced RCC treated with IFNa2a
`versus IFNa2a plus 13-CRA. Tick mark indicates last follow-up.
`
`Downloaded from ascopubs.org by Reprints Desk on November 14, 2016 from 216.185.156.028
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 9
`
`

`

`IFNa2a AND 13-CRA IN RENAL CELL CARCINOMA
`
`Table 4. Grade 2 to 4 Toxicity by Treatment Arm
`
`Toxicity
`
`IFNa2a
`(n 5 145)
`
`3
`
`No. of
`Patients
`
`5
`10
`1
`14
`19
`
`2
`
`2
`4
`5
`
`0
`
`0
`
`%
`
`3
`7
`1
`10
`13
`
`1
`
`1
`3
`3
`
`2
`
`No. of
`Patients
`
`0
`
`14
`44
`6
`28
`58
`
`4
`7
`13
`4
`1
`
`1
`
`%
`
`10
`30
`4
`19
`40
`
`3
`5
`9
`3
`1
`
`1
`
`4
`
`0
`0
`0
`
`0
`
`0
`
`0
`0
`0
`
`No. of
`Patients
`
`1
`
`1
`
`1
`
`%
`
`1
`
`1
`
`1
`
`2
`
`No. of
`Patients
`
`11
`36
`3
`35
`56
`
`3
`10
`13
`8
`3
`
`0
`
`%
`
`8
`26
`2
`25
`40
`
`2
`7
`9
`6
`2
`
`2977
`
`%
`
`1
`1
`
`4
`
`No. of
`Patients
`
`2
`2
`
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`IFNa2a 1 13-CRA
`(n 5 139)
`
`3
`
`No. of
`Patients
`
`11
`9
`3
`16
`13
`
`6
`6
`1
`
`1
`
`0
`0
`0
`
`%
`
`8
`6
`2
`12
`9
`
`4
`4
`1
`
`1
`
`Hematologic
`ANC/band forms
`Leukopenia
`Thrombocytopenia
`Hgb/anemia
`Gastrointestinal
`Neurologic
`Cerebellar toxicity
`Cortical toxicity
`Headache
`Altered mood
`Neuromotor toxicity
`Neurosensory toxicity
`Cardiac
`Dysrhythmia
`Impaired cardiac
`function
`Edema
`Hypotension
`Dermatologic/ocular
`Conjunctivitis/dry eyes
`Local toxicity
`Rash/urticaria
`Renal, creatinine
`General
`Fever
`Malaise/fatigue/lethargy
`Arthralgia/myalgia
`Pulmonary
`Dyspnea
`
`0
`
`1
`1
`
`1
`1
`6
`8
`
`37
`15
`4
`
`10
`
`1
`1
`
`1
`1
`4
`6
`
`26
`10
`3
`
`7
`
`0
`
`0
`0
`0
`0
`
`0
`
`4
`2
`
`2
`
`2
`1
`
`2
`
`3
`1
`
`1
`
`1
`1
`
`1
`
`0
`0
`
`0
`0
`
`0
`0
`0
`0
`
`0
`0
`0
`
`1
`
`, 1
`
`0
`0
`
`0
`
`1
`1
`
`4
`
`12
`8
`
`40
`12
`1
`
`8
`
`1
`
`3
`
`9
`6
`
`29
`9
`1
`
`6
`
`0
`
`0
`0
`
`0
`
`0
`
`2
`
`1
`1
`
`1
`1
`
`4
`
`1
`
`1
`1
`
`1
`1
`
`3
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`
`1
`
`1
`
`1
`
`Abbreviations: ANC, absolute neutrophil count; Hgb, hemoglobin.
`
`combination therapy showed promise in phase II trials but
`lacked survival benefit compared with monotherapy in the
`randomized trial. The outcome of these trials reaffirms the
`necessity to conduct phase III trials to evaluate the efficacy
`of combination therapies compared with treatment with
`IFNa2a or interleukin-2 alone in patients with metastatic
`RCC.
`Additional items were appended to the FACT-G scale12
`in this study, to address the impact of biologic treatment on
`patients with advanced RCC. Patients treated with IFNa2a
`alone showed a pattern of initial decrease in TOI scores
`followed by some recovery, although not to baseline values.
`Patients treated with the combination of IFNa2a and 13-
`CRA also experienced an initial decrease, although scores
`stabilized after 8 weeks. Treatment with the combination
`was associated with lower TOI scores, presumably because
`of side effects of retinoid therapy.
`
`In a QOL study using the Rotterdam Symptom checklist,
`patients were randomized to treatment with IFNa2a or
`medroxyprogesterone.25 IFNa2a was given at a dose of 10
`MU 3 days per week, and the pattern of QOL was likewise
`characterized by initial decrease and recovery. There was no
`detected difference in symptoms between treatment arms
`after 6 months of therapy. The intensive schedule of IFNa2a
`therapy used in our trial may played a role in the overall
`decrease of QOL. Treatment was administered daily, rather
`than 3 or 5 days per week, which is standard practice.5
`We have reported on a risk classification undertaken in
`670 patients with advanced RCC treated on clinical trials
`with cytotoxic therapy or cytokines.19 Patients treated on
`that trial who had poor-risk pretreatment features for sur-
`vival had inferior QOL compared with patients with inter-
`mediate or favorable prognostic features. Patients with
`poor-risk features have a short survival
`regardless of
`
`Downloaded from ascopubs.org by Reprints Desk on November 14, 2016 from 216.185 156.028
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 6 of 9
`
`

`

`2978
`
`MOTZER ET AL
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fig 3. QOL (TOI) for patients with advanced RCC treated with IFNa2a
`versus IFNa2a plus 13-CRA.
`
`whether they are treated with cytokine therapy or chemo-
`therapy.19 Also, patients with intermediate- or favorable-
`risk features may be more likely to derive therapeutic
`benefit from cytokine therapy.32 In the current study, the
`poor-risk group of patients experienced the most symptoms
`associated with IFNa2a therapy. The poor survival and
`decrease in QOL associated with cytokine therapy suggest
`that patients with poor-risk features should be considered
`for novel treatment strategies on clinical trials or supportive
`care.
`that 13-CRA
`Two outcomes from this trial suggest
`augmented response to IFNa2a therapy. First, duration of
`complete or partial response was significantly longer in
`patients treated with 13-CRA plus IFNa2a compared with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fig 4. QOL (TOI) according to risk criteria for patients with advanced
`RCC treated with IFNa2a versus IFNa2a plus 13-CRA according to risk
`criteria for patients with RCC.
`
`39
`24
`61
`
`24
`15
`62
`
`37
`25
`68
`
`41
`33
`81
`
`45
`39
`86
`
`40
`40
`100
`
`62
`63
`102
`
`59
`66
`111
`
`70
`77
`110
`
`77
`91
`118
`
`86
`95
`111
`
`81
`96
`119
`
`Compliancerate,%
`No.received
`No.distributed
`
`IFNa2a113-CRA
`
`IFNa2a
`
`IFNa2a113-CRA
`
`IFNa2a
`
`IFNa2a113-CRA
`
`IFNa2a
`
`IFNa2a113-CRA
`
`IFNa2a
`
`IFNa2a113-CRA
`
`IFNa2a
`
`IFNa2a113-CRA
`
`IFNa2a
`
`Questionnaires
`
`Week52
`
`Week34
`
`Week17
`
`Week8
`
`Week2
`
`Week0
`
`Assessment
`
`Table5.ComplianceWithQOLAssessment
`
`Downloaded from ascopubs.org by Reprints Desk on November 14, 2016 from 216.185.156.028
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2036
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 9
`
`

`

`IFNa2a AND 13-CRA IN RENAL CELL CARCINOMA
`
`those treated with IFNa2a alone. Second, progression-free
`survival at 2 years was greater in the combination therapy
`arm compared with patients treated with IFNa2a alone. One
`possible explanation is that 13-CRA lengthens response to
`IFNa2a therapy in the relatively small proportion of pa-
`tients with IFNa2a-sensitive tumors.
`This hypothesis is consistent with findings of our previ-
`ous in vitro studies on renal cancer cell lines, in which
`13-CRA enhanced the antiproliferative effect of IFNa2a in
`IFNa2a-sensitive but not IFNa2a-resistant renal cancer
`cells.8 The manner by which 13-CRA augments the effect of
`IFNa2a is unknown. Recent studies have shown that renal
`cancer cells in vitro and in vivo contain low levels of
`intracellular retinoids compared with normal kidney and
`that treatment with IFNa2a plus retinoic acid results in an
`approximately eight-fold increase in intracellular retinoid
`levels.33 Higher levels of intracellular retinoic acid may
`play an important role in the generation of a more complete
`antitumor response in IFNa2a-sensitive RCC, because an
`increase in expression of retinoid acid receptor beta in renal
`tumor cells is associated with growth inhibition in vitro7 and
`
`2979
`
`tumor regression in vivo.34 Although these studies suggest
`that retinoic acid may somehow augment the antitumor
`effects of IFNa2a therapy, this benefit has not been con-
`vincingly achieved using oral formulations of retinoic acid,
`as indicated by the results of the current trial. Continued
`studies are warranted and should focus on the mechanisms
`of IFNa2a-retinoid interaction in renal cancers. Clinical
`trials of more potent retinoids should be conducted.
`In summary, response proportion and survival did not
`improve significantly with the addition of 13-CRA to
`IFNa2a therapy in patients with advanced RCC. 13-CRA
`may lengthen response to IFNa2a therapy in the relatively
`small proportion of patients with IFNa2a-sensitive tumors.
`Treatment, particularly the combination therapy, was asso-
`ciated with a decrease in QOL as assessed by the FACT-
`BRM.
`
`ACKNOWLEDGMENT
`
`We thank Patricia Fischer for providing nursing care and Carol
`Pearce for reviewing the manuscript.
`
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